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Jung, Su Young, Dokyoung Kim, Dong Choon Park, Eun Hye Lee, Yong-Sung Choi, Jeewon Ryu, Sang Hoon Kim, and Seung Geun Yeo. "Immunoglobulins and Transcription Factors in Otitis Media." International Journal of Molecular Sciences 22, no. 6 (March 21, 2021): 3201. http://dx.doi.org/10.3390/ijms22063201.
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The causes of otitis media (OM) involve bacterial and viral infection, anatomo-physiological abnormalities of the Eustachian canal and nasopharynx, allergic rhinitis, group childcare centers, second-hand smoking, obesity, immaturity and defects of the immune system, formula feeding, sex, race, and age. OM is accompanied by complex and diverse interactions among bacteria, viruses, inflammatory cells, immune cells, and epithelial cells. The present study summarizes the antibodies that contribute to immune reactions in all types of otitis media, including acute otitis media, otitis media with effusion, and chronic otitis media with or without cholesteatoma, as well as the transcription factors that induce the production of these antibodies. The types and distribution of B cells; the functions of B cells, especially in otorhinolaryngology; antibody formation in patients with otitis media; and antibodies and related transcription factors are described. B cells have important functions in host defenses, including antigen recognition, antigen presentation, antibody production, and immunomodulation. The phenotypes of B cells in the ear, nose, and throat, especially in patients with otitis media, were shown to be CD5low, CD23high, CD43low, B220high, sIgMlow, sIgDhigh, Mac-1low, CD80(B7.1)low, CD86(B7.2)low, and Syndecam-1low. Of the five major classes of immunoglobulins produced by B cells, three (IgG, IgA, and IgM) are mainly involved in otitis media. Serum concentrations of IgG, IgA, and IgM are lower in patients with OM with effusion (OME) than in subjects without otitis media. Moreover, IgG, IgA, and IgM concentrations in the middle ear cavity are increased during immune responses in patients with otitis media. B cell leukemia/lymphoma-6 (Bcl-6) and paired box gene 5 (Pax-5) suppress antibody production, whereas B lymphocyte inducer of maturation program 1 (Blimp-1) and X-box binding protein 1 (XBP-1) promote antibody production during immune responses in patients with otitis media.
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Zhang, Elizabeth Yan, and Bao-Ting Zhu. "Estriol strongly inhibits DNCB-induced contact dermatitis: role of antigen-specific antibodies in pathogenesis." Endocrine Connections 3, no. 4 (December 2014): 161–72. http://dx.doi.org/10.1530/ec-14-0080.
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The endogenous estrogens are important modulators of the immune system and its functions. However, their effects are rather complex and many aspects have not been studied. In this study, we used the 1-chloro-2,4-dinitrobenzene (DNCB)-induced contact dermatitis as a disease model and investigated the effect of estriol (E3), along with two other estrogens, 17β-estradiol and estrone, on the pathogenesis of contact hypersensitivity. A series of parameters, such as ear swelling, skin inflammation, antigen-specific immunoglobulins, and lymphocyte compositions in peripheral lymphoid organs, were evaluated in mice following development of contact dermatitis. We found that administration of all three estrogens elicited strong inhibition of DNCB-induced dermatitis, while E3 exerted the strongest suppressive effect. Administration of E3 alleviated dermatitis, and this effect was accompanied by decreases in serum DNCB-specific immunoglobulins, such as IgA, IgG1, IgG2a, and IgG2b. Besides, treatment with E3 reduced B cell population, especially IgG-producing cells in the peripheral lymphoid organs following the induction of dermatitis. These observations consistently suggest that the antibody (Ab)-mediated humoral immune reactions play a critical role in the pathogenesis of DNCB-induced contact dermatitis. The results from this study demonstrate, for the first time, that estrogen administration has a strong suppressive effect on the pathogenesis of contact dermatitis. These findings offer important insights concerning the pathogenic role of antigen-specific Abs in contact dermatitis and the treatment of chemical-induced, Ab-mediated skin hypersensitivity reactions in humans.
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Generalov, S. V., E. G. Abramova, Zh V. Matveeva, I. M. Zhulidov, O. A. Lobovikova, R. A. Svintsov, A. V. Komissarov, M. N. Kireev, and A. K. Nikiforov. "Cultural Antigen in the Technology for Anti-Rabies Immunoglobulin Obtainment from Equine Blood Serum." Problems of Particularly Dangerous Infections, no. 4(114) (August 20, 2012): 65–68. http://dx.doi.org/10.21055/0370-1069-2012-4-65-68.
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week after immunization (specific activity is identified using neutralization reaction on the model of white mice and dot-blot immunoassay). This level of activity is sufficient for the fractioning of immune serum and extraction of anti-rabies immunoglobulin. Physicochemical and biological properties of the anti-rabies immunoglobulin, obtained with the help of cultural antigen technique, meet the requirements stated in the normative documentation on anti-rabies immunoglobulins extracted from equine blood serum. Specific activity level of experimental batches of anti-rabies immunoglobulin, obtained with the help of cultural technologies, corresponds to 242 and 214 IU/ml.
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Nagarathna, P. K. M., K. Reena, Sriram Reddy, and Johnson Wesley. "Evaluation of Immunomodulatory activity of the flavanoid from Kigelia africana." Indian Journal of Pharmaceutical and Biological Research 2, no. 02 (June 30, 2014): 41–48. http://dx.doi.org/10.30750/ijpbr.2.2.8.
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Modulation of the immune responses to alleviate the diseases has been of interest for many years. Thus a real need exists to protect our immune systems and lead healthier lives. Hence the present study is aimed to evaluate the immunomodulatory activity of Flavanoid of Kigelia africana. The effect of flavanoid of Kigelia africana on the immune system of rats and mice was evaluated by using different experimental models such asmice lethality test, Serum immunoglobulin level, Haemagglutination reaction, hypersensitivity reaction, and delayed type hypersensitivity reaction test. Flavanoid of Kigelia africana was administered orally at low dose and high dose of 100mg/kg/day, poand 200 mg/kg/day, po respectively and Levamisole (2.5 mg/kg/day, po) was used as standard drug. Flavanoid of Kigelia africanain both doses increased the levels of serum immunoglobulin and prevented the mortality induced by bovine Pasteurella multocida in mice. Exhibits a dose related increase in the early hypersensitivity reaction and Delayed type hypersensitivity reaction to the SRBC antigen. It also resulted in a significant increase in the antibody titer value, to SRBC, in experimental animals. Hence, it was concluded that flavanoid of Kigelia africana increases both humoral immunity and cell mediated immunity.
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Moshnikova, A. N., V. K. Maksimchuk, S. V. Lapin, V. D. Nazarov, E. A. Surkova, S. A. Novikov, G. S. Makshakov, et al. "Diagnostic significance of intrathecally synthesized immunoglobulins against neurotropic viruses (MRZ-reaction) in diagnosis of multiple sclerosis." Russian Journal of Infection and Immunity 9, no. 5-6 (February 1, 2020): 703–12. http://dx.doi.org/10.15789/2220-7619-2019-5-6-703-712.
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Multiple sclerosis is chronic demyelinating disease of the central nervous system with autoimmune inflammation and accretive neurodegeneration. One of the characteristics of autoimmune inflammation in multiple sclerosis is a polyspecific intrathecal humoral immune response against neurotropic viruses (Measles, Rubella and varicella Zoster) called MRZ-reaction. This immune response is based on polyclonal activation of mature B lymphocytes in the central nervous system and intrathecal synthesis of antibodies to anamnestic antigens unrelated to viral replication in the central nervous system as well as serum antibody release. Immunoglobulins produced against neurotropic viruses are an integral part of the oligoclonal antibody pool in the cerebrospinal fluid. Because immunoglobulins can penetrate the blood brain barrier, not only serum and cerebrospinal fluid specific antibody indices are calculated, but also blood-brain barrier antibody permeability (Qalbumin, QIgG) are taken into account to assess their intrathecal synthesis. The aim of the study was to assess the informative value of the intrathecal antibodies against neurotropic viruses (MRZ-reaction) in multiple sclerosis. There were enrolled 60 patients divided into 2 groups: group 1 — 35 patients diagnosed with multiple sclerosis, group 2 — 25 patients with inflammatory and non-inflammatory disоrders of the central nervous system. Paired cerebrospinal fluid and serum samples were collected from all patients to measure level of oligoclonal IgG, immunoglobulin free kappa and lambda light chains, IgG index and specific antibodies indices, followed by assessing magnitude of MRZ-reaction. We found that the MRZ-reaction was the most specific test to diagnose multiple sclerosis. Intrathecally produced antibodies against neurotropic viruses were detected in 3 of 35 multiple sclerosis patients with lacking oligoclonal IgG antibodies. In addition, a relationship between MRZ-reaction and degree of EDSS disability was found in MS patients: peak EDSS score was reported in patients with intrathecally synthesized antibodies against 3 viral agents, whereas the minimum EDSS score — among MRZ-negative patients. Thus, assessing MRZ-reaction seems rational for confirming MS diagnosis in case of other negative laboratory tests (oligoclonal immunoglobulins and free kappa/lambda light chains in cerebrospinal fluid) allowing to improves diagnostic accuracy and evaluation of MS severity.
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Voyich, Jovanka M., Raymond Ansotegui, Connie Swenson, John Bailey, and Donald E. Burgess. "Antibody Responses of Cattle Immunized with the Tf190 Adhesin of Tritrichomonas foetus." Clinical Diagnostic Laboratory Immunology 8, no. 6 (November 1, 2001): 1120–25. http://dx.doi.org/10.1128/cdli.8.6.1120-1125.2001.
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ABSTRACT The antibody response patterns of cattle after subcutaneous and intranasal immunizations with adhesin Tf190 of Tritrichomonas foetus were investigated. Reactions of antibody from cattle parenterally immunized with Tf190 revealed antigen specificity and Tf190 sensitization in the majority of the animals, as determined by Western blotting. The results also demonstrated strong preimmune immunoglobulin G2 (IgG2) binding to T. foetus antigens not seen in IgG1 profiles. Subcutaneous injections of Tf190 resulted in significant (P < 0.05) increases in serum IgG1 and IgG2 titers over time, as determined by parasite specific enzyme-linked immunosorbent assay. Immune sera also significantly inhibited parasite adhesion to mammalian cell lines compared to the level of inhibition obtained with preimmune sera (P < 0.05). Intranasal immunization with Tf190 failed to produce measurable parasite-specific antibody in serum; however, this immunization route did result in significant (P < 0.05) increases in parasite-specific IgA titers in cervical mucus secretions from immunized animals that were more resistant to intravaginal challenge with T. foetus than controls. These results suggest that systemic immunization with Tf190 results in serum antibody production and antiparasitic adhesin antibodies. Additionally, the results of challenge experiments with intranasally immunized animals suggests that Tf190 primes protective immune responses that lead to lower rates of infection among these animals.
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Papadopoulos, N. M., R. Costello, M. Ceroni, and H. M. Moutsopoulos. "Identification of HIV-specific oligoclonal immunoglobulins in serum of carriers of HIV antibody." Clinical Chemistry 34, no. 5 (May 1, 1988): 973–75. http://dx.doi.org/10.1093/clinchem/34.5.973.
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Abstract Zone electrophoresis on agarose gel was performed on serum samples from HIV-antibody carriers and negative controls. Nitrocellulose strips precoated with an HIV preparation were then placed on top of the gels and developed by an immunoblotting procedure. A positive reaction was demonstrated between the HIV antigens and the HIV-antibody-positive serum samples with hypergammaglobulinemia and oligoclonal IgG bands. A negative reaction was found between the HIV antigens and HIV-antibody-negative serum samples from a normal person and a patient with monoclonal gammopathy. The presence of oligoclonal IgG bands in the serum of HIV-antibody carriers, and their positive identification with HIV antigens, indicates a specific immune response of the host to the HIV infection and supports the use of oligoclonal IgG bands as markers to follow the course of HIV infection.
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Pfreundschuh, Michael, Natalie Fadle, Evi Regitz, Maria Kemele, and Klaus-Dieter Preuss. "Origin of (sporadic) Plasma Cell Myeloma: Lysolipids Are Not the Target of Clonal Immunoglobulins." Blood 128, no. 22 (December 2, 2016): 2055. http://dx.doi.org/10.1182/blood.v128.22.2055.2055.
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Abstract Background: Lysolipids have been claimed to be involved in the origin of sporadic monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) and of Gaucher's associated MGUS/MM because lyso-glucosylceramide (LGL1) and lysophosphatidylcholine (LPC) were purported to be the target of the clonal immunoglobulin in 31% of patients with sporadic and 85% with Gaucher's associated MGUS/MM(Nair et al. N Engl J Med 2016;374:555-61). The low titers (1:250) of the reported anti-lysolipid reactivity raised doubts as to whether these reactivities were indeed mediated by the clonal immunoglobulin (paraprotein). Patients and Methods: We analyzed the sera from 96 patients with MGUS/MM for the presence of anti-lysolipid reactivity by means of immunofixation, ELISA, serum protein electrophoresis (SPSP) before and after absorption with sphingosine beads to remove antibodies against lysolipids and paraprotein-specific antigens (paratarg-7 and sumoylated HSP90), respectively, and Western blots. Moreover, the BCR from MGUS/MM with a paraprotein-mediated reactivity against paratarg-7 and HSP90 were cloned and expressed as Fab fragments and used to determine antigen specificity by direct antigen binding and antigen-competition assays. Results: The presence of antibody reactivity against LGL1 and LPC was demonstrated in 28/96 (29%) MGUS/MM patients, confirming the rate observed in Nair's study (31%). Seven of these 28 sera also contained reactivity against paratarg-7 and 2 against HSP90 (always at titers >1x106). In none of the 28 lysolipd-reactive cases was the anti-lysolipd reactivity mediated by the clonal immunoglobulin as demonstrated by low antibody titers (<1:500), immunoglobulin subclasses different from the clonal immunoglobulin (as shown by immunofixation), inability of lysolipids to compete with specific antigens for binding with the clonal immunoglobulin or the recombinant B-cell receptor and demonstration by immunoglobulin affinity chromatography, that separated LGL1 reactivity from the monoclonal immunoglobulin. Absorption with sphingosine-beads completely removed the anti-lipd reactivity from the respective sera and the LGL1 immunoreactive bands after SPEP, but did not remove the monoclonal peak from the serum electrophoresis, while this was always the case with paratarg-7 (see figure) and HSP90 when they were the antigenic targets of the paraproteins. Anti-lysolipid reactivities were rare in 140 healthy controls (6%), but more frequent in 140 patients with autoimmune diseases (19%; p=0.002). Conclusions: Our data disprove a role of lysolipids in the origin of sporadic MGUS/MM. While we had no access to sera from patients with Gaucher'sassociated MGUS/MM, the report that lysolipds are the targets of the paraproteins in 85% of these cases and hence play a role in the pathogenesis of these diseases must also be met with caution. To prove that an observed antibody reactivity is mediated by the clonal immune globulin all of the following prerequisites must be met: 1st, the clonal immunoglobulin and the antibody mediating the reactivity against the antigen have the identical light and heavy chains; 2nd, the reaction has a serum titer >1x106; 3rd, absorption with the antigen removes the monoclonal peak in the serum electrophoresis; 4th, a specific reactivity of the expressed (clonal) B-cell receptor with the antigen is demonstrated; and 5th, convincing data is provided by competition assays that the paraprotein and the B-cell receptor recognize the same antigen and epitope of the antigen under investigation. Not a single one of these prerequisites has been met in the study of Nair et al. A role of lysolipids in the pathogenesis of any form of MGUS/MM cannot be assumed until the complete set of the 5 prerequisites is demonstrated for these autoantigens. A request for exchange of sera has been forwarded to Nair et al., and if granted, results will be reported. Supported by Wilhelm-Sander-Stiftung. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Reto, Patricia Pichilingue, Prithvi Raj, Quan-Zhen Li, Igor Dozmorov, Maria Teresa De la Morena, and Nicolai vanOers. "172. Serum Igg Profiling Healthy 1- and 2- year Old Toddlers Reveals a Subgroup with Clinically Informative Reactivities to Pathogens and Autoantigens." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S215. http://dx.doi.org/10.1093/ofid/ofaa439.482.
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Abstract Background The antibody repertoire in an infant/toddler develops in response to the microbiome, infections, environmental exposures, and vaccinations. Monitoring the specificity of these antibody responses in normal toddlers will provide indicators of disease susceptibility. Methods The serum Immunoglobulin (Ig)G and IgM antibody reactivity patterns in 1- and 2-year-old healthy toddlers was determined by examining the Ig specificity to diverse infectious agents, autoantigens and vaccine antigens with an antigen array. The toddlers were stratified based on their antibody reactivity to these diverse antigens with a normalized fluorescence intensity measure. Repeat profiling was performed at year 2 to reveal longitudinal changes in the IgG and IgM responses. Clinical information, along with DNA sequencing, and selected cytokine assays were used to establish an odds ratio for immune disease potential among the cohort. Results Healthy 1- and 2- year old IgG responses revealed cohorts of low, moderate, and high Ig responder groups that was unconnected with total serum IgG levels. The high responder group had elevated IgG reactions to selected pathogens, particularly viruses as well as to autoantigens. This high reactivity group, representing 17% of the cohort, had high odds ratios with maternal gestational diabetes, age, and a family history of asthma. While all toddlers developed strong antibody responses to Measles-Mumps-Rubella vaccines (MMR), more variation was noted towards other vaccines. In infections to Molluscum contagiosum, the IgG serum levels were transient regardless of the responder group. The high responder group had DNA polymorphisms linked to enhanced immune responses that correlated with elevated cytokine levels as well as eczema and asthma. A subset of toddlers has strong IgG responses to pathogens and vaccines Conclusion A subset of normal healthy toddlers has a high potential for immune system abnormalities and autoimmunity based on higher serum antibody responses to pathogens and autoantigens, genetic polymorphisms, and elevated cytokine responses. Disclosures All Authors: No reported disclosures
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Hodge, Lisa M., Mariarosaria Marinaro, Harlan P. Jones, Jerry R. McGhee, Hiroshi Kiyono, and Jerry W. Simecka. "Immunoglobulin A (IgA) Responses and IgE-Associated Inflammation along the Respiratory Tract after Mucosal but Not Systemic Immunization." Infection and Immunity 69, no. 4 (April 1, 2001): 2328–38. http://dx.doi.org/10.1128/iai.69.4.2328-2338.2001.
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ABSTRACT The purpose of the present study was to determine the extent of immunologic responses, particularly immunopathologic responses, within the upper and lower respiratory tracts after intranasal immunization using the mucosal adjuvant cholera toxin (CT). BALB/c mice were nasally immunized with influenza virus vaccine combined with CT. The inclusion of the mucosal adjuvant CT clearly enhanced generation of antibody responses in both the nasal passages and lungs. After nasal immunization, antigen-specific immunoglobulin A (IgA) antibody-forming cells dominated antibody responses throughout the respiratory tract. However, IgG responses were significant in lungs but not in nasal passages. Furthermore, parenteral immunization did not enhance humoral immunity in the upper respiratory tract even after a nasal challenge, whereas extrapulmonary lymphoid responses enhanced responses in the lung. After nasal immunization, inflammatory reactions, characterized by mononuclear cell infiltration, developed within the lungs of mice but not in nasal passages. Lowering dosages of CT reduced, but did not eliminate, these adverse reactions without compromising adjuvancy. Serum IgE responses were also enhanced in a dose-dependent manner by inclusion of CT. In summary, there are differences in the generation of humoral immunity between the upper respiratory tract and the lung. As the upper respiratory tract is in a separate compartment of the immune system from that stimulated by parenteral immunization, nasal immunization is an optimal approach to generate immunity throughout the respiratory tract. Despite the promise of nasal immunization, there is also the potential to develop adverse immunopathologic reactions characterized by pulmonary airway inflammation and IgE production.
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Sturgess, M. L., I. Weeks, C. N. Mpoko, I. Laing, and J. S. Woodhead. "Chemiluminescent labeled-antibody assay for thyroxin in serum, with magnetic separation of the solid-phase." Clinical Chemistry 32, no. 3 (March 1, 1986): 532–35. http://dx.doi.org/10.1093/clinchem/32.3.532.
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Abstract A chemiluminescent labeled-antibody immunoassay has been developed for measurement of total thyroxin (T4) in serum. Monoclonal antibodies to T4 labeled with a chemiluminescent acridinium ester are used. Serum samples are incubated with the labeled antibodies and a thyroxin-rabbit immunoglobulin conjugate, then reacted with magnetizable particles containing sheep anti-rabbit immunoglobulin. The total reaction time is 40 min. The chemiluminescence intensity of the solid-phase immune complexes is inversely proportional to the concentration of T4 in the sample. The sensitivity of the assay is 1 nmol/L, and the working range of 20-190 nmol/L is characterized by CVs less than or equal to 10%.
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Atchessi, Nicole, Megan Striha, Rojiemiahd Edjoc, Christine Abalos, Amanda Lien, Lisa Waddell, Imran Gabrani-Juma, Emily Thompson, and Thomas Dawson. "Serum antibody response in COVID-19-recovered patients who retested positive." Canada Communicable Disease Report 47, no. 04 (May 7, 2021): 195–201. http://dx.doi.org/10.14745/ccdr.v47i04a03.
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Background: Research studies comparing antibody response from coronavirus disease 2019 (COVID-19) cases that retested positive (RP) using reverse transcription polymerase chain reaction (RT-PCR) and those who did not retest positive (NRP) were used to investigate a possible relationship between antibody response and retesting status. Methods: Seven data bases were searched. Research criteria included cohort and case-control studies, carried out worldwide and published before September 9, 2020, that compared the serum antibody levels of hospitalized COVID-19 cases that RP after discharge to those that did NRP. Results: There is some evidence that immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody levels in RP cases were lower compared with NRP cases. The hypothesis of incomplete clearance aligns with these findings. The possibility of false negative reverse transcription polymerase chain reaction (RT-PCR) test results during viral clearance is also plausible, as concentration of the viral ribonucleic acid (RNA) in nasopharyngeal and fecal swabs fluctuate below the limits of RT-PCR detection during virus clearance. The probability of reinfection was less likely to be the cause of retesting positive because of the low risk of exposure where cases observed a 14 day-quarantine after discharge. Conclusion: More studies are needed to better explain the immune response of recovered COVID-19 cases retesting positive after discharge.
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Chen, Qing-Quan, Min Chen, Li-Hua Zhang, Yu Zeng, Liu Qi-Cai, Xiu-Lin Yang, and Xu-Chen Lin. "Costimulation blockade by combining CTLA4Ig with anti-CD40L mAb markedly inhibits the inflammatory response of experimental autoimmune myocarditis." European Journal of Inflammation 15, no. 1 (January 16, 2017): 28–34. http://dx.doi.org/10.1177/1721727x16686980.
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The aim of this study was to investigate the effect of costimulation blockade with cytotoxic T-lymphocyte-associated-antigen 4-immunoglobulin (CTLA4Ig) and anti-CD40L monoclonal antibody (anti-CD40L mAb) on an experimental autoimmune myocarditis (EAM) mouse model. Characteristics of myocardial tissue were observed by hematoxylin and eosin (H&E) staining. The messenger RNA (mRNA) levels of CTLA4, CD40L, IFN-γ, and IL-4 were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Serum concentrations of IFN-γ and IL-4 were determined by ELISA. After immune intervention, the inflammatory score, mRNA levels of CTLA4 and CD40L, and IFN-γ level were decreased. Furthermore, these parameters in the combinational intervention group (blockade by CTLA4Ig and anti-CD40L mAb) were significantly decreased, compared to the single intervention group (blockade by CTLA4Ig or anti-CD40L mAb). However, after costimulation, blockade serum IL-4 levels were increased. Therefore, costimulation blockade by combination CTLA4Ig and anti-CD40L mAb could more effectively inhibit the inflammatory response of EAM than single use of CTLA4Ig or anti-CD40L mAb.
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Wang, Hui, Qian Xu, Chanyuan Zhao, Ziqi Zhu, Xiaoqing Zhu, Junjie Zhou, Shuming Zhang, et al. "An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy." Journal for ImmunoTherapy of Cancer 8, no. 2 (August 2020): e000661. http://dx.doi.org/10.1136/jitc-2020-000661.
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BackgroundRecent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.MethodsThe distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo.ResultsIn a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy.ConclusionThere appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.
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Akula, Annapurna, Chandi Vishala, and Gummalla Pitchaiah. "IMMUNOMODULATORY ACTIVITY OF NUTRACEUTICAL FORMULATION AND ITS POTENTIATION BY SELF-FORTIFICATION AND COW URINE DISTILLATE FORTIFICATION METHODS." International Journal of Pharmacy and Pharmaceutical Sciences 9, no. 8 (August 1, 2017): 15. http://dx.doi.org/10.22159/ijpps.2017v9i8.13716.
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Objective: This study prepared, evaluated immunomodulatory activity of nutraceutical formulation and studied the effect of self-mortification and cow urine distillate fortification methods on the immunomodulatory potential of nutraceutical formulation.Methods: Three types of nutraceutical formulations i.e. Nutraceutical formulation (NF), self fortitfied nutraceutical formulation (SFNF) and self fortitfied nutraceutical formulation fortified with cow urine distillate (SFNECUD) were prepared using fine powders of amla, apple, garlic, onion, wheat grass, papaya, turmeric and cow urine distillate by different methods. The immunomodulatory activity of nutraceutical formulations at a dose of 500 mg/kg was assessed by various immune function parameters like cell-mediated immunity (neutrophil adhesion, delayed type hypersensitivity (DTH) response and cyclophosphamide-induced neutropenia), humoral immunity (serum immunoglobulins level and haemoagglutination antibody titer), and phagocytic activity (carbon clearance and polymorphonuclear (PMN) cell activity).Results: Oral administration of NF, SFNF and SFNFCUD showed significant (p<0.01) increase in adhesion of neutrophils, potentiation of the DTH reaction and attenuation of cyclophosphamide-induced neutropenia. A significant increase in serum immunoglobulin levels and production of circulating antibody titer in response to sheep red blood cells (SRBCs) was also observed. In addition, an increase in the phagocytic index in carbon clearance assay and an increase in the phagocytic activity of PMN cells was observed.Conclusion: From the above results, it can be concluded that all three types of formulations showed significant immunostimulant activity. SFNF and SFNFCUD showed better immunomodulatory activity than NF suggesting the potentiation of immunomodulatory potential of NF activity by fortification methods.
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Agustina, Dini. "Immunoblotting Detection of Immunoglobulin G Post Subcutaneous Immunization Of Protein Hemaglutinin Pili Klebsiella pneumoniae 12,8 kDa on Mice BALB / C." Journal of Agromedicine and Medical Sciences 3, no. 2 (July 20, 2017): 40. http://dx.doi.org/10.19184/ams.v3i2.5069.
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Klebsiella pneumoniae is the second most common cause of community infection and nosocomial infections due to Gram-negative bacteria. These bacteria are able to induce the onset of immune response, especially humoral immune response.Humoral immunity acts through the activation of B cells that produce antibodies. Antibodies, especially IgG, will cause encapsulated bacteria such as Klebsiella pneumoniae to be better phagocytosed. The purpose of this study was to determine the IgG response to hemagglutinin protein pili K. pneumoniae 12.8 kDa. The method used in this research is Immunoblotting method with western blot and dot blot. The primary antibodies used for the western blot and dot blot tests were isolated from BALB / C mice serum induced with the subcutaneous pili K. pneumoniae 12.8 kDa protein. To get the standard in assessing the results of dot blot were used Corel Photo-paint X6. The semi-quantitative result of dot blot was obtained with the strongest reaction of the antibody dilution at 1/100 while the antigen dilution titer at 1 / 10.000. Results from western blotting showed a positive reaction of the pili protein subunit with a molecular weight of 128.1 kDa, 114.4 kDa, 64.9 kDa, 31.1 kDa, 27.7 kDa, 24.8 kDa, 20.9 kDa, 12.8 kDa, and 10 kDa. The conclusion of this study is the immunization of hemagglutinin pili K. pneumoniae 12.8 kDa subcutaneously capable of inducing the formationof Immunoglobulin G in BALB / C mice.
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Skibo, Y. V., N. S. Kurmaeva, V. N. Tsibulkina, I. G. Mustafin, and Z. I. Abramova. "The characteristics of serum circulating immune complexes of patients with atopic asthma with different severity degree." Kazan medical journal 94, no. 5 (October 15, 2013): 744–48. http://dx.doi.org/10.17816/kmj1934.
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Aim. To evaluate the serum level of pathogenic circulating immune complexes in patients with mild and severe atopic bronchial asthma. Methods. Serum samples of patients with atopic asthma of mild persistent (30 patients) and severe persistent (20 patients) forms were analyzed. The control group consisted of 15 healthy volunteers. To detect the giant, large, medium and small-sized serum immune complexes, 3, 3.5, 4 and 7% polyethyleneglycol-6000 solutions were used. For quantitative evaluation of the immune complexes we measured the ultraviolet optical density at 280 nm wave length. To separate the immune complexes from immunoglobulin, Protein-G-Sepharose was used. Determination of the protein composition of circulating immune complexes was performed by electrophoresis in 8% polyacrylamide gel. Results. The concentration of immune complexes was increased in patients with bronchial asthma compared to healthy donors. Small and medium-sized immune complexes were prevailing, their concentrations correlated with the severity of asthma. Large, medium and small-sized immune complexes participated in immunopathological reactions in patients with both mild and severe asthma, with immune complexes pathogenicity coefficient significantly increased depending on the severity of the disease. Electrophoretic analysis of circulating immune complexes has shown the presence of proteins with molecular weight of 60 kDa in the complexes of all sizes. In the severe asthma group, an antigen fraction with a molecular mass of 36 kDa within the small-sized molecular complexes was revealed. Conclusion. The observed increase of small and medium-sized circulating immune complexes serum levels in patients with bronchial asthma may be an indicator of of these patients predisposal to autoimmune reactions development.
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Tillyashaykhov M. N., Abdiganiyeva S. R., Abdurakhmonov D. A., Tuidzhanova H. Kh., Isroilova F. Kh., and Alimova S. S. "THE STUDY OF HUMORAL FACTORS OF ADAPTIVE IMMUNITY IN PATIENTS WITH NON-HODGKIN’S LYMPHOMAS." Science Review, no. 6(23) (July 31, 2019): 13–15. http://dx.doi.org/10.31435/rsglobal_sr/31072019/6610.
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It is known that humoral factors of immunity play an important function of mediators in the cascade development of the immune response and can determine the effectiveness of the final, effector reactions of cellular immunity in the inactivation and elimination of antigens. Serum concentrations of major immunoglobulins IgG, IgA, IgM in NHL were analyzed. The highest serum content of IgG and IgA was revealed in the groups of patients with virus carrier. It has been established that one of the most important humoral markers of immunity is the circulating immune complexes (CIC). It has been established that one of the most important biological functions of immunoglobulins is antigen binding and the formation of CIC. A high level of CIC in NHL may be due not only to the activation of the immune response, but also to the suppression of the mechanisms of their elimination. Therefore, based on the results obtained, with NHL there is a pronounced imbalance of humoral immunity. CIC of large and small sizes are also increased, however, the highest increase in CIC was observed in groups of patients before chemotherapy with virus-bearing. An increase in the main immunoglobulins indicates the presence of humoral imbalance, and an increase in the CIC indicates the presence of intoxication of the body either due to the decay of the tumor cells themselves and infected cells, which almost always indicates the progression of the pathological process.
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Kopf, Manfred, Suzanne Herren, Michael V. Wiles, Mark B. Pepys, and Marie H. Kosco-Vilbois. "Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component." Journal of Experimental Medicine 188, no. 10 (November 16, 1998): 1895–906. http://dx.doi.org/10.1084/jem.188.10.1895.
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Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell–dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules involved in initial signaling events leading to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were detected on germinal center B cells isolated from the deficient mice suggesting a modification of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both in serum and germinal center cells from IL-6–deficient mice. Indeed, C3 provided an essential stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti–mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from C3–deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes. Adding IL-6 in vitro to IL-6–deficient germinal center cells stimulated cell cycle progression and increased levels of antibody production. These findings reveal that the germinal center produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.
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Gottstein, B. "Molecular and immunological diagnosis of echinococcosis." Clinical Microbiology Reviews 5, no. 3 (July 1992): 248–61. http://dx.doi.org/10.1128/cmr.5.3.248.
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Echinococcosis is an infectious disease of humans caused by the larval (metacestode) stage of the cestode species Echinococcus granulosus (cystic echinococcosis or hydatid disease) or Echinococcus multilocularis (alveolar echinococcosis or alveolar hydatid disease). Clinical manifestations depend primarily on localization and size of hepatic lesions and may include hepatomegaly, obstructive jaundice, or cholangitis. Prognostically, alveolar echinococcosis is considered similar to liver malignancies, including a lethality rate of 90% for untreated cases. Diagnosis is based on imaging techniques coupled with immunodiagnostic procedures. Antibody detection tests for E. multilocularis have markedly improved with the use of affinity-purified Em2 antigen and recombinant antigen II/3-10 in enzyme immunoassays. Antigens of corresponding quality for E. granulosus are still unavailable. The detection of circulating antigens and immune complexes in the sera of patients with cystic echinococcosis, the demonstration of in vitro lymphocyte proliferation in response to stimulation with Echinococcus antigens, and the discrimination of serum immunoglobulin isotype activity to various Echinococcus antigens in both cystic and alveolar echinococcosis have been suggested for diagnostic purposes as well as for monitoring patients after treatment. New diagnostic molecular tools include DNA probes for Southern hybridization tests and polymerase chain reaction for the amplification of E. multilocularis and E. granulosus species-specific DNA fragments.
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Winkler, André, Markus Berger, and Marc Ehlers. "Anti-rhesus D prophylaxis in pregnant women is based on sialylated IgG antibodies." F1000Research 2 (August 9, 2013): 169. http://dx.doi.org/10.12688/f1000research.2-169.v1.
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Red blood cells (RBCs) from a rhesus D (RhD)-positive fetus that reach the bloodstream of an RhD-negative pregnant woman during birth can induce a pathogenic antibody (Ab) response against the RhD-positive RBCs, leading to fetal hemolytic disease in subsequent pregnancies. To prevent a pathogenic immune reaction, the RhD-negative mother receives serum immunoglobulin G (IgG) containing polyclonal RhD-specific IgG Abs that is purified from healthy RhD-negative men immunized with RhD-positive RBCs. However, the protective mechanism of these polyclonal RhD-specific IgG Abs is unclear. It has become increasingly clear that the effector function of IgG Abs is regulated by the glycan pattern linked to the Fc region of IgG Abs. Non-fucosylated (afucosylated) IgG Abs have a higher affinity for activating Fc gamma receptors, and thus induce a stronger Ab-dependent cellular cytotoxicity (ADCC) reaction than do fucosylated IgG Abs. Agalactosylated and asialylated, autoantigen-specific serum IgG Abs correlate with pro-inflammatory immune responses and disease activity in patients with rheumatoid arthritis. In contrast, galactosylated and sialylated IgG Abs are immunosuppressive and inhibit in form of immune complexes (ICs) dendritic cell (DC) maturation and pro-inflammatory T and B cell immune responses in an antigen-specific manner. However, the galactosylation and sialylation levels of the protective polyclonal RhD-specific IgG Abs are unknown. Here, we purified RhD-specific IgG Abs from the approved commercial product Rhophylac® (CSL Behring) and found that these RhD-specific IgG Abs were even more galactosylated and sialylated than the total Rhophylac® IgG Abs. This result suggests that these galactosylated and sialylated polyclonal RhD-specific IgG Abs are immunosuppressive and induce tolerance against RhD, which would be in strong contrast to a low fucosylated, low galactosylated and low sialylated monoclonal RhD-specific IgG Ab developed to prevent fetal hemolytic disease that has recently passed a clinical phase II study.
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Hoelzle, L. E., K. Hoelzle, M. Ritzmann, K. Heinritzi, and M. M. Wittenbrink. "Mycoplasma suis Antigens Recognized during Humoral Immune Response in Experimentally Infected Pigs." Clinical and Vaccine Immunology 13, no. 1 (January 2006): 116–22. http://dx.doi.org/10.1128/cvi.13.1.116-122.2006.
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ABSTRACT Today, serodiagnostic tests for Mycoplasma suis infections in pigs have low accuracies. The development of novel serodiagnostic strategies requires a detailed analysis of the humoral immune response elicited by M. suis and, in particular, the identification of antigenic proteins of the agent. For this study, indirect enzyme-linked immunosorbent assay (ELISA) and immunoblot analyses were performed using pre- and sequential postinoculation sera from M. suis-infected and mock-infected control pigs. M. suis purified from porcine blood served as the antigen. Eight M. suis-specific antigens (p33, p40, p45, p57, p61, p70, p73, and p83) were identified as targets of the immunoglobulin G (IgG) antibody response during experimental infection, with p40, p45, and p70 being the preferentially recognized M. suis antigens. Besides the M. suis-specific antigens, porcine immunoglobulins were identified in blood-derived M. suis preparations. By immunoglobulin depletion, the specificity of the M. suis antigen for use in indirect ELISA was significantly improved. M. suis-specific Western blot and ELISA reactions were observed in all infected pigs by 14 days postinfection at the latest and until week 14, the end of the experiments. During acute clinical attacks of eperythrozoonosis, a derailment of the antibody response, determined by decreases in both the M. suis net ELISA values and the numbers of M. suis-specific immunoblot bands, was accompanied by peaking levels of autoreactive IgG antibodies. In conclusion, the M. suis-specific antigens found to stimulate specific IgG antibodies are potentially useful for the development of novel serodiagnostic tests.
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Rodero, M., C. Cuéllar, T. Chivato, J. M. Mateos, and R. Laguna. "Western blot antibody determination in sera from patients diagnosed with Anisakis sensitization with different antigenic fractions of Anisakis simplex purified by affinity chromatography." Journal of Helminthology 81, no. 3 (September 2007): 307–10. http://dx.doi.org/10.1017/s0022149x07820220.
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AbstractUsing Western blot techniques, the specificities of crude and purified (PAK and PAS) Anisakis simplex antigens were compared against 24 sera from patients diagnosed with Anisakis sensitization. All patients recognized a 60 kDa protein against the A. simplex crude extract, while 37.5% and 12.5% reacted with proteins of 40 and 25 kDa, respectively, when IgG was tested. In the case of IgE determination, 41.6% of sera were negative, while 12.5% and 20.8% appeared to cross-react against Toxocara canis and Ascaris suum, respectively. When the PAK antigen (A. simplex antigen purified by means of a column of IgG anti-A. simplex) was tested, immune recognition towards the 60, 40 and 25 kDa proteins increased in 83.3%, 16.7% and 4.2%, respectively, when the Ig antibodies were tested. In the case of the PAS antigen (PAK antigen purified by means of a column of IgG anti-A. suum), the reaction against the 40 and 25 kDa proteins increased to 45.8% and 25%, respectively, when Ig antibodies were used. Finally, when the EAS antigen (eluted from the anti-A. suum column after PAK purification) was tested, 83.3% of the assayed sera reacted against the 14 kDa protein, when the Ig antibodies, IgG and IgM immunoglobulins were measured. With the IgE determination, the reactions were observed in 41.7% of patients with proteins between 60 and 35 kDa against the PAS antigen. With the EAS antigen, reactive bands of 184, 84 and 14 kDa appeared. In conclusion, in the purification process of the A. simplex larval crude extract, the proteins implicated in cross-reactions with Ascaris and Toxocara were eliminated, with an important concentration of proteins responsible for the induction of specific responses.
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Srinivasan, Abhay, Yawei Ni, and Ian Tizard. "Specificity and Prevalence of Natural Bovine Antimannan Antibodies." Clinical Diagnostic Laboratory Immunology 6, no. 6 (November 1, 1999): 946–52. http://dx.doi.org/10.1128/cdli.6.6.946-952.1999.
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ABSTRACT Immune responses to the carbohydrate components of microorganisms, mediated both by antibodies and by lectins, are an important part of host defense. In the present experiments, the specificity and presence of natural bovine antibodies against mannan, a common fungal antigen, were examined by enzyme-linked immunosorbent assay (ELISA), usingSaccharomyces cerevisiae mannan as an antigen. The results showed that all serum samples from animals of three age groups (newborn, calf, and adult) tested contained antimannan antibodies, and the titer of these antibodies increased significantly in adults. However, titers among individual adult cattle differed widely. Inhibition assays showed that yeast mannan was the strongest inhibitor.d-Mannose exhibited only a minor inhibitory effect at high concentrations. This suggests that most of these antibodies recognize an oligosaccharide-based epitope(s) different from those recognized by lectins. Cattle possess three serum C-type lectins (collectins) capable of recognizing mannan in a calcium-dependent manner. Addition of EDTA to the reaction did not reduce antibody binding, suggesting that the binding of these antibodies to mannan was not affected by the presence of collectin. The antibodies purified from either calf or adult serum by mannan-Sepharose affinity chromatography consisted of mainly immunoglobulin G (IgG) and a smaller amount of IgM. IgG1 was shown to be the dominant antimannan IgG isotype by isotype-specific ELISA. Together, these results demonstrate the production of natural antimannan antibodies in cattle in an age-dependent manner. These antibodies might be involved in defending the host against mannan-containing pathogens as a specific line of defense in conjunction with the innate response by lectins.
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Marczak-Karpina, Beata, Maria Jasińska, Elżbieta Poniewierka, Marek Frączkowski, Robert Dudkowiak, and Radosław Kempiński. "Assessment of the usefulness of macroenzyme determination in the situation of increased plasma enzyme activity in the absence of clinical symptoms." Diagnostyka Laboratoryjna 56, no. 1 (August 21, 2020): 17–22. http://dx.doi.org/10.5604/01.3001.0014.3608.
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Introduction: The increased activity of serum enzymes is usually a reason of multiple, often expensive and invasive diagnostic procedures. However, there are situations in which abnormal enzyme activity persists for many months or years, and detailed studies do not confirm the existence of anatomic disease. Such is the case when enzymes form complexes with immunoglobulins on the basis of the immune antigen-antibody reaction. This phenomenon is usually benign condition, is transient and does not require treatment. Aim of study: Detection of the macroenzymes in patients with elevated serum enzyme activity. Evaluation of the relationship between the presence of macroenzymes and the age of patients, body mass index, lipid profile, chronic and autoimmune diseases. Material and methods: Macroenzymes were examined by polyethylene glycol precipitation (PEG) in 121 patients with elevated values of liver or pancreatic enzymes. Results: In the study group, a statistically significant difference was found comparing the BMI of men and women. BMI was significantly higher in men with macroenzymes (p = 0.006). It was shown that the BMI of people with serum macroenzymes is significantly higher (p = 0.049) than those without macroenzymes. A statistically significant correlation was observed between the presence of macroamylase and body weight, r = 0.33, p = 0.039. A positive correlation of triglycerides and macrogenzofacts in the serum was found. Macroamylase was observed the most frequently in the healthy group and those suffering from chronic diseases (45.83% and 42.86%). In the group of autoimmune diseases (autos) the most common was macro-GGTP (42.86%). In patients with inflammatory bowel disease, 80% of the confirmed macroenzymes in serum were macro-CK.
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Sasaki, Shin, Kaharu Sumino, Kenji Hamajima, Jun Fukushima, Norihisa Ishii, Susumu Kawamoto, Hiroshi Mohri, Charlotte Read Kensil, and Kenji Okuda. "Induction of Systemic and Mucosal Immune Responses to Human Immunodeficiency Virus Type 1 by a DNA Vaccine Formulated with QS-21 Saponin Adjuvant via Intramuscular and Intranasal Routes." Journal of Virology 72, no. 6 (June 1, 1998): 4931–39. http://dx.doi.org/10.1128/jvi.72.6.4931-4939.1998.
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ABSTRACT Induction of mucosal and cell-mediated immunity is critical for development of an effective vaccine against human immunodeficiency virus (HIV). We compared intramuscular and intranasal immunizations with a DNA vaccine encoding env of HIV-1 and evaluated the QS-21 saponin adjuvant for augmentation of the systemic and mucosal immune responses to HIV-1 in a murine model. Vaccination via the two routes elicited comparable systemic immune responses, and QS-21 consistently enhanced antigen-specific serum immunoglobulin G2a (IgG2a) production, delayed-type hypersensitivity reaction, and cytolytic activity of splenocytes. Intestinal secretory IgA production and cytolytic activity of the mesenteric lymph node cells are preferentially elicited by intranasal immunization, and QS-21 augmented these activities as well. This adjuvant augmented production of interleukin-2 (IL-2) and gamma interferon (IFN-γ) associated with decrease in IL-4 synthesis by antigen-restimulated splenocytes. The serum immunoglobulin subtype profile showed a dominant IgG2a response and less strong IgG1 and IgE production in a QS-21 dose-dependent manner. As expected, enhancements of humoral and cell-mediated immune responses by QS-21 were abrogated by treatment with anti-IL-2 and anti-IFN-γ monoclonal antibodies. These results suggest that the intranasal route of DNA immunization is more efficient than the intramuscular route in inducing mucosal immunity mediated by sIgA and mesenteric lymphocytes. Furthermore, QS-21 is able to act as a mucosal adjuvant in DNA vaccination and demonstrates its immunomodulatory property via stimulation of the Th1 subset. This study emphasizes the importance of the route of immunization and the use of an adjuvant for effective DNA vaccination against HIV-1.
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Alaniz, María E., Ricardo D. Lardone, Silvia L. Yudowski, María I. Farace, and Gustavo A. Nores. "Normally Occurring Human Anti-GM1 Immunoglobulin M Antibodies and the Immune Response to Bacteria." Infection and Immunity 72, no. 4 (April 2004): 2148–51. http://dx.doi.org/10.1128/iai.72.4.2148-2151.2004.
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ABSTRACT Anti-GM1 antibodies of the immunoglobulin M (IgM) isotype are normal components of the antibody repertoire of adult human serum. Using a sensitive high-performance thin-layer chromatography (HPTLC) immunostaining assay, we found that these antibodies were absent in the umbilical vein and children <1 month of age but could be detected after 1 month of age. Although most of the children older than 6 months of age were positive, there were still a few negative children. The appearance of anti-GM1 IgM antibodies showed a perfect concordance with two well-characterized antibacterial antibodies, anti-Forssman and anti-blood group A, which indicates a similar origin. We also studied IgM reactivity with lipopolysaccharides (LPSs) from gram-negative bacteria isolated from stool samples from healthy babies and from Escherichia coli HB101 in serum from individuals of different ages. We found a positive reaction with both LPSs in all the children more than 1 month of age analyzed, even in those that were negative for anti-GM1 antibodies. Anti-GM1 IgM antibodies were purified from adult serum by affinity chromatography and tested for the ability to bind LPSs from different bacteria. This highly specific preparation showed reactivity only with LPS from a strain of Campylobacter jejuni isolated from a patient with diarrhea. We conclude that normally occurring IgM antibodies are generated after birth, probably during the immune defense against specific bacterial strains.
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Schwenk, Michael, Reinhild Klein, and Douglas M. Templeton. "Immunological effects of mercury (IUPAC Technical Report)." Pure and Applied Chemistry 81, no. 1 (January 1, 2009): 153–67. http://dx.doi.org/10.1351/pac-rep-08-04-02.
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Various chemical species of mercury differ considerably with regard to their route of absorption and their distribution in the body, yet many of them and their metabolites exhibit high-affinity binding to sulfanyl groups of proteins. Among all metals, mercury appears to have the most diverse effects on the immune system. Depending on the animal species and experimental conditions, mercury compounds may cause immunosuppression or immunostimulation, autoimmune reactions, or hypersensitivity. Mercury-sensitive strains of rats and mice are often used as model organisms to study the time course and events in autoimmunity. Within about 14 days after onset of oral mercury(II) exposure, levels of immunoglobulins E and G (IgE and IgG) increase, including autoantibodies to biomolecules such as laminin and fibrillarin. Antigen-antibody complexes are formed and are the cause of subsequent autoimmune diseases of blood vessels and organs. Mercury may induce local mercury hypersensitivity in humans, but the evidence for a role of mercury in autoimmune disease of humans is at best weak. Models for the immune effects of mercury are presented on the basis of current knowledge.
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Fries, Louis F., Andrew D. Montemarano, Corey P. Mallett, David N. Taylor, Thomas L. Hale, and George H. Lowell. "Safety and Immunogenicity of a Proteosome-Shigella flexneri 2a Lipopolysaccharide Vaccine Administered Intranasally to Healthy Adults." Infection and Immunity 69, no. 7 (July 1, 2001): 4545–53. http://dx.doi.org/10.1128/iai.69.7.4545-4553.2001.
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ABSTRACT We studied the safety and immunogenicity of a Shigella flexneri 2a vaccine comprising native S. flexneri 2a lipopolysaccharide (LPS) complexed to meningococcal outer membrane proteins—proteosomes—in normal, healthy adults. A two-dose series of immunizations was given by intranasal spray, and doses of 0.1, 0.4, 1.0, and 1.5 mg (based on protein) were studied in a dose-escalating design. The vaccine was generally well tolerated. The most common reactions included rhinorrhea and nasal stuffiness, which were clearly dose related (P ≤ 0.05). These reactions were self-limited and generally mild. The vaccine elicitedS. flexneri 2a LPS-specific immunoglobulin A (IgA), IgG, and IgM antibody-secreting cells (ASCs) in a dose-responsive manner. At doses of 1.0 or 1.5 mg, highly significant (P < 0.001) increases in ASCs of all antibody isotypes occurred and 95% of subjects had an ASC response in at least one antibody isotype. Dose-related serum antibody responses were observed, with geometric mean two- to fivefold rises in specific serum IgA and IgG titers and two- to threefold rises in IgM in the 1.0- and 1.5-mg-dose groups (P < 0.0001 for each isotype). Elevated serum antibody levels persisted through day 70. Increases in fecal IgG and IgA and also in urinary IgA specific for S. flexneri 2a LPS were demonstrated. These were most consistent and approached statistical significance (P = 0.02 to 0.12 for various measures) on day 70 after the first dose. The magnitude of immune responses to intranasally administered proteosome-S. flexneri 2a LPS vaccine is similar to those reported for live vaccine candidates associated with protective efficacy in human challenge models, and further evaluation of this product is warranted.
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Hannum, Lynn G., Ann M. Haberman, Shannon M. Anderson, and Mark J. Shlomchik. "Germinal Center Initiation, Variable Gene Region Hypermutation, and Mutant B Cell Selection without Detectable Immune Complexes on Follicular Dendritic Cells." Journal of Experimental Medicine 192, no. 7 (September 25, 2000): 931–42. http://dx.doi.org/10.1084/jem.192.7.931.
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Serum antibody (Ab) can play several roles during B cell immune responses. Among these is to promote the deposition of immune complexes (ICs) on follicular dendritic cells (FDCs). ICs on FDCs are generally thought to be critical for normal germinal center (GC) formation and the development and selection of memory B cells. However, it has been very difficult to test these ideas. To determine directly whether FDC-bound complexes do indeed function in these roles, we have developed a transgenic (Tg) mouse in which all B lymphocytes produce only the membrane-bound form of immunoglobulin M. Immune Tg mice have 10,000-fold less specific Ab than wild-type mice and lack detectable ICs on FDCs. Nonetheless, primary immune responses and the GC reaction in these mice are robust, suggesting that ICs on FDCs do not play critical roles in immune response initiation and GC formation. Moreover, as indicated by the presence and pattern of somatic mutations, memory cell formation and selection appear normal in these IC-deficient GCs.
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Ababneh, Mustafa, Mu'men Alrwashdeh, and Mohammad Khalifeh. "Recombinant adenoviral vaccine encoding the spike 1 subunit of the Middle East Respiratory Syndrome Coronavirus elicits strong humoral and cellular immune responses in mice." October-2019 12, no. 10 (October 2019): 1554–62. http://dx.doi.org/10.14202/vetworld.2019.1554-1562.
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Background and Aim: Middle East respiratory syndrome coronavirus (MERS-CoV) has rapidly spread throughout the Middle East since its discovery in 2012. The virus poses a significant global public health threat with potentially devastating effects. In this study, a recombinant adenoviral-based vaccine encoding the spike 1 (S1) subunit of the MERS-CoV genome was constructed, and its humoral, and cellular immune responses were evaluated in mice. Materials and Methods: Mice were immunized initially by intramuscular injection and boosted 3 weeks later by intranasal application. Expression of the S1 protein in the lungs and kidneys was detected using conventional polymerase chain reaction (PCR) and immunohistochemistry (IHC) targeting specific regions within the S1 subunit at weeks 3, 4, 5, and 6 after the first vaccination. Antigen-specific humoral and cellular immune responses were evaluated in serum and in cell culture following in vitro stimulation with a specific 9-mer epitope within the S1 protein (CYSSLILDY). Results: S1 protein expression was only detected by IHC in the kidneys of the Ad-MERS-S1 group at week 6 from first immunization, and in both lungs and kidneys of Ad-MERS-S1 group by conventional PCR at weeks 3 and 5 post-prime. The vaccine elicited a specific S1-immunoglobulin G antibody response, which was detected in the sera of the vaccinated mice at weeks 4 and 6 from the onset of the first immunization. There was a significant increase in the amount of Th1-related cytokines (interferon-γ and interleukin [IL] 12), and a significant decrease in the Th2-related cytokine IL-4 in splenocyte cell culture of the vaccinated group compared with the control groups. Conclusion: The results of this study suggest that this recombinant adenovirus vaccine encoding the S1 subunit of MERS-CoV elicits potentially protective antigen-specific humoral and cellular immune responses in mice. This study demonstrates a promising vaccine for the control and/or prevention of MERS-CoV infection in humans.
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Shibata, Yoshimi, Ikuro Honda, J. Paul Justice, Michael R. Van Scott, Reiko M. Nakamura, and Quentin N. Myrvik. "Th1 Adjuvant N-Acetyl-d-Glucosamine Polymer Up-Regulates Th1 Immunity but Down-Regulates Th2 Immunity against a Mycobacterial Protein (MPB-59) in Interleukin-10-Knockout and Wild-Type Mice." Infection and Immunity 69, no. 10 (October 1, 2001): 6123–30. http://dx.doi.org/10.1128/iai.69.10.6123-6130.2001.
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ABSTRACT Treatment of mice with heat-killed (HK) Mycobacterium bovis BCG or 1- to 10-μm chitin particles (nonantigenic N-acetyl-d-glucosamine polymers) is known to induce innate immune responses, including gamma interferon (IFN-γ) production, which plays a Th1 adjuvant role. However, HK BCG further induces prostaglandin E2-releasing spleen macrophages (Mφ) (PGE2-Mφ), which potentially inhibit Th1 adjuvant activities. We found that chitin particles did not induce PGE2-Mφ formation. To further assess whether chitin has Th1 adjuvant effects, interleukin-10 (IL-10)-knockout (KO) mice and their wild-type (WT, C57BL/6) controls were immunized with a 30-kDa MPB-59 mycobacterial protein mixed with chitin. Immunization with MPB-59 alone induced Th2 responses, characterized by increases in total serum immunoglobulin E (IgE) and specific serum IgG1 levels and spleen Th2 cells producing IL-4, IL-5, and IL-10. No IFN-γ-producing spleen Th1 cells, specific serum IgG2a, or delayed-type hypersentivity (DTH) footpad reactions were detected. On the other hand, chitin–MPB-59 immunization significantly increased spleen Th1 responses, DTH reaction, and serum IgG2a levels along with decreases of Th2 responses. The magnitude of these Th1 adjuvant effects was greater in IL-10-KO mice than in WT mice. In contrast, immunization with HK BCG–MPB-59 showed little or no Th1 adjuvant effect. These data indicate that chitin has a unique Th1 adjuvant effect on the development of Th1 immunity against a mycobacterial antigen. IL-10 down-regulates the adjuvant effect of chitin.
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Panev, N. I., A. S. Kazitskaya, O. Yu Korotenko, G. A. Gerasimova, O. A. Morozova, and S. O. Kungurova. "Clinical and experimental studies of immunо-infl ammatory mechanisms of anthracosilicosis formation." Russian Journal of Occupational Health and Industrial Ecology, no. 6 (July 10, 2020): 364–70. http://dx.doi.org/10.31089/1026-9428-2020-60-6-364-370.
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Introduction. In the structure of occupational diseases of employees of the main professions of the coal industry, respiratory diseases are widespread, in the process of formation of which the key role belongs to the immune system of the body. Early manifestations of the development of professional pathology, as a rule, remain unnoticed, and therefore there is a need to study the pathogenetic mechanisms underlying its formation, not only in clinical, but also in experimental conditions, allowing to assess the premorbid state of the body for timely diagnosis and treatment and prevention.The aim of the study is to study the immune-infl ammatory mechanisms of anthracosilicosis formation on the basis of clinical and experimental studies.Materials and methods. We examined 204 miners working in underground conditions with a signifi cant dustiness of workplaces exceeding the maximum permissible concentration by 10 or more times. Th e main group consisted of 115 workers with a previously established diagnosis of “anthracosilicosis”. Th e comparison group was formed from 89 miners without a diagnosis of respiratory pathology, working in similar sanitary conditions. To assess the dynamics of immuno-infl ammatory mechanisms in the experiment, modeling of dust pathology of the lungs was performed on 310 white male laboratory rats (220-experimental and 90 — control).Results. In patients with anthracosilicosis, the development of immune failure of humoral immunity mechanisms was revealed, which was manifested by a signifi cant decrease in the level of serum IgG against the background of an increase in the absolute and relative number of B-lymphocytes. Th e formation of anthracosilicosis is characterized by the active development of the immuno-infl ammatory process (an increase in the level of pro-infl ammatory cytokines and proteins of the acute phase of infl ammation), the severity of which increases when the disease is complicated by respiratory failure. Activation of the synthesis of anti-infl ammatory IL-4, which is a powerful inhibitor of macrophage infl ammation and slows down the processes of fi brosis in the bronchopulmonary system, acts as a protective mechanism that prevents the formation of respiratory failure in miners with anthracosilicosis. Experimental modeling of anthracosilicosis revealed phase changes in the immune response. In the early period of exposure to dust factor was observed activation of humoral (increased level of all classes of immunoglobulins) and the subsequent development of the inflammatory process (increased concentrations of acute phase proteins of inflammation) in the background of the balance between subpopulations of T-lymphocytes to ensure proper development of protective immune response. Long-term intake of antigen was characterized by violations of humoral immunity, the predominance of cell-type reactions and the chronization of the infl ammatory process.Conclusions. Th e study of immuno-infl ammatory mechanisms of anthracosilicosis formation in clinical and experimental conditions indicates the activation of urgent adaptation and maintenance of compensatory and adaptive reactions of the body in the early period of contact with dust antigen. Th e chronic form of anthracosilicosis is characterized by an imbalance of regulatory mechanisms, ineffi ciency of local immunity and the intensive development of generalized immune infl ammation, which increases with the addition of infection and complication of respiratory failure.
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Kozłowska, Kamila, Magdalena Rydlewska, Marta Ząbczyńska, and Ewa Pocheć. "IgG glycosylation in autoimmune diseases." Postępy Higieny i Medycyny Doświadczalnej 72 (November 12, 2018): 975–90. http://dx.doi.org/10.5604/01.3001.0012.7351.
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Immunoglobulin G (IgG) is the most abundant glycoprotein in human serum. All IgG subclasses have a single-conserved N-linked glycosylation site at Asn297 of the heavy chain and 10–30% of IgGs are N-glycosylated also in a Fab region. N-glycans of Fc are sialylated and fucosylated biantennary complex-type structures. Glycosylation plays a key role in antibody function, and IgG N-glycans are essential for the proper activity of the immune system. Fc glycans are important for IgG effector functions, whereas Fab oligosaccharides modulate antigen binding. Glycosylation changes of IgG are associated with the development of various human diseases, including autoimmune states. The modification of one sugar moiety in N-glycan structure may result in the stimulation or suppression of immune response. The lack of core fucose leads to the enhancement of pro-inflammatory activity, whereas an increase of sialylation determines immunosuppressive properties of IgG. The contribution of IgG Fc glycosylation changes has been demonstrated in the pathogenesis of rheumatoid arthritis, lupus erythematosus and Crohn’s disease. A decrease in IgG galactosylation and sialylation, found in these diseases, activates effector cells and triggers inflammatory reactions. A detailed analysis of changes in IgG glycosylation and their effects on the development of autoimmune diseases is important in the treatment of these diseases. IgGs with modified α2,6-sialylation are used as therapeutic antibodies with anti-inflammatory properties. Numerous studies on IgG glycosylation have provided evidence of the role of this post-translational modification in the proper functioning of antibodies and the importance of changes in the structure of IgG glycans, mainly incomplete galactosylation and desialylation, in the pathogenesis of many diseases. The continuation of these studies may contribute to explaining the mechanisms of autoimmunity that is still poorly understood.
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Savransky, Vladimir, Michael Lacy, Boris Ionin, Mario H. Skiadopoulos, and Jeffry Shearer. "Repeat-Dose Toxicity Study of a Lyophilized Recombinant Protective Antigen-Based Anthrax Vaccine Adjuvanted With CpG 7909." International Journal of Toxicology 38, no. 3 (May 2019): 163–72. http://dx.doi.org/10.1177/1091581819848722.
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A recombinant protective antigen (rPA) anthrax vaccine candidate (rPA7909) was developed as a next-generation vaccine indicated for postexposure prophylaxis of disease resulting from suspected or confirmed Bacillus anthracis exposure. The lyophilized form of rPA7909-vaccinated candidate contains 75 µg purified rPA, 750 µg aluminum (as Alhydrogel adjuvant), and 250 µg of an immunostimulatory Toll-like receptor 9 agonist oligodeoxynucleotide CpG 7909 in a 0.5 mL phosphate-buffered suspension. General toxicity and local reactogenicity were evaluated in Sprague Dawley rats vaccinated with the full human dose of rPA7909 by intramuscular injection. Animals were immunized on study days 1, 15, and 29. Control groups were administered diluent only or adjuvant control (excipients, CpG 7909, and Alhydrogel adjuvant in diluent) intramuscularly at the same dose volume and according to the same schedule used for rPA7909. Toxicity was assessed based on the results of clinical observations, physical examinations, body weights, injection site reactogenicity, ophthalmology, clinical pathology (hematology, coagulation, and serum chemistry), organ weights, and macroscopic and microscopic pathology evaluation. The immune response to rPA7909 vaccination was confirmed by measuring serum anti-PA immunoglobulin G levels. The rPA7909 vaccine produced no apparent systemic toxicity and only transient reactogenicity at the injection site. The injection site reaction from animals receiving the adjuvant control was very similar to those receiving rPA7909 with respect to the inflammation. The inflammatory response observed in the injection site and the draining lymph nodes was consistent with expected immune stimulation. The overall results indicated a favorable safety profile for rPA7909.
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Bromuro, Carla, Antonella Torosantucci, Paola Chiani, Stefania Conti, Luciano Polonelli, and Antonio Cassone. "Interplay between Protective and Inhibitory Antibodies Dictates the Outcome of Experimentally Disseminated Candidiasis in Recipients of a Candida albicans Vaccine." Infection and Immunity 70, no. 10 (October 2002): 5462–70. http://dx.doi.org/10.1128/iai.70.10.5462-5470.2002.
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ABSTRACT Mice immunized with heat-inactivated, whole yeast-form cells (Y cells) of Candida albicans developed intense, specific humoral and cell-mediated immune responses. However, they were modestly protected against a lethal challenge by the fungus, and their sera did not confer passive protection upon nonimmunized animals. Surprisingly, this immune serum conferred an elevated degree of passive protection to normal and SCID mice when preadsorbed on whole C. albicans cells. After adsorption, no antibodies specific to mannoprotein (MP)-rich extracts or secretions were detected by indirect enzyme-linked immunosorbent assay and no serum reaction with the fungal cell surface was seen in immunofluorescence assays. However, this serum had totally preserved the level of other antibodies, in particular those reacting with β-1,3 and β-1,6 glucan (GG). The hypothesis that anti-GG antibodies contributed to the passive protection was suggested by the following circumstantial evidence: (i) mice immunized with C. albicans cells treated with dithiothreitol and protease (YDP cells), which exposed GG on their surfaces and generated anti-GG but not anti-MP antibodies, were substantially protected against a lethal fungus challenge; (ii) the sera, and their immunoglobulin fractions, of mice immunized with YDP cells transferred protection to nonimmune animals; and (iii) this passive protection was substantially abolished by preadsorption on GG but not on intact cells. Overall, our findings demonstrate that some anti-Candida antibodies can block the protective potential of immune serum, a potential to which anti-GG antibodies appear to contribute. Our observations may also help explain why subjects with elevated anti-Candida antibody titers, inclusive of anti-MP and anti-GG antibodies, remain nonetheless susceptible to invasive candidiasis.
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Schecter, Jordan M., Irene Dy, Jonathan Saniel, Helen Richards, and David Savage. "Evans Syndrome Associated with En a Antibody Leading to Fatal Immune Hemolytic Anemia." Blood 114, no. 22 (November 20, 2009): 3148. http://dx.doi.org/10.1182/blood.v114.22.3148.3148.
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Abstract Abstract 3148 Poster Board III-85 A 40 year old man presented with epistaxis. The patient presented to another institution with Stage 2A lymphocyte-predominant Hodgkin's lymphoma (HL) at the age of 28, thirteen years prior to the current admission. The patient received mantle irradiation without chemotherapy. One year later he developed thrombocytopenia. Workup was negative for relapse of his HL. He was HIV-seronegative. Idiopathic thrombocytopenic purpura (ITP) was diagnosed; his platelet count recovered on prednisone therapy, which was then tapered. One year later, the patient presented with a platelet count of 2,000/μl in association with CT evidence of disseminated lymphadenopathy and bone marrow involvement with relapsed HL for which he received salvage chemotherapy. In Sept 2000, he had high dose therapy and underwent autologous stem cell transplantation. The HL remained in remission over the next 9 years, but the patient reported multiple episodes of thrombocytopenia treated with several courses of steroids and intravenous immunoglobulin (IVIG) and splenectomy in 2001. The patient presented to our hospital in May 2009 with flu-like symptoms, epistaxis of one day's duration, and a platelet count of 6,000/μL. The WBC was 18,000/μL, hemoglobin 10.5 g/dl, and MCV 86 fl. The peripheral smear showed markedly reduced platelets, Howell Jolly bodies, mild anisocytosis, many nucleated rbcs, and microspherocytes, but no schistocytes. The reticulocyte count was 4.6%, ferritin 13,495 ng/ml, iron 216 μg/dl, TIBC 255 μg/dl, folate, B12, PT, and PTT normal, haptoglobin < 8 mg/dl, LDH 376 IU/l, and indirect bilirubin 2.9 mg/dl. Cultures of blood and urine were negative. The patient's antibody studies were done at a local Immunohematology Reference Laboratory. The direct and indirect antiglobulin tests were positive. The patient's red cells were coated with IgG (strong) and C3 (weak). An acid eluate from the red cells reacted strongly by the indirect antiglobulin test with all panel cells tested but was non-reactive with red cells of the rare MkMk phenotype (null phenotype of the MNS blood group system). The patient's serum by saline indirect antiglobulin test showed the same reactivity as the eluate and also an autoanti-I. These results were consistent with the presence of a warm autoantibody with anti-Ena specificity, defined as an antibody directed at the epitopes on glycophorin A. No alloantibodies were detected. Anti-I is a common cold autoagglutinin found in human sera and is not clinically significant. Evans syndrome (autoimmune hemolytic anemia and immune thrombocytopenic purpura) was diagnosed. The patient began prednisone 1 mg/kg daily, with improvement in his platelet count to 70,000/μl in three days. However, his hemoglobin fell from 10.5 to 4.0 g/dl within 24 hours, with an increase in leukocytes to 44,600/μL. IVIG (2 g/kg in divided doses) was added. Due to the presence of anti-Ena antibodies, no cross-match-compatible blood was available from the regional blood center. One day later, the patient became somnolent, hypoxemic and acidotic requiring intubation and mechanical ventilation. Due to his deteriorating clinical status, blood incompatible with the autoantibody was transfused. Immediately after the transfusion began, the patient became pulse-less. Cardiopulmonary resuscitation was begun, but the patient succumbed to cardiovascular collapse. His serum was noted to be amber (in contrast to yellow in a pre-transfusion sample), suggesting hemolysis. The direct antiglobulin test was strongly positive on the pre and post transfusion specimens and Ena autoantibody was again detected. Anti- Ena is an immune antibody that reacts with high incidence antigens on glycophorin A (GPA), the MN antigen-carrying molecule. This antibody reacts against all or part of GPA and may cause hemolytic transfusion reactions. As illustrated in our fatal case, it is difficult, if not impossible, to find compatible donor blood for patients with anti- Ena autoantibody. This is the first patient, to our knowledge, to be reported with anti-Ena associated with Evans syndrome. Disclosures No relevant conflicts of interest to declare.
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Korytov, K. M., V. V. Voitkova, V. I. Dubrovina, A. B. Pyatidesyatnikova, A. K. Noskov, E. A. Glushkov, I. S. Akimova, et al. "Efficiency of Human Plague Vaccination in Tuvinian Natural Plague Focus." Acta Biomedica Scientifica 4, no. 5 (November 14, 2019): 31–37. http://dx.doi.org/10.29413/abs.2019-4.5.5.
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Background. Plague is an especially dangerous natural focal infectious disease belonging to a group of quarantine infections. There are eleven natural plague foci in Russian Federation. In Republic Tyva plague endemic territories include Ovyur, Mongun-Taigin and Tes-Hem areas where Y. pestis strains are intermittently isolated from Citellus undulates. Population living at the territory of the natural foci get immunoprophylaxis against plague at complication of epizootic and epidemic conditions.This paper presents the results of monitoring indicators of the immune status of people vaccinated with the plague vaccine living in the territory of the Tuva natural focus.Materials and methods. The study involved 76 volunteers who had not previously been vaccinated. The study included the determination of production IFN-γ, IL-4, TNF-α by blood cells, titers of specific IgG antibodies to the capsule F1 antigen of the Yersinia pestis, and concentrations of immunoglobulins in serum blood, as well as immunophenotyping of blood lymphocytes.Results. In the course of a comprehensive immunological study, features of the development of cellular and humoral reactions in people living in the territory of the Tuva natural plague focus were established in the first months after vaccination. Changes in the concentration dynamics of the main classes of immunoglobulins were accompanied by an increase in the level of specific IgGs to the F1 within 6 months after immunization. In the same period, a significant increase in the production of cytokines, as well as significant changes in terms of the subpopulation composition of the vaccinated blood.Conclusion. It is necessary to note the importance of studying of the human immune status in 1–3 months after plague vaccination as this period coincides with potentially dangerous season from epidemiological point of view. Nevertheless, much important role for improvement of tactics of the specific prevention measures plays the data received after the revaccination.
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MITCHELL, MAIRI C., THOMAS TZELOS, IAN HANDEL, HAMISH E. G. MCWILLIAM, JANE E. HODGKINSON, ALASDAIR J. NISBET, VITALIY O. KHARCHENKO, STEWART T. G. BURGESS, and JACQUELINE B. MATTHEWS. "Development of a recombinant protein-based ELISA for diagnosis of larval cyathostomin infection." Parasitology 143, no. 8 (May 13, 2016): 1055–66. http://dx.doi.org/10.1017/s0031182016000627.
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SUMMARYCyathostomins are ubiquitous nematodes of horses. Once ingested, they can spend a substantial time as encysted larvae in the intestinal wall. The larvae can comprise up to 90% of the total burden, with up to several million worms reported in individuals. These stages can emerge in large numbers to cause life-threatening colitis. Direct methods for detection of encysted larval burdens in live horses do not exist. Previously, two antigen complexes were identified as promising markers for infection. A component of these, cyathostomin gut associated larval antigen-1 (Cy-GALA-1), was identified following immunoscreening of a complementary DNA library. Serum immunoglobulin G(T) (IgG(T)) responses to Cy-GALA-1 were shown to inform on larval infection. Sequence analysis of polymerase chain reaction products amplified from individual worms indicated that Cy-GALA-1 was derived from Cyathostomum pateratum. As cyathostomin infections always comprise multiple species, a diagnostic test must account for this. Here, segments of the Cy-gala gene were isolated from four common species, Cyathostomum catinatum, Cylicocyclus ashworthi, Cylicostephanus goldi and Cylicostephanus longibursatus, and the associated proteins expressed in recombinant form. The specificity and immunogenicity of each protein was confirmed. Each protein was assessed by enzyme linked immuno sorbent assay (ELISA) for its ability for informing on the presence of encysted larval infection and the level of burden.
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Gorringe, Andrew R., Stephen Taylor, Charlotte Brookes, Mary Matheson, Michelle Finney, Moyra Kerr, Michael Hudson, et al. "Phase I Safety and Immunogenicity Study of a Candidate Meningococcal Disease Vaccine Based on Neisseria lactamica Outer Membrane Vesicles." Clinical and Vaccine Immunology 16, no. 8 (June 24, 2009): 1113–20. http://dx.doi.org/10.1128/cvi.00118-09.
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ABSTRACT Natural immunity to meningococcal disease in young children is associated epidemiologically with carriage of commensal Neisseria species, including Neisseria lactamica. We have previously demonstrated that outer membrane vesicles (OMVs) from N. lactamica provide protection against lethal challenge in a mouse model of meningococcal septicemia. We evaluated the safety and immunogenicity of an N. lactamica OMV vaccine in a phase I placebo-controlled, double-blinded clinical trial. Ninety-seven healthy young adult male volunteers were randomized to receive three doses of either an OMV vaccine or an Alhydrogel control. Subsequently, some subjects who had received the OMV vaccine also received a fourth dose of OMV vaccine, 6 months after the third dose. Injection site reactions were more frequent in the OMV-receiving group, but all reactions were mild or moderate in intensity. The OMV vaccine was immunogenic, eliciting rises in titers of immunoglobulin G (IgG) against the vaccine OMVs, together with a significant booster response, as determined by an enzyme-linked immunosorbent assay. Additionally, the vaccine induced modest cross-reactive immunity to six diverse strains of serogroup B Neisseria meningitidis, including IgG against meningococcal OMVs, serum bactericidal antibodies, and opsonophagocytic activity. The percentages of subjects showing ≥4-fold rises in bactericidal antibody titer obtained were similar to those previously reported for the Norwegian meningococcal OMV vaccine against the same heterologous meningococcal strain panel. In conclusion, this N. lactamica OMV vaccine is safe and induces a weak but broad humoral immune response to N. meningitidis.
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Sudol, M., and H. Hanafusa. "Cellular proteins homologous to the viral yes gene product." Molecular and Cellular Biology 6, no. 8 (August 1986): 2839–46. http://dx.doi.org/10.1128/mcb.6.8.2839.
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We raised antibodies in rabbits against the amino-terminal portion of the viral yes protein produced in bacteria with the use of an expression vector based on the lac operon. The anti-yes serum thus obtained precipitated P90gag-yes from Yamaguchi 73 virus-transformed chicken embryo fibroblasts, and this immunoprecipitation was blocked by the purified antigen. The anti-yes serum did not recognize viral src, fps, or fgr proteins. Affinity-purified anti-yes immunoglobulin G (IgG) precipitated two proteins of 59 and 62 kilodaltons from lysates of normal chicken embryo fibroblasts. Two-dimensional tryptic peptide mapping showed that these proteins are closely related to P90gag-yes and that they are different from pp60c-src. Similar to P90gag-yes, the 59- and 62-kilodalton proteins were phosphorylated exclusively on tyrosine in an in vitro kinase reaction, whereas in vivo they were phosphorylated on serine and, to a lesser extent, on tyrosine as well. Expression of the 59- and 62-kilodalton proteins, determined by the immune complex kinase assay, was relatively high in brain, retina, kidney, and liver. The presence in normal chicken embryo fibroblasts and in chicken kidney of two transcripts, 3.7 and 3.9 kilobases in length, that hybridize with a yes-specific DNA probe, as well as the two proteins recognized by anti-yes IgG, suggests either differential splicing of cellular yes gene transcripts or the existence of another yes-related gene.
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Sudol, M., and H. Hanafusa. "Cellular proteins homologous to the viral yes gene product." Molecular and Cellular Biology 6, no. 8 (August 1986): 2839–46. http://dx.doi.org/10.1128/mcb.6.8.2839-2846.1986.
Full textAbstract:
We raised antibodies in rabbits against the amino-terminal portion of the viral yes protein produced in bacteria with the use of an expression vector based on the lac operon. The anti-yes serum thus obtained precipitated P90gag-yes from Yamaguchi 73 virus-transformed chicken embryo fibroblasts, and this immunoprecipitation was blocked by the purified antigen. The anti-yes serum did not recognize viral src, fps, or fgr proteins. Affinity-purified anti-yes immunoglobulin G (IgG) precipitated two proteins of 59 and 62 kilodaltons from lysates of normal chicken embryo fibroblasts. Two-dimensional tryptic peptide mapping showed that these proteins are closely related to P90gag-yes and that they are different from pp60c-src. Similar to P90gag-yes, the 59- and 62-kilodalton proteins were phosphorylated exclusively on tyrosine in an in vitro kinase reaction, whereas in vivo they were phosphorylated on serine and, to a lesser extent, on tyrosine as well. Expression of the 59- and 62-kilodalton proteins, determined by the immune complex kinase assay, was relatively high in brain, retina, kidney, and liver. The presence in normal chicken embryo fibroblasts and in chicken kidney of two transcripts, 3.7 and 3.9 kilobases in length, that hybridize with a yes-specific DNA probe, as well as the two proteins recognized by anti-yes IgG, suggests either differential splicing of cellular yes gene transcripts or the existence of another yes-related gene.
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Mok, Hoyin, Sujin Lee, Thomas J. Utley, Bryan E. Shepherd, Vasiliy V. Polosukhin, Martha L. Collier, Nancy L. Davis, Robert E. Johnston, and James E. Crowe. "Venezuelan Equine Encephalitis Virus Replicon Particles Encoding Respiratory Syncytial Virus Surface Glycoproteins Induce Protective Mucosal Responses in Mice and Cotton Rats." Journal of Virology 81, no. 24 (October 10, 2007): 13710–22. http://dx.doi.org/10.1128/jvi.01351-07.
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ABSTRACT Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-γ)-secreting T cells in the lungs and spleen, as measured by reaction with an H-2K d -restricted CD8+ T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.
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Manohar, Muniraj, Donald O. Baumann, Nicolaas A. Bos, and John J. Cebra. "Gut Colonization of Mice withactA-Negative Mutant of Listeria monocytogenesCan Stimulate a Humoral Mucosal Immune Response." Infection and Immunity 69, no. 6 (June 1, 2001): 3542–49. http://dx.doi.org/10.1128/iai.69.6.3542-3549.2001.
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ABSTRACT We used Listeria monocytogenes, a gram-positive, facultative intracellular bacterium, to study the gut mucosal immune responses following oral infection. We employed a germfree (GF) mouse model to try to accentuate the development of a humoral mucosal immune response in the gut, and we used oral colonization with one of the mutants, actA-negative (ΔactA) L. monocytogenes, to restrict infection largely to the gut. The ΔactA mutant was able to colonize the intestinal mucosa of formerly GF mice for long periods of time without causing disease while eliciting secretory immunoglobulin A (IgA) responses, as evidenced by gut tissue fragment culture assays. Flow cytometric analyses and immunohistochemical methods showed the development of only minimal germinal center reactions (GCR) in Peyer's patches and more robust GCR in mesenteric lymph nodes. Pronounced increases in total (natural) IgA production occurred in gut tissues by day 7 and were maintained for up to 90 days. Levels of specific IgA were modest in gut tissues on day 14, increased until day 76, and stabilized at day 90. We also observed a significant rise in serum IgA and IgG1 levels following oral infection by listeriae. Upon colonization, the organisms mainly infected the intestines and intestinal lumen, and we only sporadically observed few colony-forming bacteria in the liver and spleen. We observed a marked rise in IgA-secreting cells, including listeria-specific IgA antibody-secreting cells, in the lamina propria of the small intestine by enzyme-linked immunospot assays. To ascertain whether some of the IgA was specific for listeriae, we performed Western blot analysis to test the reactivity of IgA from fragment cultures to antigens in sonicates of L. monocytogenes. We detected IgA binding to antigenic proteins with molecular masses of 96, 60, 40, and 14 kDa in theListeria sonicates.
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Warkentin, Theodore E., Richard M. Jay, Michael Makris, and John G. Kelton. "Platelet-Activating Anti-Platelet Factor 4/Polyanion Antibodies without Preceding Heparin Therapy: A Transient Autoimmune Disorder Resembling Heparin-Induced Thrombocytopenia (“Spontaneous HIT”)." Blood 108, no. 11 (November 16, 2006): 1047. http://dx.doi.org/10.1182/blood.v108.11.1047.1047.
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Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder with autoimmune features: its target antigen is a “self” protein, platelet factor 4 (PF4), that is conformationally modified in the presence of heparin or certain other polyanions. A central dogma in HIT is that the antibodies are invariably triggered by treatment with heparin. We report four patients who developed an acute illness strongly resembling immune HIT despite the absence of any preceding heparin administration [Table 1]. Various inflammatory or invasive events were documented during the two-week period prior to each patient’s acute illness, suggesting that factors other than heparin can trigger an immune response against PF4/polyanion complexes. Following onset of their HIT-like illness, three of the patients received unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to treat proven or suspected thrombosis, which precipitated abrupt platelet count falls in all. Serum from all four patients contained antibodies serologically indistinguishable from those causing HIT, namely platelet-activating immunoglobulin G (IgG) recognizing PF4 bound to heparin or polyvinyl sulfonate [Table 2]. Two patients died from thrombosis; in the two survivors, antibodies became undetectable during follow-up, consistent with the transient nature of the anti-PF4/heparin immune response reported in HIT. Conclusion: These four patient cases suggest that on rare occasions a transient prothrombotic autoimmune disorder strongly resembling immune HIT can occur, “spontaneous HIT”. Table 1. Clinical features: 4 patients with “spontaneous HIT” Case Age M/F Platelet count nadir (× 10^9^/L) Sequelae Event(s) in preceding two weeks * UFH or LMWH were only given for proven or suspected thrombosis after “spontaneous HIT” disorder was established; DIC = disseminated intravascular coagulation 1 69 M 17 (no heparin given) Limb artery thromboses (amputations); pulmonary embolism; DIC; fatal myocardial infarction Ampicillin (sore tooth); corticosteroid injection into wrist 2 40 F 175 (pre-UFH*); 59 (post-UFH*) Stroke; limb artery thrombosis (amputation) Incision & draining procedures (recurrent groin cyst) 3 69 F 33 (pre-UFH*); 11 (post-UFH*) Bilateral adrenal infarction; digital infarcts; deep-vein thrombosis; DIC Knee replacement surgery 4 24 F 301 (pre-LMWH*); 62 (post-LMWH*) Acute systemic reaction after LMWH Pneumonia Table 2. Serologic features: 4 patients with “spontaneous HIT” Case Maximum serotonin release (0.1-0.3 U/mL UFH) (N<10%) Serotonin release (Fc receptor-blocking monoclonal antibody) Serotonin release (100 U/mL UFH) Anti-PF4/H ELISA (IgG) (N<0.450 OD U)* Anti-PF4/polyanion ELISA, GTI (N<0.400 OD U)* * >80% inhibition in presence of 100 U/mL UFH was seen with all 4 blood samples and in both ELISAs (not shown) 1 99% 1% 0% 2.028 2.722 2 95% 0% 0% 2.909 2.284 3 100% 0% 0% 1.888 2.950 4 80% 0% 0% 1.866 2.622
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Diamant, S. C., D. G. Gall, and R. B. Scott. "The effect of intestinal anaphylaxis on postprandial motility in the rat." Canadian Journal of Physiology and Pharmacology 67, no. 10 (October 1, 1989): 1326–30. http://dx.doi.org/10.1139/y89-211.
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We have previously utilized a rat animal model to demonstrate that challenge of fasted sensitized animals with antigenic food protein is associated with diarrhea and altered intestinal myoelectric and motor activities. In this paper we examine the effect of intestinal anaphylaxis on postprandial motility in the same animal model. Hooded Lister rats were sensitized (S) by intraperitoneal injection of 10 μg egg albumin (i.e., antigen (Ag)) and compared with sham-sensitized controls (C). Seven days later, three bipolar jejunal electrodes and a jejunostomy tube, for motility recording and Ag administration, were implanted. On day 14, intestinal myoelectric and motor activities were measured in fed animals before and after intraluminal challenge with Ag (100 mg egg albumin/0.5 mL saline) or placebo (P; 0.5 mL saline). Specific immunoglobulin E serum titres were [Formula: see text] in S animals, while C animals showed no response. None of the C animals challenged with P or Ag and none of the S animals challenged with P defecated after challenge, but all the S animals challenged with Ag developed diarrhea (p < 0.001). There was no disruption or alteration of the fed motility pattern in C animals challenged with P or Ag, or S animals challenged with P. In fed S animals challenged with Ag the fed motility pattern persisted, but there was a significant (p < 0.05) increase in the number of high-amplitude aborally propagating clustered contractions, where the phasic contractile activity was superimposed on a sustained tonic elevation of intraluminal pressure lasting 5–10 s. In this animal model, an immune-mediated reaction to food protein was associated with diarrhea and alteration of postprandial intestinal motility.Key words: small intestine, motility, myoelectric activity, immunoglobulin E, anaphylaxis, immediate hypersensitivity, gut allergy, food allergy.
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Baccili, Camila Costa, Natália Meirelles Sobreira, Bruno Toledo Silva, Edviges Maristela Pituco, and Viviane Gomes. "Interface between Maternal Antibodies and Natural Challenge for Bovine Viral Diarrhea Virus (BVDV) in Holstein Heifers." Acta Scientiae Veterinariae 44, no. 1 (March 19, 2018): 6. http://dx.doi.org/10.22456/1679-9216.81177.
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Background: Newborn calves are agammaglobulinemic, immunosuppressed and immunologically immature at birth. The passive immune transfer is fundamental to protect calves against pathogens. The decay of maternal antibodies precedes the immune maturation at puberty enhancing the susceptibility of calves to infections caused by BVDV. Then, the objective of this research was to evaluate the interface between passive and active immunity for Bovine Viral Diarrhea Virus (BVDV) in Holstein dairy heifers in the first 13 months of age to detect susceptibility periods and establish prophylactic measures on prevention of Bovine Viral Diarrhea.Materials, Methods & Results: Sera were analyzed from 585 heifers by serum neutralization (SN) and enzyme linked immunosorbent assay (ELISA) for the p80 protein of BVDV. Heifers were categorized according to their age by the month of life. Heifers were seropositive (100%) from 1st to 13th. Median of neutralizing antibodies (Ab) titers obtained from 1st up to 13th month were 316.2; 125.9; 63.1; 50.1; 50.1; 39.8; 63.1; 63.1; 39.8; 79.4, 100.0; 74.4; and 79.4, respectively. The neutralizing Ab titers obtained in 1st month were different of the values observed from 2nd until 13th (P < 0.001), furthermore the Ab titers from 2nd month was statistical different of 4th (P = 0.01) and 6th (P = 0.05). The frequencies (%) of positive heifers for p80 from 1st up to 13th were 24.7; 18.2; 10.4; 11.8; 73.3; 73.8; 72.4; 58.1; 45.9; 48.4; 46.2; 43.8 and 61.5, respectively. The correlation observed for neutralizing Ab titers and age was negative and weak (ρ= -0.299; P < 0.001). On the other hand, the correlation between positive heifers for p80 and age was positive and moderate (ρ= 0.319; P < 0.001).Discussion: The newborn calves had higher titers of neutralizing antibodies than other age groups and some calves were seropositive for the p80 protein. This profile points to the transfer of maternal antibodies produced by vaccination and/or natural exposure to BVDV. The exposure of the cows to the inactivated and live virus stimulates the production of neutralizing antibodies to the structural proteins of the virus, particularly the glycoprotein E2, detected by the serum neutralization test. The titers of serum neutralizing antibodies and the frequencies of seropositive for p80 protein decreased gradually from the first to the 4-6th month of life due to the metabolization of maternal immunoglobulins acquired by ingestion of colostrum. Frequencies of seropositive animals for protein p80 increased from the fifth month of life, which is the same moment that was observed declined of neutralizing maternal antibody titers. The phase of higher frequency of p80 positive animals coincides with greater rates of Babesiosis and Anaplasmosis. This history could justify the importance of the BVDV immunodepression as a risk factor for concomitant diseases. In general, the neutralizing antibody titers increased after the peaks of positive reactions to the p80 protein, but this moment coincides with the primo-vaccination in calves. Therefore, it is not possible to state the origin of these antibodies. Correlations between ages and serologic tests are consistent with previous data reporting the decrease in antibody titers and increase of seropositive animals for p80 protein, from the first month of life to puberty. In conclusion, maternal neutralizing Ab titers had gradual decreased whereas the frequency of positive heifers for p80 had increased values. The inversion observed between the maternal antibody titers and the increase in antibody for p80 indicates the moment of greatest risk for natural infections caused by BVDV.
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Sizyakina, L. P., I. I. Andrreeva, and A. I. Sergeeva. "Immunotropic effects of mesotherapy used for correction of age-related skin changes." Medical Immunology (Russia) 23, no. 3 (June 22, 2021): 585–92. http://dx.doi.org/10.15789/1563-0625-ieo-2205.
Full textAbstract:
Rapid progression of aesthetic medicine is a distinctive feature of present decade. In this area, leading position is taken by injection cosmetology, which is associated with an opportunity of pathogenetic approach to resolution of cosmetic problems primarily caused by skin aging. The most commonly used mesotherapy drugs, along with hyaluronic acid, are vitamins, amino acids, and microelements. Skin aging is associated with quantitative and functional changes in the local immune cell populations. In this case, it is rational to assume distinct effects of peptide complexes upon functional potential of immunocompetent cells. The aim of this study was to analyze time-dependent changes of some immune parameters after mesotherapy with a complex of hyaluronic acid and peptides. The observation group consisted of 26 women who received their course of mesotherapy for the first time. Objective instrumental evaluation of the effect with Aramo Smart Lite device showed that, after mesotherapy, the skin quality was significantly improving in comparison with pre-treatment conditions, due to decreased relief of skin creases and wrinkles, with a tendency for reduction of this effect six months later. When comparing the results of immunological testing in the patients after the course of treatment with the data before starting the therapy, we have found redistribution in the lymphoid cell populations, i.e., increased proportion of T-lymphocytes, decreased amounts of B cells, and CD16+ natural killers. Declined numbers of T-lymphocytes expressing early activation marker were associated with increased proportion of peripheral Treg lymphocytes. We have also detected activation of antibody production which manifested as increased levels of all major classes of serum immunoglobulins. Enhanced spontaneous oxidative activity of neutrophils was also noted. The results of immunological monitoring showed that, three months post-treatment, none of the quantitative and functional parameters of immunity was changed, as compared with the results obtained immediately after ending the mesotherapy. Six months later, however, all these indexes returned to their initial positions assessed before the cosmetic procedure. The changes in systemic immune response following mesotherapy with peptide complexes affect the mechanisms of both innate and acquired immunity, including differentiation of lymphocytes, their regulatory functions and activation potential, and provide modulation of effector reactions. Complete restoration of initial immune parameters is observed within six months.
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Luke, Jason J., John D. Powderly, Jaime R. Merchan, Minal A. Barve, Andrew N. Hotson, Mehrdad Mobasher, Long Kwei, et al. "Immunobiology, preliminary safety, and efficacy of CPI-006, an anti-CD73 antibody with immune modulating activity, in a phase 1 trial in advanced cancers." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2505. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2505.
Full textAbstract:
2505 Background: CPI-006 inhibits CD73, a nucelotidase that converts AMP to adenosine and functions as a lymphocyte adhesion molecule. CPI-006 is a humanized IgG1 FcγR binding-deficient antibody that binds to CD73+ T and B lymphocytes leading to activation of B cells and expression of CD69. This study investigates the immunobiology, safety, and efficacy of CPI-006 monotherapy and in combination with CPI-444, an adenosine A2A receptor (A2AR) antagonist (NCT03454451). Methods: Patients with relapsed solid tumors were treated in a 3 + 3 escalation study with 1, 3, 6 or 12 mg/kg CPI-006 (Q3w IV infusion) monotherapy or in combination with CPI-444 (100 mg, PO, BID). Flow cytometry was performed on blood samples for lymphocyte subset analysis and receptor occupancy. Results: 17 patients were enrolled; 11 monotherapy and 6 combination. CPI-006 was associated with Grade 1 infusion reactions occuring within 30 minutes of the first infusion and were eliminated by premedication with non-steroidals. No DLTs with monotherapy or combination therapy were seen. Receptor occupancy on peripheral lymphocytes was maintained for the full dosing interval at 12 mg/kg. Pharmacodynamic effects suggesting immune modulation were observed within 1 hr of infusion at all dose levels and included a decrease in peripheral blood CD73pos B cells (mean reduction 86%, p < 0.05), increased CD73neg CD4 T cells (mean increase 37%, p < 0.01), and decreased CD8 T cells (mean reduction 20%, p < 0.01) compared to baseline. Overall, CD4:CD8 ratios were increased. Tumor regression was observed in a prostate cancer patient after 5 cycles of monotherapy at 6 mg/kg; peripheral B cells partially returned by the second cycle and reached a new homeostatic level through subsequent cycles. No change in serum immunoglobulins were observed. Conclusions: CPI-006 induces a rapid lymphocyte redistribution, including a transient reduction of circulating CD73pos B cells suggesting redistribution to lymphoid tissues, and an increased CD4:CD8 ratio, consistent with increased TH effector/memory cells in the blood. The treatment has been well-tolerated, and there is early evidence of anti-tumor activity of CPI-006 monotherapy. Clinical trial information: NCT03454451.
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Quigg, Richard J., Chun He, Alice Lim, Dawn Berthiaume, Jessy J. Alexander, Damian Kraus, and V. Michael Holers. "Transgenic Mice Overexpressing the Complement Inhibitor Crry as a Soluble Protein Are Protected from Antibody-induced Glomerular Injury." Journal of Experimental Medicine 188, no. 7 (October 5, 1998): 1321–31. http://dx.doi.org/10.1084/jem.188.7.1321.
Full textAbstract:
Complement receptor 1–related gene/protein y (Crry) is a potent murine membrane complement regulator that inhibits classical and alternative pathway C3 convertases. In nephrotoxic serum (NTS) nephritis, injected antibodies (Abs) bind to glomeruli, leading to complement activation and subsequent glomerular injury and albuminuria. To study the phenotypic effects of continuous complement pathway blockade, transgenic mice were created that express recombinant soluble (rs) Crry directed by the broadly active and heavy metal-inducible metallothionein-I promoter. One transgenic line expressing high levels of rsCrry was propagated. Serum rsCrry levels were 18.7 ± 2.7 μg/ml (n = 5) at basal level and increased to 118.1 ± 20.6 μg/ml 4 d after addition of zinc to the drinking water. By reverse transcription polymerase chain reaction (RT-PCR), transgene messenger (m)RNA was present in liver, kidney, brain, lung, and spleen, but not in heart. By in situ RT-PCR analysis of kidneys, transgene mRNA was widely expressed both in renal glomeruli and tubules. Urinary excretion of rsCrry was 113.4 ± 22.4 μg/ml with a fractional excretion relative to creatinine of 13.2 ± 2.7%, consistent with local renal production of rsCrry and secretion into urine. The founder and all transgene positive adult animals have remained healthy with no mortality or apparent phenotypic abnormalities, including infection or immune complex disease. To determine whether rsCrry blocked complement-mediated injury, NTS nephritis was induced by injection of NTS immunoglobulin (Ig)G, followed by an 18-h urine collection to quantitate the excretion of albumin as a measure of glomerular injury. In transgene-negative littermates (n = 15), transgene-positive animals (n = 10), and transgene-positive animals fed zinc (n = 10), albuminuria was 4,393 ± 948, 1,783 ± 454, and 1,057 ± 277 μg/mg creatinine, respectively (P < 0.01 by ANOVA). Glomerular C3 was evident by immunofluorescence staining in 12/15 transgene-negative animals, but in none of the transgene-positive animals fed zinc. Thus, we have produced the first transgenic animals that overexpress a soluble C3 convertase inhibitor. rsCrry expression markedly ameliorates an Ab-induced disease model in vivo. These results support the hypothesis that continuous complement inhibition at the C3 convertase step is feasible and effective in complement-mediated injury states.