Статті в журналах: "Neonatal immune tolerance"

1

Tai, Denise S., Chuhong Hu, and Gerald S. Lipshutz. "Immune tolerance induction with neonatal gene therapy." Journal of the American College of Surgeons 217, no. 3 (September 2013): S136. http://dx.doi.org/10.1016/j.jamcollsurg.2013.07.316.

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2

Shi, Yimin, Rustom Falahati, and Karin ML Gaensler. "Tolerance Induction by Neonatal Gene Delivery." Blood 112, no. 11 (November 16, 2008): 4628. http://dx.doi.org/10.1182/blood.v112.11.4628.4628.

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Abstract Advances in the design and efficiency of gene delivery vectors have enabled the initiation of clinical trials in gene therapy for genetic and other disorders. However, the development of inhibitory immune responses to vector antigens and to therapeutic proteins remains an obstacle. Efforts to limit these immune responses by immunosuppressive and immuno-modulatory approaches have met with limited success. Our approach is to deliver and express viral vectors early in immune ontogeny and thereby induce immune tolerance to both vectors and therapeutic proteins. We have previously shown that in utero delivery of AAV-2 vectors produces lifelong gene expression without immune responses, and that augmented levels of gene expression are achieved with re-administration of AAV vectors. Because fetal injections are limited by technical issues, our current focus is to use a neonatal model for defining the critical period when tolerance to vector and transgene may be achieved by primary injection. We are also exploring mechanisms of tolerance induction to neo-antigens. We have delivered AAV serotypes 1 and 8 with higher transduction efficiencies than AAV-2, to assess the expression levels, duration, and tissue distribution of luciferase by semi-quantitative longitudinal in vivo bioluminescence assays. In both C57BL/6 and BALB/c strains, neonatal injection of AAV1-Luc or AAV8-Luc by either IP, IV or IT routes produces lifelong gene expression. After IP injection at day 1–2 of life, gene expression increases 10–20 fold over the next several months. Highest levels of expression were achieved by IP injection, with lowest levels observed after IV injection. Injection of AAV1-Luc achieved higher levels of luciferase expression than did injection of AAV8- Luc. In contrast to the localized distribution of AAV1 mediated luciferase expression in the injected area, widespread, systemic expression of luciferase mediated by AAV8 after neonatal delivery is observed, regardless of the route of delivery. The effect of this altered tropism on gene expression levels and tolerance induction is being examined. In both C57BL/6 and BALB/c mice, IP injection of AAV1-Luc or AAV8-Luc at 1–2 days, 1 week, 2 weeks, or 3 weeks of age produced lifelong expression of luciferase and resulted in increasing levels of antibody responses against AAV1 or AAV8 with increasing age at primary injection. Antibody titers to AAV1 or AAV8 in animals injected at day 1–2 of life were comparable to background levels in uninjected animals. In C57BL/6 mice receiving a primary injection of AAV8-Luc, secondary injection of AAV8-Luc boosted the antibody response to AAV8 in the animals first injected at 1 week, 2 weeks or 3 weeks, but not in the animals injected at 1–2 day of life. We are currently exploring whether augmented expression with re-administration of AAV vectors in adult animals is due to an active process such as tolerance, partial tolerance or anergy. Developing strategies for the induction of tolerance to gene delivery vectors and therapeutic gene products will be an important advance for gene therapy for genetic and other disorders.

3

Ohsaki, Asa, Nicholas Venturelli, Tess M. Buccigrosso, Stavroula K. Osganian, John Lee, Richard S. Blumberg, and Michiko K. Oyoshi. "Maternal IgG immune complexes induce food allergen–specific tolerance in offspring." Journal of Experimental Medicine 215, no. 1 (November 20, 2017): 91–113. http://dx.doi.org/10.1084/jem.20171163.

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The role of maternal immune responses in tolerance induction is poorly understood. To study whether maternal allergen sensitization affects offspring susceptibility to food allergy, we epicutaneously sensitized female mice with ovalbumin (OVA) followed by epicutaneous sensitization and oral challenge of their offspring with OVA. Maternal OVA sensitization prevented food anaphylaxis, OVA-specific IgE production, and intestinal mast cell expansion in offspring. This protection was mediated by neonatal crystallizable fragment receptor (FcRn)–dependent transfer of maternal IgG and OVA immune complexes (IgG-IC) via breast milk and induction of allergen-specific regulatory T (T reg) cells in offspring. Breastfeeding by OVA-sensitized mothers or maternal supplementation with IgG-IC was sufficient to induce neonatal tolerance. FcRn-dependent antigen presentation by CD11c+ dendritic cells (DCs) in offspring was required for oral tolerance. Human breast milk containing OVA-IgG-IC induced tolerance in humanized FcRn mice. Collectively, we demonstrate that interactions of maternal IgG-IC and offspring FcRn are critical for induction of T reg cell responses and control of food-specific tolerance in neonates.

4

Nivsarkar, Megha S., Suzanne M. K. Buckley, Alan L. Parker, Dany Perocheau, Tristan R. McKay, Ahad A. Rahim, Steven J. Howe, and Simon N. Waddington. "Evidence for Contribution of CD4+CD25+ Regulatory T Cells in Maintaining Immune Tolerance to Human Factor IX following Perinatal Adenovirus Vector Delivery." Journal of Immunology Research 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/397879.

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Following fetal or neonatal gene transfer in mice and other species immune tolerance of the transgenic protein is frequently observed; however the underlying mechanisms remain largely undefined. In this study fetal and neonatal BALB/c mice received adenovirus vector to deliver human factor IX (hFIX) cDNA. The long-term tolerance of hFIX was robust in the face of immune challenge with hFIX protein and adjuvant but was eliminated by simultaneous administration of anti-CD25+ antibody. Naive irradiated BALB/c mice which had received lymphocytes from donors immunised with hFIX developed anti-hFIX antibodies upon immune challenge. Cotransplantation with CD4+CD25+ cells isolated from neonatally tolerized donors decreased the antibody response. In contrast, cotransplantation with CD4+CD25− cells isolated from the same donors increased the antibody response. These data provide evidence that immune tolerance following perinatal gene transfer is maintained by a CD4+CD25+ regulatory population.

5

Mattis, Virginia B., Dustin R. Wakeman, Colton Tom, Hemraj B. Dodiya, Sylvia Y. Yeung, Andrew H. Tran, Ksenija Bernau, et al. "Neonatal immune-tolerance in mice does not prevent xenograft rejection." Experimental Neurology 254 (April 2014): 90–98. http://dx.doi.org/10.1016/j.expneurol.2014.01.007.

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6

Černý, Viktor, Olga Novotná, Petra Petrásková, Kateřina Hudcová, Kristýna Boráková, Ludmila Prokešová, Libuše Kolářová, and Jiří Hrdý. "Lower Functional and Proportional Characteristics of Cord Blood Treg of Male Newborns Compared with Female Newborns." Biomedicines 9, no. 2 (February 9, 2021): 170. http://dx.doi.org/10.3390/biomedicines9020170.

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Understanding the early events involved in the induction of immune tolerance to harmless environmental antigens and microbiota compounds could reveal potential targets for allergic disease therapy or prevention. Regulatory T cells (Treg), particularly induced Treg (iTreg), are crucial for the induction and maintenance of tolerance against environmental antigens including allergens. A decrease in the number and/or function of Treg or iTreg could represent an early predictor of allergy development. We analyzed proportional and functional properties of Treg in the cord blood of children of allergic mothers (neonates at high risk of allergy development) and healthy mothers (neonates with relatively low risk of allergy development). We observed a higher number of induced Treg in the cord blood of females compared to males, suggesting an impaired capacity of male immunity to set up tolerance to allergens, which could contribute to the higher incidence of allergy observed in male infants. The decreased proportion of iTreg in cord blood compared with maternal peripheral blood documents the general immaturity of the neonatal immune system. We observed a positive correlation in the demethylation of the Treg-specific demethylated region (TSDR) and the proportion of Treg in cord blood. Our data suggest that immaturity of the neonatal immune system is more severe in males, predisposing them to increased risk of allergy development.

7

Secher, Thomas, Delphine Payros, Camille Brehin, Michele Boury, Claude Watrin, Marion Gillet, Isabelle Bernard-Cadenat, et al. "Oral Tolerance Failure upon Neonatal Gut Colonization with Escherichia coli Producing the Genotoxin Colibactin." Infection and Immunity 83, no. 6 (March 30, 2015): 2420–29. http://dx.doi.org/10.1128/iai.00064-15.

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The intestinal barrier controls the balance between tolerance and immunity to luminal antigens. When this finely tuned equilibrium is deregulated, inflammatory disorders can occur. There is a concomitant increase, in urban populations of developed countries, of immune-mediated diseases along with a shift inEscherichia colipopulation from the declining phylogenetic group A to the newly dominant group B2, including commensal strains producing a genotoxin called colibactin that massively colonized the gut of neonates. Here, we showed that mother-to-offspring early gut colonization by colibactin-producingE. coliimpairs intestinal permeability and enhances the transepithelial passage of luminal antigen, leading to an increased immune activation. Functionally, this was accompanied by a dramatic increase in local and systemic immune responses against a fed antigen, decreased regulatory T cell population, tolerogenic dendritic cells, and enhanced mucosal delayed-type hypersensitivity response. Conversely, the abolition of colibactin expression by mutagenesis abrogates the alteration of oral tolerance induced by neonatal colonization byE. coli. In conclusion, the vertical colonization byE. coliproducing the genotoxin colibactin enhances intestinal translocation and subsequently alters oral tolerance. Thus, early colonization byE. colifrom the newly dominant phylogenetic group B2, which produces colibactin, may represent a risk factor for the development of immune-mediated diseases.

8

Elahi, Shokrollah. "Neonatal and Children’s Immune System and COVID-19: Biased Immune Tolerance versus Resistance Strategy." Journal of Immunology 205, no. 8 (August 21, 2020): 1990–97. http://dx.doi.org/10.4049/jimmunol.2000710.

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9

Matsui, Hideto, Masaru Shibata, Brian Brown, Andrea Labelle, Carol Hegadorn, Chandler Andrews, Marinee Chuah, et al. "A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells." Blood 114, no. 3 (July 16, 2009): 677–85. http://dx.doi.org/10.1182/blood-2009-03-202267.

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Abstract Under certain instances, factor VIII (FVIII) stimulates an immune response, and the resulting neutralizing antibodies present a significant clinical challenge. Immunotherapies to re-establish or induce long-term tolerance would be beneficial, and an in-depth knowledge of mechanisms involved in tolerance induction is essential to develop immune-modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunologic tolerance to FVIII in hemophilia A mice. We used lentiviral vectors to deliver the canine FVIII transgene to neonatal hemophilic mice and demonstrated that induction of long-term FVIII tolerance could be achieved. Hemophilia A mice are capable of mounting a robust immune response to FVIII after neonatal gene transfer, and tolerance induction is dependent on the route of delivery and type of promoter used. High-level expression of FVIII was not required for tolerance induction and, indeed, tolerance developed in some animals without evidence of detectable plasma FVIII. Tolerance to FVIII could be adoptively transferred to naive hemophilia recipient mice, and FVIII-stimulated splenocytes isolated from tolerized mice expressed increased levels of interleukin-10 and decreased levels of interleukin-6 and interferon-γ. Finally, induction of FVIII tolerance mediated by this protocol is associated with a FVIII-expandable population of CD4+CD25+Foxp3+ regulatory T cells.

10

Tourneur, Emilie, and Cecilia Chassin. "Neonatal Immune Adaptation of the Gut and Its Role during Infections." Clinical and Developmental Immunology 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/270301.

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The intestinal tract is engaged in a relationship with a dense and complex microbial ecosystem, the microbiota. The establishment of this symbiosis is essential for host physiology, metabolism, and immune homeostasis. Because newborns are essentially sterile, the first exposure to microorganisms and environmental endotoxins during the neonatal period is followed by a crucial sequence of active events leading to immune tolerance and homeostasis. Contact with potent immunostimulatory molecules starts immediately at birth, and the discrimination between commensal bacteria and invading pathogens is essential to avoid an inappropriate immune stimulation and/or host infection. The dysregulation of these tight interactions between host and microbiota can be responsible for important health disorders, including inflammation and sepsis. This review summarizes the molecular events leading to the establishment of postnatal immune tolerance and how pathogens can avoid host immunity and induce neonatal infections and sepsis.

11

McCusker, Christine. "Teaching tolerance: using the neonatal immune system to prevent allergic asthma." Expert Review of Clinical Immunology 4, no. 4 (July 2008): 429–32. http://dx.doi.org/10.1586/1744666x.4.4.429.

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12

Levan, Sophia R., Kei E. Fujimura, Din L. Lin, Kelsey A. Stamnes, Edward M. Zoratti, Nicholas W. Lukacs, Dennis Ownby, Homer A. Boushey, Christine Cole Johnson та Susan V. Lynch. "Neonatal gut-microbiome-derived 12,13 DiHOME suppresses immune tolerance via PPARγ". Journal of Allergy and Clinical Immunology 141, № 2 (лютий 2018): AB206. http://dx.doi.org/10.1016/j.jaci.2017.12.651.

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13

Lambrecht, Bart N. "FcRn is mother’s milk to allergen tolerance." Journal of Experimental Medicine 215, no. 1 (December 1, 2017): 1–3. http://dx.doi.org/10.1084/jem.20172022.

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In this issue Ohsaki et al. (https://doi.org/10.1084/jem.20171163) explain how breastfeeding can prevent the onset of food allergies in offspring by instructing T reg formation via neonatal Fc receptor (FcRn)–mediated transfer and uptake of allergen-containing IgG immune complexes (Ig-ICs) by gut dendritic cells (DCs).

14

Gluhovschi, Cristina, Gheorghe Gluhovschi, Ligia Petrica, Silvia Velciov, and Adrian Gluhovschi. "Pregnancy Associated with Systemic Lupus Erythematosus: Immune Tolerance in Pregnancy and Its Deficiency in Systemic Lupus Erythematosus—An Immunological Dilemma." Journal of Immunology Research 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/241547.

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Pregnancy is a physiological condition that requires immune tolerance to the product of conception. Systemic lupus erythematosus (SLE) is a disease with well-represented immune mechanisms that disturb immune tolerance. The association of pregnancy with systemic lupus erythematosus creates a particular immune environment in which the immune tolerance specific of pregnancy is required to coexist with alterations of the immune system caused by SLE. The main role is played by T regulatory (Treg) cells, which attempt to regulate and adapt the immune system of the mother to the new conditions of pregnancy. Other components of the immune system also participate to maintain maternal-fetal immune tolerance. If the immune system of pregnant women with SLE is not able to maintain maternal immune tolerance to the fetus, pregnancy complications (miscarriage, fetal hypotrophy, and preterm birth) or maternal complications (preeclampsia or activation of SLE, especially in conditions of lupus nephritis) may occur. In certain situations this can be responsible for neonatal lupus. At the same time, it must be noted that during pregnancy, the immune system is able to achieve immune tolerance while maintaining the anti-infectious immune capacity of the mother. Immunological monitoring of pregnancy during SLE, as well as of the mother’s disease, is required. It is important to understand immune tolerance to grafts in transplant pathology.

15

Rudd, Brian D. "Neonatal T Cells: A Reinterpretation." Annual Review of Immunology 38, no. 1 (April 26, 2020): 229–47. http://dx.doi.org/10.1146/annurev-immunol-091319-083608.

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Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.

16

Tai, D. S., C. Hu, and G. S. Lipshutz. "Elucidation of the Mechanism of Immune Tolerance Induction in Neonatal Gene Therapy." Journal of Surgical Research 186, no. 2 (February 2014): 576. http://dx.doi.org/10.1016/j.jss.2013.11.509.

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17

Field, A. C., L. Caccavelli, J. Fillion, J. Kuhn, C. Mandet, and B. Bellon. "Neonatal induction and maintenance of tolerance to Th2-induced immune manifestations in rats." Transplantation Proceedings 33, no. 3 (May 2001): 2275–76. http://dx.doi.org/10.1016/s0041-1345(01)01989-3.

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18

Xu, Lingfei, Manxue Mei, Mark E. Haskins, Karyn Cullen, and Katherine P. Ponder. "Neonatal Gene Transfer Induces Tolerance to Human Factor VIII in Mice and Cats." Blood 106, no. 11 (November 16, 2005): 215. http://dx.doi.org/10.1182/blood.v106.11.215.215.

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Abstract Hemophilia A is a bleeding disorder due to Factor VIII (FVIII) deficiency. FVIII is a very immunogenic protein, as approximately 30% of patients develop inhibitory antibodies (inhibitors) after FVIII protein replacement therapy. In addition, inhibitors often develop after gene therapy for hemophilia A. Identification of a treatment that could prevent inhibitor formation would be important. In this study, we explored the possibility of inducing tolerance to FVIII by neonatal gene transfer. An amphotropic gamma retroviral vector (RV) expressing human B domain-deleted FVIII (hFVIII) from the human α1-antitrypsin promoter was used to define the level of hFVIII that is necessary to achieve tolerance. Hemophilia A mice were injected with 1010 (high), 109 (medium) or 108 (low) transducing units (TU)/kg of RV at 2 to 3 days after birth, which resulted in expression of 63%, 7.3% or <2% of normal hFVIII antigen, respectively. Animals that received the high or medium dose of RV achieved hemostasis in vivo, although those that received the low dose did not. None of the mice produced antibodies to hFVIII. Similar results were also achieved in normal C3H mice, although some animals with low expression (2% of normal) developed low levels of anti-hFVIII antibodies. In contrast, hemophilia A and C3H mice that were challenged with hFVIII protein made potent inhibitors. Thus, neonatal gene transfer does not induce antibodies to hFVIII if the level of expression achieved is sufficiently high (>2x10−9 M). Mice that are tolerant to gene transfer are being challenged with recombinant BDD-hFVIII protein to determine if they are truly tolerant. Although induction of tolerance with neonatal gene transfer in mice is encouraging, tolerance has been more difficult to achieve in large outbred animals because their immune systems are more mature. Cats appear to have a much more mature immune system at birth than mice, as they mount a potent cytotoxic T lymphocyte response to canine iduronidase after neonatal gene therapy. Cats were therefore chosen as a large animal model in which to study tolerance induction with neonatal gene transfer. Neonatal cats were injected IV with 8.5x108 TU/kg of RV (medium dose) at day 5 after birth. Four cats achieved 37±3 ng/ml hFVIII (19% of normal) at 2 weeks after RV transduction. Three cats maintained hFVIII expression for 4 months. The two cats with the highest level of expression (~40 ng/ml) never developed antibodies, while the cat with a medium level of expression (30 ng/ml) developed only very low levels of anti-hFVIII antibodies. The cat with the lowest level of expression (20 ng/ml) lost expression at 2 months after RV transduction, and developed high titer inhibitors. We conclude that neonatal gene transfer does not induce antibodies to hFVIII in most cats. However, a high level of hFVIII expression may be necessary to achieve tolerance after neonatal gene transfer in cats. RV-treated cats will be challenged with hFVIII protein to determine if they are truly tolerant. In addition, normal cats will be challenged with hFVIII protein to determine the frequency of inhibitor formation in cats. Since the cat immune system is relatively mature at birth, these data are encouraging that neonatal gene or protein therapy might induce tolerance to hFVIII in humans. (This project is supported by National Hemophilia Foundation and the Bayer Hemophilia Awards Program.)

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MONAHAN, P. E. "Neonatal immune tolerance for hemophilia: can we ‘tolerate’ new paradigms for gene therapy trials?" Journal of Thrombosis and Haemostasis 5, no. 9 (June 15, 2007): 1801–4. http://dx.doi.org/10.1111/j.1538-7836.2007.02659.x.

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20

Bascom, R. A., K. Tao, S. L. Tollenaar, and L. J. West. "Regulatory T Cells (Tregs) in Neonatal Tolerance: Allogeneic Tregs Regulate the Neonatal Immune System and Prolong Heart Graft Survival." Journal of Heart and Lung Transplantation 32, no. 4 (April 2013): S297. http://dx.doi.org/10.1016/j.healun.2013.01.844.

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21

PENTTILA, IRMELI A., MIN F. ZHANG, EDNA BATES, GEOFFREY REGESTER, LEANNA C. READ, and HEDDY ZOLA. "Immune modulation in suckling rat pups by a growth factor extract derived from milk whey." Journal of Dairy Research 68, no. 4 (November 2001): 587–99. http://dx.doi.org/10.1017/s0022029901005180.

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Oral tolerance to foreign enteral antigens is not fully developed in early neonatal life. Epidemiological evidence supports a role for maternal milk in the development of immune responses, including oral tolerance. Formula fed infants have an increased susceptibility to food allergy and the later development of autoimmune disease. This may relate to the lack in infant formula of growth factors found in maternal milk. Bovine milk contains proteins, growth factors and cytokines. Various studies have outlined the immune modulating potential of bovine milk-derived products. Fractionated whey extracts have therapeutic potential in disease states where there is an excessive inflammatory reaction, and disease preventive potential for infants who are not breast-fed. We have shown that daily oral administration of a growth factor-enriched fraction from milk whey to naturally suckling rat pups between days 4–9 postnatal can down-regulate immune activation to a specific orally administered food antigen, ovalbumin, assessed by lymphocyte proliferation. In addition, non-specific down-regulation in the intestine was observed as assessed by the expression of MHC I. Treatment of rat pups with whey extract at the time of oral sensitisation to ovalbumin also resulted in an increased secretion of TGF-β into the culture supernatant of spleen cells incubated with specific antigen. TGF-β is an immuno-down-regulatory cytokine involved in tolerance induction. Immune modulation by extracts derived from milk whey could be of potential benefit for formula-fed and pre-term infants in reducing susceptibility to inappropriate activation to food antigens.

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Guerau-de-Arellano, Mireia, Marianne Martinic, Christophe Benoist, and Diane Mathis. "Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity." Journal of Experimental Medicine 206, no. 6 (June 1, 2009): 1245–52. http://dx.doi.org/10.1084/jem.20090300.

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There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge.

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Touraine, Jean-Louis, and Kamel Sanhadji. "Transplantation Tolerance Induced in Humans at the Fetal or the Neonatal Stage." Journal of Transplantation 2011 (2011): 1–4. http://dx.doi.org/10.1155/2011/760319.

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Patients transplanted with HLA-mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens. Engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity, especially T-cell differentiation. The chimeric patients have donor-derived T lymphocytes which progressively demonstrate positive interactions with other host cells. They also can be shown to be tolerant toward both host and donor antigens. The latter tolerance relies upon clonal deletion from the T-cell repertoire, and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells. The former tolerance does not imply clonal deletion of T-cells with host reactivity. Numerous T-cells recognizing the allogeneic, host-type antigens are identified in these patients, but these cells are anergized, following interaction with epithelial cells of the host thymus. Induction of transplantation tolerance at the fetal stage requires minimal engraftment only; in the future it will be possible to further amplify the clinical benefit, using additional cell transplants after birth.

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Cobbold, Stephen P. "T cell tolerance induced by therapeutic antibodies." Philosophical Transactions of the Royal Society B: Biological Sciences 360, no. 1461 (August 16, 2005): 1695–705. http://dx.doi.org/10.1098/rstb.2005.1698.

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Ever since the discovery of Medawar, over 50 years ago, that immunological tolerance was an acquired phenomenon that could be manipulated in neonatal mice, the ability to induce therapeutic tolerance against autoantigens, allergens and organ grafts has been a major driving force in immunology. Within the last 20 years we have found that a brief treatment with monoclonal antibodies that block certain functional molecules on the surface of the T cell is able to reprogramme the established immune repertoire of the adult mouse, allowing indefinite acceptance of allografts or effective curing of autoimmune diseases. We are only now just beginning to define many of the regulatory mechanisms that induce and maintain the tolerant state with the aim of being able to safely and reliably apply these technologies to human clinical situations.

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Phillips-Farfán, Bryan, Fernando Gómez-Chávez, Edgar Alejandro Medina-Torres, José Antonio Vargas-Villavicencio, Karla Carvajal-Aguilera, and Luz Camacho. "Microbiota Signals during the Neonatal Period Forge Life-Long Immune Responses." International Journal of Molecular Sciences 22, no. 15 (July 29, 2021): 8162. http://dx.doi.org/10.3390/ijms22158162.

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The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut–brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.

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Leech, J. M., K. Chu, E. G. Leitner, J. J. Moon, B. A. Diep, and T. C. Scharschmidt. "925 Neonatal priming shapes preferential capacity for immune tolerance to skin commensal vs. pathogenic bacteria." Journal of Investigative Dermatology 138, no. 5 (May 2018): S157. http://dx.doi.org/10.1016/j.jid.2018.03.937.

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27

Bailey, M., F. J. Plunkett, H. J. Rothkötter, M. A. Vega-Lopez, K. Haverson, and C. R. Stokes. "Regulation of mucosal immune responses in effector sites." Proceedings of the Nutrition Society 60, no. 4 (November 2001): 427–35. http://dx.doi.org/10.1079/pns2001118.

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In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer’s patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In our piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. We suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.

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Muturi, K. N., M. Birnie, M. Wallace, J. Struthers, J. R. Scaife, and M. A. Lomax. "Influence of dietary fatty acids on the fatty acid composition of gut mucosa in calves during the first 3 weeks of life." Proceedings of the British Society of Animal Science 2003 (2003): 87. http://dx.doi.org/10.1017/s1752756200012461.

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The balance between pro and anti-inflammatory elements of the immune system can be influenced by provision of specific dietary polyunsaturated fatty acids (PUFA) (Calder, 1998). The gut associated lymphoid tissue (GALT) is the largest immune organ and an important regulator of tolerance and sensitivity to dietary and environmental antigens in the gut (Harbige and Fisher, 2001). Changing the fatty acid composition of the gut mucosa could influence the immune function of the GALT. This study was carried out to establish the extent to which dietary n-3 or n-6 PUFA-rich oil supplements could change the fatty acid composition of gut mucosa of the neonatal calf.

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Lirussi, Darío, Sebastian Felix Weissmann, Thomas Ebensen, Ursula Nitsche-Gloy, Heiko B. G. Franz, and Carlos A. Guzmán. "Cyclic Di-Adenosine Monophosphate: A Promising Adjuvant Candidate for the Development of Neonatal Vaccines." Pharmaceutics 13, no. 2 (February 1, 2021): 188. http://dx.doi.org/10.3390/pharmaceutics13020188.

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Underdeveloped immunity during the neonatal age makes this period one of the most dangerous during the human lifespan, with infection-related mortality being one of the highest of all age groups. It is also discussed that vaccination during this time window may result in tolerance rather than in productive immunity, thus raising concerns about the overall vaccine-mediated protective efficacy. Cyclic di-nucleotides (CDN) are bacterial second messengers that are rapidly sensed by the immune system as a danger signal, allowing the utilization of these molecules as potent activators of the immune response. We have previously shown that cyclic di-adenosine monophosphate (CDA) is a potent and versatile adjuvant capable of promoting humoral and cellular immunity. We characterize here the cytokine profiles elicited by CDA in neonatal cord blood in comparison with other promising neonatal adjuvants, such as the imidazoquinoline resiquimod (R848), which is a synthetic dual TLR7 and TLR8 agonist. We observed superior activity of CDA in eliciting T helper 1 (Th1) and T follicular helper (TfH) cytokines in cells from human cord blood when compared to R848. Additional in vivo studies in mice showed that neonatal priming in a three-dose vaccination schedule is beneficial when CDA is used as a vaccine adjuvant. Humoral antibody titers were significantly higher in mice that received a neonatal prime as compared to those that did not. This effect was absent when using other adjuvants that were reported as suitable for neonatal vaccination. The biological significance of this immune response was assessed by a challenge with a genetically modified influenza H1N1 PR8 virus. The obtained results confirmed that CDA performed better than any other adjuvant tested. Altogether, our results suggest that CDA is a potent adjuvant in vitro on human cord blood, and in vivo in newborn mice, and thus a suitable candidate for the development of neonatal vaccines.

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Liu, Yuying, Thomas K. Hoang, Jasmin Freeborn, Sinyoung Park, Dat Q. Tran, Stefan Roos, and J. Marc Rhoads. "482 PROBIOTIC-EDUCATED TREGS ARE MORE POTENT THAN NAIVE TREGS FOR IMMUNE TOLERANCE IN NEONATAL STRESS." Gastroenterology 158, no. 6 (May 2020): S—95. http://dx.doi.org/10.1016/s0016-5085(20)30918-5.

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31

Madoiwa, S., T. Yamauchi, Y. Hakamata, E. Kobayashi, M. Arai, T. Sugo, J. Mimuro, and Y. Sakata. "Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A." Journal of Thrombosis and Haemostasis 2, no. 5 (May 2004): 754–62. http://dx.doi.org/10.1111/j.1538-7933.2004.00671.x.

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32

Wood, Hannah, Animesh Acharjee, Hayden Pearce, Mohammed Nabil Quraishi, Richard Powell, Amanda Rossiter, Andrew Beggs, Andrew Ewer, Paul Moss, and Gergely Toldi. "Breastfeeding promotes early neonatal regulatory T‐cell expansion and immune tolerance of non‐inherited maternal antigens." Allergy 76, no. 8 (January 28, 2021): 2447–60. http://dx.doi.org/10.1111/all.14736.

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33

Lotz, Michael, Dominique Gütle, Sabrina Walther, Sandrine Ménard, Christian Bogdan, and Mathias W. Hornef. "Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells." Journal of Experimental Medicine 203, no. 4 (April 10, 2006): 973–84. http://dx.doi.org/10.1084/jem.20050625.

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The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor κB (NF-κB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IκB-α and nuclear translocation of NF-κB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis.

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Donnet-Hughes, Anne, Pablo F. Perez, Joël Doré, Marion Leclerc, Florence Levenez, Jalil Benyacoub, Patrick Serrant, Iris Segura-Roggero, and Eduardo J. Schiffrin. "Potential role of the intestinal microbiota of the mother in neonatal immune education." Proceedings of the Nutrition Society 69, no. 3 (July 15, 2010): 407–15. http://dx.doi.org/10.1017/s0029665110001898.

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Mucosal dendritic cells are at the heart of decision-making processes that dictate immune reactivity to intestinal microbes. They ensure tolerance to commensal bacteria and a vigorous immune response to pathogens. It has recently been demonstrated that the former involves a limited migration of bacterially loaded dendritic cells from the Peyer's patches to the mesenteric lymph nodes. During lactation, cells from gut-associated lymphoid tissue travel to the breast via the lymphatics and peripheral blood. Here, we show that human peripheral blood mononuclear cells and breast milk cells contain bacteria and their genetic material during lactation. Furthermore, we show an increased bacterial translocation from the mouse gut during pregnancy and lactation and the presence of bacterially loaded dendritic cells in lactating breast tissue. Our observations show bacterial translocation as a unique physiological event, which is increased during pregnancy and lactation. They suggest endogenous transport of intestinally derived bacterial components within dendritic cells destined for the lactating mammary gland. They also suggest neonatal immune imprinting by milk cells containing commensal-associated molecular patterns.

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Piccand, Matthieu, Juliana Bessa, Eginhard Schick, Claudia Senn, Carole Bourquin, and Wolfgang F. Richter. "Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice." AAPS Journal 18, no. 2 (November 24, 2015): 354–61. http://dx.doi.org/10.1208/s12248-015-9850-5.

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36

Min, Booki, Kevin L. Legge, Christopher Pack та Habib Zaghouani. "Neonatal Exposure to a Self-Peptide–Immunoglobulin Chimera Circumvents the Use of Adjuvant and Confers Resistance to Autoimmune Disease by a Novel Mechanism Involving Interleukin 4 Lymph Node Deviation and Interferon γ–mediated Splenic Anergy". Journal of Experimental Medicine 188, № 11 (7 грудня 1998): 2007–17. http://dx.doi.org/10.1084/jem.188.11.2007.

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Induction of neonatal T cell tolerance to soluble antigens requires the use of incomplete Freund's adjuvant (IFA). The side effects that could be associated with IFA and the ill-defined mechanism underlying neonatal tolerance are setbacks for this otherwise attractive strategy for prevention of T cell–mediated autoimmune diseases. Presumably, IFA contributes a slow antigen release and induction of cytokines influential in T cell differentiation. Immunoglobulins (Igs) have long half-lives and could induce cytokine secretion by binding to Fc receptors on target cells. Our hypothesis was that peptide delivery by Igs may circumvent the use of IFA and induce neonatal tolerance that could confer resistance to autoimmunity. To address this issue we used the proteolipid protein (PLP) sequence 139–151 (hereafter referred to as PLP1), which is encephalitogenic and induces experimental autoimmune encephalomyelitis (EAE) in SJL/J mice. PLP1 was expressed on an Ig, and the resulting Ig–PLP1 chimera when injected in saline into newborn mice confers resistance to EAE induction later in life. Mice injected with Ig–PLP1 at birth and challenged as adults with PLP1 developed T cell proliferation in the lymph node but not in the spleen, whereas control mice injected with Ig–W, the parental Ig not including PLP1, developed T cell responses in both lymphoid organs. The lymph node T cells from Ig–PLP1 recipient mice were deviated and produced interleukin (IL)-4 instead of IL-2, whereas the spleen cells, although nonproliferative, produced IL-2 but not interferon (IFN)-γ. Exogenous IFN-γ, as well as IL-12, restored splenic proliferation in an antigen specific manner. IL-12–rescued T cells continued to secrete IL-2 and regained the ability to produce IFN-γ. In vivo, administration of anti–IL-4 antibody or IL-12 restored disease severity. Therefore, adjuvant-free induced neonatal tolerance prevents autoimmunity by an organ-specific regulation of T cells that involves both immune deviation and a new form of cytokine- dependent T cell anergy.

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Christensen, Hanne R., Susanne Brix, and Hanne Frøkiær. "Immune response in mice to ingested soya protein: antibody production, oral tolerance and maternal transfer." British Journal of Nutrition 91, no. 5 (May 2004): 725–32. http://dx.doi.org/10.1079/bjn20041093.

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While allergic reactions to soya are increasingly investigated, the normal immune response to ingested soya is scarcely described. In the present study, we wanted to characterise the soya-specific immune response in healthy mice ingesting soya protein. Mice fed a soya-containing diet (F0) and mice of the first (F1) and second (F2) offspring generation bred on a soya protein-free diet were used either directly or were transferred between the soya-containing and soya protein-free diet during pregnancy or neonatal life. The mice were compared as to levels of naturally occurring specific antibodies analysed by ELISA, and to the presence of oral tolerance detected as a suppressed antibody and cell-proliferation response upon immunisation with soya protein. F0 mice generated soya-specific antibodies, while oral tolerance to the same soya proteins was also clearly induced. When F0 dams were transferred to soya protein-free feed before mating, the F1 and F2 offspring generations showed no significantly different response, indicating that soya-specific immune components were not maternally transmitted. However, the ingestion of dietary soya protein by F1 mice during late pregnancy and lactation caused a lasting antibody response in the offspring, but in this case in the absence of oral tolerance. This indicates that, under certain conditions, factors involved in spontaneous antibody production can be transmitted from mother to offspring. Understanding the immune response to soya protein ingested under healthy conditions is important in the assessment of adverse effects of soya protein and in the use of animal allergy models. The present results add to this understanding.

38

Fallarino, Francesca, Giovanni Luca, Mario Calvitti, Francesca Mancuso, Claudio Nastruzzi, Maria C. Fioretti, Ursula Grohmann, et al. "Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone." Journal of Experimental Medicine 206, no. 11 (October 12, 2009): 2511–26. http://dx.doi.org/10.1084/jem.20090134.

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Type I diabetes mellitus is caused by autoimmune destruction of pancreatic β cells, and effective treatment of the disease might require rescuing β cell function in a context of reinstalled immune tolerance. Sertoli cells (SCs) are found in the testes, where their main task is to provide local immunological protection and nourishment to developing germ cells. SCs engraft, self-protect, and coprotect allogeneic and xenogeneic grafts from immune destruction in different experimental settings. SCs have also been successfully implanted into the central nervous system to create a regulatory environment to the surrounding tissue which is trophic and counter-inflammatory. We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional β cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-β–dependent emergence of autoantigen-specific regulatory T cells and recovery of β cell function in the diabetic recipients.

39

Singh, R. R., B. H. Hahn, and E. E. Sercarz. "Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity." Journal of Experimental Medicine 183, no. 4 (April 1, 1996): 1613–21. http://dx.doi.org/10.1084/jem.183.4.1613.

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Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.

40

Manno, Catherine S. "Management of Bleeding Disorders in Children." Hematology 2005, no. 1 (January 1, 2005): 416–22. http://dx.doi.org/10.1182/asheducation-2005.1.416.

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Abstract Diagnosis and management of congenital and acquired bleeding disorders in children requires not only an understanding of the unique characteristics of pediatric hemostasis but also the natural course of bleeding disorders in children, which may differ substantially from the course observed in adult patients. In this article, three bleeding disorders of great importance to the pediatric hematologist are reviewed: neonatal alloimmune thrombocytopenia (NAIT), hemophilia and immune-mediated thrombocytopenic purpura (ITP). Current aspects of management are outlined. The unique physiology of transplacental transfer of maternally derived anti-platelet antibodies can result in neonatal immune thrombocytopenia, a significant cause of morbidity and mortality from bleeding in affected infants. For patients with hemophilia, approaches to treatment have shifted over the past decade from on-demand therapy to prophylaxis, either primary of secondary, resulting in delay of onset or complete avoidance of hemophilic arthropathy. Hemophilic inhibitors often develop in young children, prompting the need for a thorough understanding of the use of bypassing agents as well as immune tolerance induction in the young child. Finally, although several management strategies for ITP of childhood have been shown to improve the platelet count, side effects associated with corticosteroids, IVIg, anti-D and splenectomy force the practitioner to also consider the option of carefully observing, but not treating, the child with ITP.

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Kizu, Kumiko, Ayu Matsunaga, Junko Hirose, Akihiro Kimura, and Hiroshi Narita. "Induction of Oral Tolerance in Neonatal Mice by Transfer of Food Allergens as IgA-Immune Complexes in Breast Milk." Food and Nutrition Sciences 06, no. 02 (2015): 221–33. http://dx.doi.org/10.4236/fns.2015.62023.

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42

Deng, B., O. V. Pakhomov, and G. A. Bozhok. "Long-term effects of acute cadmium exposure on testis immune privilege." Regulatory Mechanisms in Biosystems 11, no. 2 (April 2, 2020): 180–85. http://dx.doi.org/10.15421/022027.

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Cadmium (Cd) is a widespread and non-biodegradable pollutant of great concern to human health. This element can affect cellular signal transduction and cell-to-cell interaction in the testis. Immune tolerance towards auto- and alloantigens is an important component of testis immunity. It is involved in spermatogenesis and hormone secretion. Plus, the immune tolerance may help to reveal the changes in testis immunity over a long period after Cd exposure. The current research was aimed at investigating the long-term effects of acute Cd exposure on testis immunity by means of elicitation of testicular immune cell composition shift induced by Cd. Cadmium chloride was intraperitoneally injected at 3 mg Cd/kg to mice. After that testis interstitial cells were stained with surface markers for leukocyte and lymphocyte subpopulations (CD45, CD11b, CD3, CD4, CD8, CD25) and analyzed cytofluorimetrically by week 4, 6, 8 and 12 after Cd administration (Cd group). To identify the delayed effects of cadmium on immune tolerance two groups of animals were subjected to intratesticular allotransplantation of neonatal testis (groups ITT and Cd+ ITT). One of the groups was administered with Cd four weeks before the transplantation (Cd+ITT group). I group served as a control that did not undergo any transplantation or Cd injection. For a better demonstration of the phenomenon of immunological tolerance of the testicles, an additional group (UKT group) was used which got grafts under the kidney capsule (non-immune privileged site).Investigation of the cell population showed that CD45+, CD11b+, CD4+, CD8+ cells were permanently present in testicular interstitial tissue in I group. Intratesticular testis transplantation increased the proportion of CD11b+ but did not have such a pronounced effect on CD8+ cells in ITT group. Moreover, the transplantation elevated CD4+ CD25+ cells known for their immunosuppressive property and promoted graft development by week 2 (histological data). Cd injection resulted in severe inflammation that quenched by week 4 (Cd and Cd+ ITT groups). This time point was chosen for transplantation in Cd+ ITT group. Such Cd pretreatment led to a high CD8+ cell proportion and to the delayed appearance of CD4+ CD25+ cells by week 2 (Cd+ ITTgroup). The finding is consistent with the impairment of graft development in Cd+ ITTgroup pretreated with Cd. Observation suggest that Cd pretreatment was associated with disproportion of interstitial immune cell populations which resulted in the impairment of immunoprotective function of the testis. The impairment of testis immunity showed itself only after several weeks of Cd administration, and only when the recipient testis immunity was provoked by alloantigens of donor testes.

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Imam, S. A., E. F. Esteban, L. L. Young, and C. R. Taylor. "Generation of a murine monoclonal antibody to normal mammary epithelium using mice rendered immune-tolerant to malignant mammary epithelium." Journal of Histochemistry & Cytochemistry 42, no. 5 (May 1994): 585–91. http://dx.doi.org/10.1177/42.5.7512585.

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A monoclonal antibody (MAb) that distinguishes normal from malignant mammary epithelia in tissue or cell lines was generated using a procedure that involved immune-tolerization before immunization. Immune-tolerance to two transformed mammary epithelial cell lines (MCF.7 and MDA.MB.231 cell lines combined) was induced in neonatal mice within 24 hr of birth. Successful induction of immune-tolerance was determined by an indirect immunohistological method, testing sera from mice against the tolerogen (i.e., the MCF.7 and MDA.MB.231 cell lines). Mice lacking antibodies in their sera against the immune-tolerogen were subsequently immunized with an extract of normal breast epithelium. One mouse was selected for hybridoma production based on evidence of serum antibody that showed reactivity with normal mammary epithelial cells (MEC) but not with invasive breast carcinoma cells, as determined by an indirect immunohistological method. Spleen cells from the selected mouse were fused with a mouse myeloma cell line to generate MAb. After extensive screening, one MAb was further studied on the basis of reactivity with normal MEC in tissue and absence of staining of malignant MEC in tissue or tumorigenic MEC lines. This test of specificity of reactivity revealed that the antigen detected by the specific antibody was expressed on the apical plasma membrane of normal glandular epithelia that included breast, cervix, colon, lung, pancreas, and stomach, but not on their malignant counterparts in tissue sections. The antigen recognized by the MAb was termed luminal epithelial antigen with an apparent MW of 92 KD (LEA.92). This study illustrates the practical usefulness of the immune-tolerization/immunization approach in the generation of antibodies with particular specificity requirements, as in the identification of an antigen that is differentially expressed in two tissues (e.g., normal and malignant) which otherwise have a multiplicity of antigens in common.

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Matsui, Hideto, Masaru Shibata, Brian Brown, Andrea Labelle, Carol Hegadorn, Chandler Andrews, Marinee Chuah, et al. "1091. Successful Induction of Immune Tolerance to Canine Factor VIII after Lentiviral-Mediated Gene Therapy in Neonatal Hemophilia A Mice." Molecular Therapy 13 (2006): S419. http://dx.doi.org/10.1016/j.ymthe.2006.08.1193.

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45

Falahati, Rustom, Linda Flebbe-Rehwaldt, Yimin Shi, Jianqing Zhang, Stanton L. Gerson, and Karin M. L. Gaensler. "Neonatal Bone Marrow Transplantation Following Ex Vivo Gene Transfer and in Vivo Chemoselection for Hereditary Disorders." Blood 112, no. 11 (November 16, 2008): 3478. http://dx.doi.org/10.1182/blood.v112.11.3478.3478.

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Abstract Transplantation of genetically engineered hematopoietic stem cells (HSC) holds promise for treatment of genetic and other disorders; however, several obstacles restrict the clinical application of this approach. These include leukemogenesis resulting from insertional mutagenesis, the lack of a competitive advantage for transplanted genetically engineered autologous HSCs, and the requirement for the construction and clinical approval of a gene transfer vehicle specific to each disorder. Allogenic transplantation approaches are further limited by a shortage of compatible donors, the toxicity of preparative regimens, immunosuppression, and graft versus host disease (GVHD). We have established a neonatal transplantation model to develop strategies to overcome these hurdles to HSC transplantation and gene therapy. We have uniquely combined allogenic transplantation during the neonatal period, when tolerance may be more readily achieved, with a positive selection strategy for in vivo amplification of drug-resistant donor HSC. This model system enables the evaluation of tolerance induction mechanisms to neo-antigens, and allogenic stem cell engraftment during immune ontogeny. In this model, bone marrow-derived HSC are transduced ex vivo by lentivirus-mediated gene transfer of P140K-O6-methylguanine-methyltransferase (MGMTP140K) and GFP (MAG vector). The MGMTP140K DNA repair enzyme confers resistance to benzylguanine, an inhibitor of endogenous MGMT, and to chloroethylating agents such as BCNU. This enables enrichment of donor cells at the stem cell level by in vivo chemoselection. Furthermore, in vivo administration of BG/BCNU may potentially deplete allo-reactive cells of donor and host origin, reducing the need for toxic ablative or immunosuppressive treatment. The in vivo selection strategy was first tested in neonates in the absence of MHC barriers. Syngenic whole bone marrow (WBM) was transduced with MAG and 5 × 105 cells were transplanted. Five weeks after transplantation and prior to chemoselection, 0.5% of cells expressed GFP in peripheral blood. Following two cycles of in vivo selection we observed 39.5% expression of GFP in peripheral blood. To assess the engraftment of fully MHC-mismatched HSC in neonates without in vivo selection, 107 B10.Br (H-2k) WBM was transplanted into C57BL/6 (H-2b) neonates using a non-myleoablative regimen. This resulted in 98% engraftment in adults without development of GVHD. To evaluate in vivo selection in an allogenic setting, 2 × 106 MAG transduced WBM from BALB/c (H-2d) adult mice were transplanted into C57BL/6 × BALB/c F1 (H-2b/d) neonatal mice. Despite having a graft versus host MHC disparity, we observed an increase from 4.7% (5 weeks after transplant) to 37.4% GFP expression following two cycles of in vivo chemoselection without evidence of GVHD. We have demonstrated successful engraftment and enrichment of both syngenic and allogenic HSC expressing MGMTP140K following neonatal transplantation and in vivo selection. Stable engraftment was achieved without myeloablation or post-transplant immunosuppression. No evidence of GVHD was observed after full MHC-mismatched transplantation. These results hold promise for the development of non-myeloablative allogenic transplant approaches using this in vivo selection strategy.

46

Hayek, Alberto, and Gillian M. Beattie. "Reversal of Experimental Diabetes by Injection of Syngeneic Islets into Peripheral Veins." Cell Transplantation 1, no. 1 (January 1992): 83–85. http://dx.doi.org/10.1177/096368979200100112.

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This study was undertaken to evaluate the safety and effectiveness of intravenous (i.v.) injection of islets, via a peripheral vein, in the treatment of experimental diabetes in highly inbred Lewis rats. Rats were made diabetic by the i.v. injection of streptozocin, and donor islets were isolated from neonatal rats. Two wk after the induction of diabetes, rats with glucose concentrations > 19 mM were divided into two groups: one group of six rats was injected with 2000 neonatal islets into the external jugular vein; the second group of rats, acting as control, was injected in the same vein with medium alone. Within 2 wk of the islet transplant, 100% (6/6) of the rats were cured of the diabetes. None of the control rats experienced any improvement. As expected, pancreatic islets so administered embolized to the lungs. Glucose tolerance tests in the rats receiving the islet transplant were indistinguishable from normal rats. These results could be important to clinical transplantation if the procedure is as successful in larger animals using autotransplanted islets or allografts protected from immune rejection.

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Gill, Harsharnjit S., F. Doull, K. J. Rutherfurd, and M. L. Cross. "Immunoregulatory peptides in bovine milk." British Journal of Nutrition 84, S1 (November 2000): 111–17. http://dx.doi.org/10.1017/s0007114500002336.

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Bovine milk is known to contain a number of peptide fractions that can affect immune function. The vast majority of immunoregulatory peptides that have been characterised are hydrolysate derivatives of major milk proteins. Recent research has also indicated that the metabolic activity of probiotic lactic acid bacteria can generate de novo immunoregulatory peptides from milk, via enzymatic degradation of parent milk protein molecules. In contrast, relatively little is known of endogenous, preformed immunoregulatory peptides in milk that may be relevant to modulating human health. The natural in vivo role of preformed and enzymatically derived peptides is likely to be one of regulation of the neonatal (bovine) gastrointestinal tract immune system, in order to modulate immune function with respect to the development of immunocompetence and avoidance of undesirable immunological responses (e.g. tolerance, and hypersensitivity to nutrients). There is scope for the further characterisation of both the origin and function of milk-derived immunoregulatory peptides, so that their potential to influence human health can be fully appraised. This review highlights our current knowledge of milk-derived immunoregulatory peptides, and outlines areas that are of relevance for further research.

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Esteve-Solé, Ana, Yiyi Luo, Alexandru Vlagea, Ángela Deyà-Martínez, Jordi Yagüe, Ana Plaza-Martín, Manel Juan, and Laia Alsina. "B Regulatory Cells: Players in Pregnancy and Early Life." International Journal of Molecular Sciences 19, no. 7 (July 19, 2018): 2099. http://dx.doi.org/10.3390/ijms19072099.

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Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players.

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Xu, Lingfei, Cuihua Gao, Mark S. Sands, Shi-Rong Cai, Timothy C. Nichols, Dwight A. Bellinger, Robin A. Raymer, Stephanie McCorquodale, and Katherine Parker Ponder. "Neonatal or hepatocyte growth factor–potentiated adult gene therapy with a retroviral vector results in therapeutic levels of canine factor IX for hemophilia B." Blood 101, no. 10 (May 15, 2003): 3924–32. http://dx.doi.org/10.1182/blood-2002-10-3050.

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AbstractHemophilia B is a bleeding disorder resulting from factor IX (FIX) deficiency that might be treated with gene therapy. Neonatal delivery would correct the disease sooner than would transfer into adults, and could reduce immunological responses. Neonatal mice were injected intravenously with a Moloney murine leukemia virus–based retroviral vector (RV) expressing canine FIX (cFIX). They achieved 150% to 280% of normal cFIX antigen levels in plasma (100% is 5 μg/mL), which was functional in vitro and in vivo. Three newborn hemophilia B dogs that were injected intravenously with RV achieved 12% to 36% of normal cFIX antigen levels, which improved coagulation tests. Only one mild bleed has occurred during 14 total months of evaluation. This is the first demonstration of prolonged expression after neonatal gene therapy for hemophilia B in mice or dogs. Most animals failed to make antibodies to cFIX, demonstrating that neonatal gene transfer may induce tolerance. Although hepatocytes from newborns replicate, those from adults do not. Adult mice therefore received hepatocyte growth factor to induce hepatocyte replication prior to intravenous injection of RV. This resulted in expression of 35% of normal cFIX antigen levels for 11 months, although all mice produced anti-cFIX antibodies. This is the first demonstration that high levels of FIX activity can be achieved with an RV in adults without a partial hepatectomy to induce hepatocyte replication. We conclude that RV-mediated hepatic gene therapy is effective for treating hemophilia B in mice and dogs, although the immune system may complicate gene transfer in adults.

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Liuba, Karina, Cornelis J. H. Pronk, Simon R. W. Stott, and Sten-Eirik W. Jacobsen. "Polyclonal T-cell reconstitution of X-SCID recipients after in utero transplantation of lymphoid-primed multipotent progenitors." Blood 113, no. 19 (May 7, 2009): 4790–98. http://dx.doi.org/10.1182/blood-2007-12-129056.

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Abstract Although successful in utero hematopoietic cell transplantation (IUHCT) of X-linked severe combined immune deficiency (X-SCID) with enriched stem and progenitor cells was achieved more than a decade ago, it remains applied only in rare cases. Although this in part reflects that postnatal transplantations have overall given good results, there are no direct comparisons between IUHCT and postnatal transplantations of X-SCID. The proposed tolerance of the fetal immune system to foreign human leukocyte antigen early in gestation, a main rationale behind IUHCT, has recently been challenged by evidence for a considerable immune barrier against in utero transplanted allogeneic bone marrow cells. Consequently, there is need for further exploring the application of purified stem and progenitor cells to overcome this barrier also in IUHCT. Herein, we demonstrate in a congenic setting that recently identified lymphoid-primed multipotent progenitors are superior to hematopoietic stem cells in providing rapid lymphoid reconstitution after IUHCT of X-SCID recipients, and sustain in the long-term B cells, polyclonal T cells, as well as short-lived B-cell progenitors and thymic T-cell precursors. We further provide evidence for IUHCT of hematopoietic stem cells giving superior B- and T-cell reconstitution in fetal X-SCID recipients compared with neonatal and adolescent recipients.

Статті в журналах з теми "Neonatal immune tolerance"

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