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1
Roth, R., and M. J. Mamula. "Trafficking of adoptively transferred B lymphocytes in B-lymphocyte-deficient mice." Journal of Experimental Biology 200, no. 14 (1997): 2057–62. http://dx.doi.org/10.1242/jeb.200.14.2057.
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Many studies have investigated the fate of adoptively transferred lymphocytes in recipient mice, although little is known of the sites where these transferred cells reside at particular time points. Using flow cytometry, we analyzed the trafficking pattern of adoptively transferred naive B cells into the lymphoid organs of syngeneic B-cell-deficient (microMT) mice. Within the first 24 h of transfer, the location of B cells was highly dependent on the mode of B-cell transfer. When B cells were injected subcutaneously into microMT mice, they showed a different trafficking pattern from cells administered into the peritoneal cavity or injected intravenously. After subcutaneous transfer into the thigh, the greatest number of B cells was detected in the popliteal lymph node nearest to the injection site, whereas the lowest number was detected in the axillary lymph node opposite to the injection side. Within the first 24 h of either intraperitoneal and intravenous injection, B cells were found in approximately equal numbers in the lymph nodes and the spleen. Two days later, the B-cell distribution in the lymphoid organs appeared to be independent of the mode of B-cell transfer. A transient decrease in the numbers of splenic and lymph node B cells occurred 9 days after B-cell transfer (a decrease from 70 to 87%) prior to the outgrowth of B cells that occurs 21 days after transfer. These studies are useful for understanding the numbers of B cells that may be required in adoptive transfer studies and their potential cellular interactions at particular physiological sites based on the route of cell transfer.
2
Denis, K. A., K. Dorshkind, and O. N. Witte. "Regulated progression of B lymphocyte differentiation from cultured fetal liver." Journal of Experimental Medicine 166, no. 2 (1987): 391–403. http://dx.doi.org/10.1084/jem.166.2.391.
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Lymphoid fetal liver cultures (LFLC) are long-term, nontransformed cultures of early B lymphoid lineage cells which appear developmentally blocked at the pre-B stage in vitro. When injected into severe combined immunodeficient (SCID) mice, cells from LFLC could reconstitute splenic B lymphocytes and serum IgM. T lymphocyte reconstitution was not observed and serum IgG levels were very low. IgG3 was the predominant gamma subisotype in the serum of the LFLC-reconstituted mice, indicating impaired class switching in these B lymphocytes. When thymocytes were coinjected with LFLC, the B lymphocytes were able to class switch fully and respond to T-dependent antigens. These serological responses were heterogeneous. This experimental system allows separation of three B lymphocyte developmental stages: early differentiation in vitro, progression to IgM secretion in vivo, and late differentiation dependent upon mature T lymphocytes in vivo. The unique advantage of this system is the ability to regulate the B lymphocyte developmental pathway in a defined, stepwise manner.
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Paciorkowski, Natalia, Leonard D. Shultz, and T. V. Rajan. "Primed Peritoneal B Lymphocytes Are Sufficient To Transfer Protection against Brugia pahangi Infection in Mice." Infection and Immunity 71, no. 3 (2003): 1370–78. http://dx.doi.org/10.1128/iai.71.3.1370-1378.2003.
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ABSTRACT Lymphatic filariasis is a tropical disease caused by the nematode parasites Wuchereria bancrofti and Brugia malayi. Whereas the protective potential of T lymphocytes in filarial infection is well documented, investigation of the role of B lymphocytes in antifilarial immunity has been neglected. In this communication, we examine the role of B lymphocytes in antifilarial immunity, using Brugia pahangi infections in the murine peritoneal cavity as a model. We find that B lymphocytes are required for clearance of primary and challenge infections with B. pahangi third-stage larvae (L3). We assessed the protective potential of peritoneal B lymphocytes by adoptive transfer experiments. Primed but not naïve peritoneal B cells from wild-type mice that had been immunized with B. pahangi L3 protected athymic recipients from challenge infection. We evaluated possible mechanisms by which B cells mediate protection. Comparisons of cytokine mRNA expression between B-lymphocyte-deficient and immunocompetent mice following B. pahangi infection suggest that B cells are required for the early production of Th2-type cytokines by peritoneal cells. In addition, B-cell-deficient mice demonstrate a defect in inflammatory cell recruitment to the peritoneal cavity following B. pahangi infection. The data demonstrate a critical role of B lymphocytes in antifilarial immunity in naïve mice and in the memory response in primed mice.
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Serreze, D. V., H. D. Chapman, D. S. Varnum, et al. "B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD.Ig mu null mice." Journal of Experimental Medicine 184, no. 5 (1996): 2049–53. http://dx.doi.org/10.1084/jem.184.5.2049.
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The T lymphocytes mediating autoimmune destruction of pancreatic beta cells in the nonobese diabetic (NOD) mouse model of insulin-dependent diabetes mellitus (IDDM) may be generated due to functional defects in hematopoietically derived antigen-presenting cells (APC). However, it has not been clear which particular subpopulations of APC (B lymphocytes, macrophages, and dendritic cells) contribute to the development and activation of diabetogenic T cells in NOD mice. In the current study we utilized a functionally inactivated immunoglobulin (Ig) mu allele (Ig mu null) to generate a "speed congenic" stock of B lymphocyte-deficient NOD mice that are fixed for linkage markers delineating previously identified diabetes susceptibility (Idd) genes. These B lymphocyte NOD.Ig mu null mice had normal numbers of T cells but were free of overt IDDM and insulitis resistant, while the frequency of disease in the B lymphocyte intact segregants was equivalent to that of standard NOD mice in our colony. Thus, B lymphocytes play a heretofore unrecognized role that is essential for the initial development and/or activation of beta cell autoreactive T cells in NOD mice.
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Carvalho, Thiago L., Tomaz Mota-Santos, Ana Cumano, Jocelyne Demengeot, and Paulo Vieira. "Arrested B Lymphopoiesis and Persistence of Activated B Cells in Adult Interleukin 7−/− Mice." Journal of Experimental Medicine 194, no. 8 (2001): 1141–50. http://dx.doi.org/10.1084/jem.194.8.1141.
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Interleukin 7 is a crucial factor for the development of murine T and B lymphocytes. We now report that, in the absence of interleukin 7, B lymphocyte production takes place exclusively during fetal and perinatal life, ceasing after 7 wk of age. In peripheral organs, however, the pool of B lymphocytes is stable throughout adult life and consists only of cells that belong to the B1 and marginal zone (MZ) compartments. This is accompanied by a 50-fold increase in the frequency of immunoglobulin (Ig)M- and IgG-secreting cells, and the concentration of serum immunoglobulins is increased three- to fivefold. Both the MZ phenotype and the increase in serum IgM are T cell independent. These findings reveal a previously undescribed pathway of B lymphopoiesis that is active in early life and is interleukin 7 independent. This pathway generates B1 cells and a normal sized MZ B lymphocyte compartment.
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Scielzo, Cristina, Maria T. S. Bertilaccio, Giorgia Simonetti, et al. "HS1 has a central role in the trafficking and homing of leukemic B cells." Blood 116, no. 18 (2010): 3537–46. http://dx.doi.org/10.1182/blood-2009-12-258814.
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Abstract The function of the intracellular protein hematopoietic cell–specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1−/− mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2−/−γc−/− mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone Eμ-TCL1 transgenic mice crossed with HS1-deficient mice were compared with Eμ-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL.
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Rajakariar, Ravindra, Toby Lawrence, Jonas Bystrom, et al. "Novel biphasic role for lymphocytes revealed during resolving inflammation." Blood 111, no. 8 (2008): 4184–92. http://dx.doi.org/10.1182/blood-2007-08-108936.
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Abstract Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1−/− mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D2. However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), γ/δ T, CD4+/CD25+, and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1−/− and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox−/− mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.
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Way, Sing Sing, Alain C. Borczuk, and Marcia B. Goldberg. "Thymic Independence of Adaptive Immunity to the Intracellular Pathogen Shigella flexneri Serotype 2a." Infection and Immunity 67, no. 8 (1999): 3970–79. http://dx.doi.org/10.1128/iai.67.8.3970-3979.1999.
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ABSTRACT Shigella flexneri is a facultative intracellular pathogen. While immunity to several intracellular pathogens is mediated by T lymphocytes, it is unknown whether cellular immune responses are important to adaptive immunity to S. flexneri. We show that vaccination with S. flexneri serotype 2a confers protection to mice that lack T lymphocytes or gamma interferon (IFN-γ), specific depletion of T lymphocytes does not alter the protection, and adoptive transfer of splenocytes from vaccinated mice does not confer protection to naive mice. In contrast, vaccination conferred no protection to mice that lack B lymphocytes and adoptive transfer of immune sera conferred partial protection to naive mice. These data demonstrate that in the mouse bronchopulmonary model, adaptive immunity to S. flexneri 2a is an antibody-mediated, B-lymphocyte-dependent process and can be generated in the absence of T lymphocytes or IFN-γ.
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Bosma, G. C., M. Fried, R. P. Custer, A. Carroll, D. M. Gibson, and M. J. Bosma. "Evidence of functional lymphocytes in some (leaky) scid mice." Journal of Experimental Medicine 167, no. 3 (1988): 1016–33. http://dx.doi.org/10.1084/jem.167.3.1016.
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Although the majority of severe combined immune deficiency (scid) mice lack functional lymphocytes, some (2-23%) appear to develop a limited number of B and T cells between 3 and 9 mo old. Most of these leaky scid mice were shown to contain very few clones (less than or equal to 3) of Ig-producing plasmacytes. Clonal progeny were distributed unevenly in the lymphatic tissues and appeared as discrete plasmacytic foci. In many cases, individual clones persisted for several months and produced abnormally high concentrations of Ig that included multiple isotypes. Functional T cells were inferred from the ability of leaky mice to reject allogeneic skin grafts, a T cell-dependent reaction. Interestingly, approximately 40% of leaky mice developed thymic lymphomas. In other respects, leaky mice resembled regular scid mice; e.g., their splenic cells failed to express common lymphocyte antigens (Ly-5[B220], Ly-1) and to proliferate in response to lymphocyte mitogens. Histologically, their lymphoid tissues retained the same general pattern of severe lymphocytic deficiency as scid mice.
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Seo, Sachiko, Takashi Asai, Toshiki Saito, et al. "Cas-L/Hef1 Is Required for Marginal Zone B Cell Maintenance and Lymphocyte Trafficking." Blood 106, no. 11 (2005): 3920. http://dx.doi.org/10.1182/blood.v106.11.3920.3920.
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Abstract Cas-L (Crk-associated substrate lymphocyte type) which is also known as Hef1 (human enhancer of filamentation 1) was first identified as a protein tyrosine-phosphorylated upon stimulation of b1 integrin. Cas-L possesses a single Src homology (SH) 3 domain and multiple YXXP motifs (substrate domain) as a member of Cas protein family, and is well expressed in peripheral lymphocytes. Previous studies suggest that Cas-L might be involved in Bcr-Abl positive leukemia and adult T cell leukemia. However, the biological function of Cas-L in lymphocytes is little known. We generated Cas-L-deficient mice using a gene targeting strategy. The mice showed a deficit of marginal zone (MZ) B cells and a decrease of cell number in secondary lymphoid organs. To elucidate the mechanism of the MZ B cell defect, the reciprocal bone marrow transfer assays were performed. The results revealed that the defect of MZ B cells in Cas-L-deficient mice is cell autonomous. Next, we analyzed B cell receptor signaling by measurement of intracellular Ca2+ concentration and lymphocyte proliferation. However, we could not find any significant differences between wild type and Cas-L-deficient mice. Cas-L-deficient lymphocytes showed reduced chemotactic response to CXCL12 and CXCL13. The adhesion assay also showed the decreased adhesiveness to VCAM-1 and ICAM-1, which are important for retention of MZ B cells in spleen. Moreover, we found that the lymphocyte trafficking to spleen and lymph nodes was altered in Cas-L-deficient mice. Thus, Cas-L affects homeostasis of MZ B cells and peripheral lymphoid organs, which is considered to be relevant to impaired lymphocyte migration and adhesion.
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Lu, Di, Tian Ma, XiangBin Zhou, YanMing Jiang, Yan Han, and Hong Li. "B Lymphocytes Are the Target of Mesenchymal Stem Cells Immunoregulatory Effect in a Murine Graft-versus-Host Disease Model." Cell Transplantation 28, no. 9-10 (2019): 1279–88. http://dx.doi.org/10.1177/0963689719860127.
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There is growing clinical interest in the utilization of mesenchymal stem cells (MSCs) in the management of acute graft-versus-host disease (aGvHD), yet the effect of major histocompatibility complexes (MHCs) on B lymphocytes in this process has been less well documented. Working in an MHC fully mismatched murine aGvHD model, we found that MSC co-transfer significantly prolonged the survival time of the recipients. More interestingly, analysis on immunophenotypic profiles of posttransplant splenocytes showed that surface expression of CD69 (an early activation marker) and CD86 (a costimulatory molecule) was suppressed predominantly on donor derived B lymphocytes by MSC infusion. Additionally, mRNA level of interleukin-4, a potent B lymphocyte stimulator, was strikingly reduced from MSC-treated mice, while interleukin-10, the regulatory B lymphocytes inductor, was increased; these may underlie the lesser activation of B lymphocytes. In consistence, depletion of B lymphocytes in the transfusion inoculum further prolonged the survival time of aGvHD mice regardless of MSC administration. Therefore, B lymphocytes played an important role in the development of aGvHD, and they are targets in MSC-regulated immune response cascade in vivo. This study may provide a mechanistic clue for the treatment of human clinical aGvHD.
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Oh, Chanho, Youngahn Kim, Jaesoon Eun, Toshihiro Yokoyama, Masashi Kato, and Izumi Nakashima. "Induction of T Lymphocyte Apoptosis by Treatment with Glycyrrhizin." American Journal of Chinese Medicine 27, no. 02 (1999): 217–26. http://dx.doi.org/10.1142/s0192415x99000252.
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The effect of glycyrrhizin (GL), a Chinese herbal drug extracted from licolice roots, on murine lymphocytes for inducing apoptotic cell death was studied. Addition of GL (25-400 μg/ml) to cultured splenocytes and thymocytes from BALB/c mice definitely promoted DNA fragmentation. A single injection of GL (100 μg/mouse) into BALB/c mice did not cause any detectable DNA fragmentation or cell death of splenocytes and thymocytes. Cytofluorometric analysis of these cells, however, demonstrated a reduction in mitochondrial transmembrane potentials (ΔΨm). Repeated injections of GL (100 μg/mouse/day) into mice for 7 days actually resulted in induction of low grade DNA fragmentation selectively in splenocytes. Cell population analysis of viable lymphocytes suggested that both CD4+ Th lymphocytes and CD8+ Tc lymphocytes may have been relatively more sensitive than B220+ B lymphocytes for the apoptotic cell death. We concluded from these results that GL acts as a rather selective inducer of mature T lymphocyte apoptosis with a reduction in ΔΨm potentially preceding lymphocyte death.
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Fagoaga, Omar R., Steven M. Yellon, and Sandra L. Nehlsen-Cannarella. "Maturation of Lymphocyte Immunophenotypes and Memory T Helper Cell Differentiation During Development in Mice." Developmental Immunology 8, no. 1 (2000): 47–60. http://dx.doi.org/10.1155/2000/56106.
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The goal of this study was to systematically investigate the ontogeny of lymphoid populations throughout postnatal development. In CD-1 mice, peak lymphocyte numbers occurred in blood on postnatal day 10 (dl0) including those for natural killers (NK1.1), B cells (CD19), T helper (CD3CD4), naïve T helper (CD4CD62LposCD44low), memory T helper (CD4CD62LnegCD44high), and T cytotoxic (CD3CD8) cells. As percent of total lymphocytes, peaks were achieved by d10 for all T helper subtypes but not B cells which declined to a nadir. In spleen, lymphocyte numbers increased exponentially after d10. Proportionately, NK and T cells peaked on d10, declined by d20, and increased 2–3-fold by d45. Naive T cells constituted the majority of lymphocytes during development while memory cells gained to 2.2% (blood) and 12 % (spleen) by d20. C57BL/6 mice had similar profiles except that the B cell nadir and T cell subset peaks were at d5. Peripheralization of critical numbers of lymphocytes by d10, and importantly, development of a repertoire of memory cells by d20, may define immune response capabilities that close the period of immaturity for the neonate.
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Ferraz, Marcela L., Ricardo T. Gazzinelli, Rosana O. Alves, Julio A. Urbina, and Alvaro J. Romanha. "Absence of CD4+ T Lymphocytes, CD8+ T Lymphocytes, or B Lymphocytes Has Different Effects on the Efficacy of Posaconazole and Benznidazole in Treatment of Experimental Acute Trypanosoma cruzi Infection." Antimicrobial Agents and Chemotherapy 53, no. 1 (2008): 174–79. http://dx.doi.org/10.1128/aac.00779-08.
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ABSTRACT We investigated the influence of CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes on the efficacy of posaconazole (POS) and the reference drug benznidazole (BZ) during treatment of acute Trypanosoma cruzi infection in a murine model. Wild-type mice infected with T. cruzi and treated with POS or BZ presented no parasitemia, 100% survival, and 86 to 89% cure rates, defined as the percentages of animals with negative hemocultures at the end of the observation period. CD4+-T-lymphocyte-knockout (KO) mice infected with T. cruzi and treated with BZ or POS controlled parasitemia during treatment, although circulating parasites reappeared after drug pressure cessation, leading to only a 6% survival rate and no cure. CD8+-T-lymphocyte-KO mice infected with T. cruzi and treated with POS or BZ had intermediate results, displaying discrete parasitemia after the treatment was ended, 81 and 86% survival, and cure rates of 31 and 66%, respectively. B-lymphocyte-KO mice infected with T. cruzi and treated with BZ relapsed with parasitemia 1 week after the end of treatment and had a 67% survival rate and only a 22% cure rate. In contrast, the activity of POS was much less affected in these animals, with permanent suppression of parasitemia, 100% survival, and a 71% cure rate. Our results demonstrate that abrogation of different lymphocytes’ activities has distinct effects on the efficacy of POS and BZ in this experimental model, probably reflecting different parasite stages preferentially targeted by the two drugs and distinct cooperation patterns with the host immune system.
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Barrington, Robert A., Olga Pozdnyakova, Mohammad R. Zafari, Christopher D. Benjamin, and Michael C. Carroll. "B Lymphocyte Memory." Journal of Experimental Medicine 196, no. 9 (2002): 1189–200. http://dx.doi.org/10.1084/jem.20021110.
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To dissect the influence of CD21/CD35 and FcγRIIB in antigen retention and humoral memory, we used an adoptive transfer model in which antigen-primed B and T lymphocytes were given to sublethally irradiated wild-type mice or mice deficient in CD21/CD35 (Cr2−/−) or FcγRIIB receptors (FcγRIIB−/−). Cr2−/− chimeras showed impaired memory as characterized by a decrease in antibody titer, reduced frequency of antibody secreting cells, an absence of affinity maturation, and significantly reduced recall response. The impaired memory in Cr2−/− chimeras corresponded with the reduced frequency of antigen-specific memory B cells. Interestingly, FcγRIIB−/− chimeras showed a differential phenotype with impaired splenic but normal bone marrow responses. These data suggest that CD21/CD35 on stroma, including follicular dendritic cells, is critical to the maintenance of long-term B lymphocyte memory.
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Haas, Karen M. "B-1 lymphocytes in mice and nonhuman primates." Annals of the New York Academy of Sciences 1362, no. 1 (2015): 98–109. http://dx.doi.org/10.1111/nyas.12760.
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Chung, Chun-Shiang, Weiyang Wang, Irshad H. Chaudry, and Alfred Ayala. "Increased apoptosis in lamina propria B cells during polymicrobial sepsis is FasL but not endotoxin mediated." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 5 (2001): G812—G818. http://dx.doi.org/10.1152/ajpgi.2001.280.5.g812.
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Recent studies from our laboratory demonstrated that mucosal lymphoid tissue such as Peyer's patch cells and lamina propria (LP) B lymphocytes from mice shows evidence of increased apoptosis after sepsis that is associated with localized inflammation/activation. The mechanism for this is poorly understood. Endotoxin as well as Fas/Fas ligand (FasL) have been shown to augment lymphocyte apoptosis; however, their contribution to the increase of apoptosis in LP B-cells during sepsis is not known. To study this, sepsis was induced by cecal ligation and puncture (CLP) in endotoxin-tolerant C3H/HeJ or FasL-deficient C3H/HeJ- FasLgld(FasL−) mice and LP lymphocytes were isolated 24 h later. Phenotypic, apoptotic, and functional indexes were assessed. The number of LP B cells decreased markedly in C3H/HeJ mice but not in FasL-deficient animals at 24 h after CLP. This was associated with comparable alteration in apoptosis and Fas antigen expression in the B cells of these mice. Septic LP lymphocytes also showed increased IgA production, which was absent in the FasL-deficient CLP mice. Furthermore, Fas ligand deficiency appeared to improve survival of septic challenge. These data suggest that the increase in B cell apoptosis in septic animals is partially due to a Fas/FasL-mediated process but not endotoxin.
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Cachat, Julien, Christine Deffert, Stephanie Hugues, and Karl-Heinz Krause. "Phagocyte NADPH oxidase and specific immunity." Clinical Science 128, no. 10 (2015): 635–48. http://dx.doi.org/10.1042/cs20140635.
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The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.
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Grahnemo, Louise, Caroline Jochems, Annica Andersson, et al. "Possible role of lymphocytes in glucocorticoid-induced increase in trabecular bone mineral density." Journal of Endocrinology 224, no. 1 (2014): 97–108. http://dx.doi.org/10.1530/joe-14-0508.
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Treatment with anti-inflammatory glucocorticoids is associated with osteoporosis. Many of the treated patients are postmenopausal women, who even without treatment have an increased risk of osteoporosis. Lymphocytes have been shown to play a role in postmenopausal and arthritis-induced osteoporosis, and they are targeted by glucocorticoids. The aim of this study was to investigate the mechanisms behind effects of glucocorticoids on bone during health and menopause, focusing on lymphocytes. Female C57BL/6 or SCID mice were therefore sham-operated or ovariectomized and 2 weeks later treatment with dexamethasone (dex), the nonsteroidal anti-inflammatory drug carprofen, or vehicle was started and continued for 2.5 weeks. At the termination of experiments, femurs were phenotyped using peripheral quantitative computed tomography and high-resolution micro-computed tomography, and markers of bone turnover were analyzed in serum. T and B lymphocyte populations in bone marrow and spleen were analyzed by flow cytometry. Dex-treated C57BL/6 mice had increased trabecular bone mineral density, but lower cortical content and thickness compared with vehicle-treated mice. The dex-treated mice also had lower levels of bone turnover markers and markedly decreased numbers of spleen T and B lymphocytes. In contrast, these effects could not be repeated when mice were treated with the nonsteroidal anti-inflammatory drug carprofen. In addition, dex did not increase trabecular bone in ovariectomized SCID mice lacking functional T and B lymphocytes. In contrast to most literature, the results from this study indicate that treatment with dex increased trabecular bone density, which may indicate that this effect is associated with corticosteroid-induced alterations of the lymphocyte populations.
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Telieps, Tanja, Meike Köhler, Irina Treise, et al. "Longitudinal Frequencies of Blood Leukocyte Subpopulations Differ between NOD and NOR Mice but Do Not Predict Diabetes in NOD Mice." Journal of Diabetes Research 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/4208156.
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Immune phenotyping provides insight into disease pathogenesis and prognostic markers. Trajectories from age of 4 to 36 weeks were modeled for insulin autoantibodies and for leukocyte subpopulations in peripheral blood from female NOD (n=58) and NOR (n=22) mice. NOD mice had higher trajectories of insulin autoantibodies, CD4+and CD8+T lymphocytes, B lymphocytes, IgD+IgM−B lymphocytes, and NK cells and lower trajectories of CD4+CD25+T lymphocytes, IgM+B lymphocytes, granulocytes, and monocytes than NOR mice (allp<0.001). Of these, only the increased IAA trajectory was observed in NOD mice that developed diabetes as compared to NOD mice that remained diabetes-free. Therefore, the profound differences in peripheral blood leukocyte proportions observed between the diabetes-prone NOD mice and the diabetes-resistant mice do not explain the variation in diabetes development within NOD mice and do not provide markers for diabetes prediction in this model.
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Mosier, D. E., R. A. Yetter, and H. C. Morse. "Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice." Journal of Experimental Medicine 161, no. 4 (1985): 766–84. http://dx.doi.org/10.1084/jem.161.4.766.
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We have shown that a mixture of murine leukemia viruses (MuLV) causes the acute onset of lymphoproliferation and immunosuppression when injected into adult C57BL/6 mice. The ecotropic/MCF (mink cell focus-inducing) mixture of MuLV stimulates polyclonal B lymphocyte proliferation and differentiation to antibody-secreting cells. Serum Ig levels are elevated for all isotypes except IgA. The viral infection leads to a rapid decline in T lymphocyte responses to mitogens and alloantigens, as well as a decrease in helper cell activity. Specific antibody responses to both T-dependent and T-independent antigens are impaired, and the response of B lymphocytes to mitogens is abolished. The profound immunosuppression seems to be due to the MuLV-induced polyclonal activation of lymphocytes. No active suppression of normal lymphocyte responses by cells from virus-infected mice was observed. The disease induced by the LP-BM5 MuLV isolate thus seems a promising model for the study of lymphocyte activation and the mechanisms of retrovirus-induced immunosuppression.
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Shappell, S. B., T. Gurpinar, J. Lechago, W. N. Suki, and L. D. Truong. "Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: lymphocyte infiltration is not required for progressive tubulointerstitial injury." Journal of the American Society of Nephrology 9, no. 6 (1998): 1008–17. http://dx.doi.org/10.1681/asn.v961008.
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Progressive renal injury in humans and experimental animal models is characterized by tubular atrophy, infiltration of mononuclear inflammatory cells, and interstitial fibrosis. Permanent unilateral ureter ligation represents a reproducible model for investigating mechanisms of progressive kidney injury, and in the rat is characterized by tubular epithelial cell proliferation followed by apoptosis and progressive infiltration of monocytes and lymphocytes. Nevertheless, whether monocytes or lymphocytes play a dominant role in causing tubulointerstitial damage remains to be elucidated. In the current study, a model of chronic obstructive uropathy in the mouse is established and the role of lymphocyte infiltration in the evolution of the tubule and interstitial alterations is investigated. Permanent ligation of the left ureter in wild-type (C3H/HeJ) mice resulted in progressive atrophy of tubules and interstitial fibrosis compared with the contralateral kidney over a 30-d period. Immunoperoxidase studies on frozen sections taken from kidneys at 0, 3, 10, 20, and 30 d after ureter ligation showed that the tubulointerstitial injury was accompanied by a marked and progressive increase in interstitial macrophages and T lymphocytes, with no appreciable increase in B lymphocytes. No increase in inflammatory cells was detected in contralateral kidneys over the same time frame. The significance of T lymphocyte infiltration was examined by comparing the degree of tubular atrophy and interstitial fibrosis and the nature and quantity of the inflammatory infiltrate in wild-type mice and C3HSMn.C-Scid/J (SCID) mice subjected to permanent left ureter ligation. SCID mice have genetic defects in immunoglobulin and T cell receptor gene rearrangements and are devoid of circulating mature B and T lymphocytes. Wild-type and SCID mice developed tubular atrophy and interstitial volume expansion in the ligated kidney to the same degree and at the same rate. SCID mice developed a prominent and marked monocyte/macrophage infiltrate in the ligated kidney, which was essentially equal to that in wild-type mice. In contrast, consistent with the known absence of mature lymphocytes in SCID mice, there was essentially no T lymphocyte infiltration into the ligated kidney of SCID mice. These results demonstrate the effective establishment of the model of maintained unilateral ureter ligation in mice, which is readily applicable to genetic mutant strains thus allowing for specific investigation of the role of individual components of the inflammatory response in progressive tubulointerstitial injury. These studies further demonstrate that lymphocyte infiltration is not required for progressive tubular atrophy and increased interstitial fibrosis after maintained unilateral ureter ligation.
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Dudley, Darryll D., JoAnn Sekiguchi, Chengming Zhu, et al. "Impaired V(D)J Recombination and Lymphocyte Development in Core RAG1-expressing Mice." Journal of Experimental Medicine 198, no. 9 (2003): 1439–50. http://dx.doi.org/10.1084/jem.20030627.
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RAG1 and RAG2 are the lymphocyte-specific components of the V(D)J recombinase. In vitro analyses of RAG function have relied on soluble, highly truncated “core” RAG proteins. To identify potential functions for noncore regions and assess functionality of core RAG1 in vivo, we generated core RAG1 knockin (RAG1c/c) mice. Significant B and T cell numbers are generated in RAG1c/c mice, showing that core RAG1, despite missing ∼40% of the RAG1 sequence, retains significant in vivo function. However, lymphocyte development and the overall level of V(D)J recombination are impaired at the progenitor stage in RAG1c/c mice. Correspondingly, there are reduced numbers of peripheral RAG1c/c B and T lymphocytes. Whereas normal B lymphocytes undergo rearrangement of both JH loci, substantial levels of germline JH loci persist in mature B cells of RAG1c/c mice, demonstrating that DJH rearrangement on both IgH alleles is not required for developmental progression to the stage of VH to DJH recombination. Whereas VH to DJH rearrangements occur, albeit at reduced levels, on the nonselected alleles of RAG1c/c B cells that have undergone D to JH rearrangements, we do not detect VH to DH rearrangements in RAG1c/c B cells that retain germline JH alleles. We discuss the potential implications of these findings for noncore RAG1 functions and for the ordered assembly of VH, DH, and JH segments.
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Robles, Eloy F., Beatriz Aldaz, Takashi Akasaka, et al. "Homeobox NKX2-3 Is Over-Expressed in Human B-Cell Lymphomas and Drives Marginal Zone B-Cell Lymphomagenesis in Mice." Blood 118, no. 21 (2011): 260. http://dx.doi.org/10.1182/blood.v118.21.260.260.
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Abstract Abstract 260 While the molecular study of the common immunoglobulin (IG) translocations, hallmarks of B-cell lymphomas, led to the discovery of seminal cancer genes such as MYC and BCL2, cloning of other less frequent rearrangements has also identified genes with critical biological functions, including BCL10 and BCL11A. Therefore, molecular cloning of rare IG-related translocations may still pinpoint genes with unappreciated roles in lymphomagenesis. We identified a novel chromosomal translocation t(10;14)(q24;q32) involving the IGH locus in a case of mature B-cell lymphoma in leukemic phase. Molecular cloning by long-distance inverse PCR revealed involvement of NKX2-3. Subsequent screening of lymphoma cases with 10q chromosome breaks using fluorescence in situ hybridization identified a t(10;14)(q24;q12) translocation fusing NKX2-3 with TCRA. Both cases were classified as atypical low-grade mature B-cell lymphoma and exhibited increased expression of NKX2-3 with respect to normal B lymphocytes. In addition, NKX2-3 over-expression using quantitative RT-PCR and immunohistochemistry was detected in 42 of 166 (25%) primary mature B-cell lymphoma samples, including 15 of 29 (51%) splenic marginal zone lymphomas (SMZL), 14 of 46 (30%) mucosa-associated lymphoid tissue (MALT) lymphomas, and 13 of 42 (31%) diffuse large B-cell lymphomas (DLBCLs), but not in follicular lymphomas (0 of 18), mantle cell lymphomas (0 of 8) or chronic B-cell lymphocytic leukemias (0 of 23). NKX2-3 belongs to the NKX family of homeodomain transcription factors that regulate cell-specific gene expression during differentiation and development. In mice, Nkx2-3 is essential for spleen and MALT development by regulating lymphocyte migration and homing to these sites. To determine whether NKX2-3 might, like some other family members, play an oncogenic role in hematopoietic neoplasms, Eμ-NKX2-3 transgenic mice were generated in which the EμSR enhancer drove restricted expression of human NKX2-3 to lymphocytes. Mice were fertile and developed normally. However, from 4 months of age, a progressive block in the pro-B (B220+CD19+Kit+) to pre-B cell (B220+CD25+) transition was detected in the bone marrow (BM), accompanied by a decrease in the number of circulating B220+IgM+B lymphocytes. Notably, an expansion of CD21highCD23low marginal-zone splenic B cells was identified, which correlated with progressive spleen enlargement upon ultrasound monitoring of transgenic animals. From ∼12 months of age, mice started to develop clinical signs of disease and were euthanized, showing massive splenomegaly (5–10 times larger than normal controls) in all cases (n=46). Histolopathological analysis of enlarged spleens revealed a complete red pulp infiltration of large and irregular nodules composed of cells with a biphasic morphology comprising an inner zone of small lymphocytes and a peripheral zone of larger lymphoid cells. Immunohistochemical studies showed that the infiltrating cells were mature CD20+IgM+IgD− B lymphocytes, with reactive CD3+ T lymphocytes, results that were concordant with flow cytometry studies. In 55% of the mice, additional extranodal tumors involving the lungs, liver and kidneys were detected, showing infiltrates of small mature B lymphocytes. Study of Igh, Igk and Igl rearrangements by PCR and sequencing revealed that most lymphomas were of clonal origin. Using gene expression microarray analysis, a significant overlap was found between the transcriptional signatures of the mouse NKX2-3 splenic lymphomas and human SMZLs, including genes known to be involved in human SMZL pathogenesis such as Notch2, Jun, Junb, Cyclin-D2, Ikzf3, Cxcr4, Traf5 and Maml2, as well as other genes implicated in mature B-cell lymphoma development such as Bcl3, Pax5, Bcl11a, Foxo3, Cebpb, Litaf, Socs1, IL10, Ccl5 and Cdkn1a. Taken together, these data indicate that the murine tumors closely resembled human splenic and extranodal marginal-zone (MALT) lymphomas. Furthermore, analysis of splenic and extranodal lymphomas from mice older than 18 months revealed areas of high-grade transformation to DLBCL, further highlighting the parallelism between splenic and human lymphomas. In conclusion, NKX2-3 protein is over-expressed in a subset of patients with SMZL, MALT lymphoma and DLBCL, and that the ectopic expression of NKX2-3 in mouse B lymphocytes recapitulates the main features of the human lymphoma counterparts. Disclosures: Siebert: Abbott/Vysis: Speakers Honorarium.
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Nakayama, K., K. Nakayama, L. B. Dustin, and D. Y. Loh. "T-B cell interaction inhibits spontaneous apoptosis of mature lymphocytes in Bcl-2-deficient mice." Journal of Experimental Medicine 182, no. 4 (1995): 1101–9. http://dx.doi.org/10.1084/jem.182.4.1101.
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Bcl-2 expression is tightly regulated during lymphocyte development. Mature lymphocytes in Bcl-2-deficient mice show accelerated spontaneous apoptosis in vivo and in vitro. Stimulation of Bcl-2-deficient lymphocytes by anti-CD3 antibody inhibited the spontaneous apoptosis not only in T cells but also in B cells. The rescue of B cells was dependent on the presence of T cells, mainly through CD40L and interleukin (IL)-4. Furthermore, we generated Bcl-2-deficient mice transgenic for a T cell receptor or an immunoglobulin, both specific for chicken ovalbumin, to test for antigen-specific T-B cell interaction in the inhibition of the spontaneous apoptosis. The initial T cell activation by antigenic peptides presented by B cells suppressed apoptosis in T cells. Subsequently, T cells expressed CD40L and released ILs, leading to the protection of B cells from spontaneous apoptosis. These results suggest that the antiapoptotic signaling via CD40 or IL-4 may be largely independent of Bcl-2. Engagement of the Ig alone was not sufficient for the inhibition of B cell apoptosis. Thus, the physiological role of Bcl-2 in mature lymphocytes may be to protect cells from spontaneous apoptosis and to extend their lifespans to increase the opportunity for T cells and B cells to interact with each other and specific antigens in secondary lymphoid tissues. Bcl-2, however, appears to be dispensable for survival once mature lymphocytes are activated by antigen-specific T-B cell collaboration.
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Prete, Pamela E. "Membrane surface properties of lymphocytes of normal (DBA/2) and autoimmune (NZB/NZW)F1 mice: effects of L-canavanine and a proposed mechanism for diet-induced autoimmune disease." Canadian Journal of Physiology and Pharmacology 64, no. 9 (1986): 1189–96. http://dx.doi.org/10.1139/y86-202.
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Partitioning cells in a dextran polyethylene glycol aqueous two-phase system (countercurrent distribution, CCD) is a sensitive method for learning about cell surface membrane properties and for subfractionating cell populations. In this study, we subjected lymphocytes from normal DBA/2 mice and autoimmune F1 New Zealand black/New Zealand white ((NZB/NZW)F1) mice to countercurrent distribution and found that T cells partition to the right and B cells partition to the left of the CCD curve. We found no difference between the CCD patterns of normal and autoimmune mice. When the murine lymphocytes were exposed to a cationic dietary amino acid (L-canavanine) in vitro, L-canavanine selectively affected the CCD pattern of autoimmune B cells, reflecting an alteration in surface membrane properties. We separated these lymphocytes with altered surface membrane properties by CCD. Impaired B-cell immune responses associated with L-canavanine were isolated to this lymphocyte fraction. This study provides the first evidence that alterations in the charged surface membrane properties are associated with abnormal (auto) immune response.
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Casellas, Rafael, Qingzhao Zhang, Nai-Ying Zheng, Melissa D. Mathias, Kenneth Smith та Patrick C. Wilson. "Igκ allelic inclusion is a consequence of receptor editing". Journal of Experimental Medicine 204, № 1 (2007): 153–60. http://dx.doi.org/10.1084/jem.20061918.
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The discovery of lymphocytes bearing two light chains in mice carrying self-reactive antibody transgenes has challenged the “one lymphocyte–one antibody” rule. However, the extent and nature of allelically included cells in normal mice is unknown. We show that 10% of mature B cells coexpress both Igκ alleles. These cells are not the result of failure in allelic exclusion per se, but arise through receptor editing. We find that under physiological conditions, editing occurs both by deletion and by inclusion with equal probability. In addition, we demonstrate that B lymphocytes carrying two B-cell receptors are recruited to germinal center reactions, and thus fully participate in humoral immune responses. Our data measure the scope of allelic inclusion and provide a mechanism whereby autoreactive B cells might “escape” central tolerance.
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Rodrigues de Santana, Fabiana, Cidéli de Paula Coelho, Thayná Neves Cardoso, et al. "Modulation of inflammation response to murine cutaneous Leishmaniasis by homeopathic medicines: Antimonium crudum 30cH." Homeopathy 103, no. 04 (2014): 264–74. http://dx.doi.org/10.1016/j.homp.2014.08.006.
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Background: Leishmaniasis is a zoonotic disease caused by protozoan parasites of the mononuclear phagocytic system. The modulation activity of these cells can interfere in the host/parasite relationship and influences the prognosis.Methods: We evaluated the effects of the homeopathic preparation Antimonium crudum 30cH on experimental infection induced by Leishmania (L.) amazonensis. Male Balb/c mice were inoculated with 2 × 106 Leishmania (L.) amazonensis promastigotes into the footpad and, after 48 h (acute phase) or 60 days (chronic phase), cell population of lymphocytes and phagocytes present in the peritoneal washing fluid and spleen were analyzed by flow cytometry and histopathology, with histometry of the subcutaneous primary lesion, local lymph node and spleen. Immunohistochemistry was performed to quantify CD3 (T lymphocyte), CD45RA (B lymphocyte) and CD11b (phagocytes) positive cells.Results: In treated mice, during the acute phase, there was significant increase of the macroscopic lesion, associated to inflammatory edema, as well increase in the number of free amastigotes and B lymphocytes inside the lesion. Increase of B lymphocytes (predominantly B-2 cells) was also seen in the local lymph node, spleen and peritoneum. In the chronic phase, the inflammatory process in the infection focus was reduced, with reduced phagocyte migration and peritoneal increase of B-1a cells (precursors of B-2 immunoglobulin producers cells) and T CD8+ cells.Conclusion: The treatment of mice with Antimonium crudum 30cH induced a predominantly B cell pattern of immune response in Leishmania (L.) amazonensis experimental infection, alongside the increase of free amastigote forms number in the infection site. The clinical significance of this study is discussed, further studies are suggested.
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Sánchez-González, Berenice, Francisco Javier García-Vázquez, José Eduardo Farfán-Morales, and Luis Antonio Jiménez-Zamudio. "Increased NHC Cells in the Peritoneal Cavity of Plasmacytoma Susceptible BALB/c Mouse." Mediators of Inflammation 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/313140.
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BALB/c strain mice are unique in that they develop murine plasmacytoma (MPC) as a consequence of the inflammation induced by pristane oil injection in the peritoneal cavity. In this work the Treg, Th17, B1, B2, and NHC lymphocyte populations from the peritoneal environment of BALB/c, the susceptible strain, and C57BL/6 mice, which do not develop MPC after oil treatment, were studied. Both oil-treated strains showed decreased levels of Th17 lymphocytes, no significant variation in Treg lymphocytes, and a drastic decrease of all B lymphocyte populations. However, only oil-induced BALB/c showed increased levels of natural helper cells (NHC) which could be important in the myeloma induction.
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Neumann, B., A. Luz, K. Pfeffer, and B. Holzmann. "Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor." Journal of Experimental Medicine 184, no. 1 (1996): 259–64. http://dx.doi.org/10.1084/jem.184.1.259.
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Lymphotoxin alpha (LT-alpha) may form secreted homotrimers binding to p55 and p75 tumor necrosis factor (TNF) receptors or cell surface-bound heterotrimers with LT-beta that interact with the LT-beta receptor. Genetic ablation of LT-alpha revealed that mutant mice have no detectable lymph nodes or Peyer's patches and that the organization of the splenic white pulp in T and B cell areas is disturbed. In this report we describe a novel function for the p55 TNF receptor during ontogeny and demonstrate that mice deficient for p55 completely lack organized Peyer's patches. In contrast, lymph nodes and spleen are present in p55-deficient mice and lymphocytes segregate normally into B and T cell areas in these organs. Lamina propria and intraepithelial lymphocytes of the small intestine were detected in normal number and distribution in p55 mutant mice. Lymphocytes and endothelial cells from p55-deficient mice express normal levels of adhesion molecules considered important for lymphocyte migration to mucosal organs; this indicates that the lack of Peyer's patches does not result from a defect in lymphocyte homing. In summary, the p55 receptor for TNF selectively mediates organogenesis of Peyer's patches throughout ontogeny, suggesting that the effects of LT-alpha on the development of lymphoid organs may be mediated by distinct receptors, each functioning in an organ-specific context.
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Vacani-Martins, Natalia, Marcelo Meuser-Batista, Otacilio C. Moreira та ін. "After Experimental Trypanosoma cruzi Infection, Dying Hepatic CD3+TCRαβ+B220+ T Lymphocytes Are Rescued from Death by Peripheral T Cells and Become Activated". Pathogens 9, № 9 (2020): 717. http://dx.doi.org/10.3390/pathogens9090717.
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The unusual phenotype of CD3+ T lymphocyte expressing B220, a marker originally attributed to B lymphocytes, was first observed in the liver of Fas/Fas-L-deficient mice as a marker of apoptotic T lymphocytes. However, other CD3+B220+ T lymphocyte populations were later described in the periphery as functional cytotoxic or regulatory cells, for example. Then, in this work, we studied whether hepatic CD3+B220+ T lymphocytes could play a role in experimental Trypanosoma cruzi infection. In control and infected mice, we observed two subpopulations that could be discerned based on CD117 expression, which were conventional apoptotic CD3+B220+(CD117−) and thymus-independent CD3+B220+CD117+ T lymphocytes. Regardless of CD117 expression, most B220+ T lymphocytes were 7AAD+, confirming this molecule as a marker of dying T cells. However, after infection, we found that around 15% of the CD3+B220+CD117+ hepatic population became B220 and 7AAD negative, turned into CD90.2+, and upregulated the expression of CD44, CD49d, and CD11a, a phenotype consistent with activated T lymphocytes. Moreover, we observed that the hepatic CD3+B220+CD117+ population was rescued from death by previously activated peripheral T lymphocytes. Our results extend the comprehension of the hepatic CD3+B220+ T lymphocyte subpopulations and illustrate the complex interactions that occur in the liver.
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Ostrowski, Matias, Monica Vermeulen, Osvaldo Zabal, et al. "The Early Protective Thymus-Independent Antibody Response to Foot-and-Mouth Disease Virus Is Mediated by Splenic CD9+ B Lymphocytes." Journal of Virology 81, no. 17 (2007): 9357–67. http://dx.doi.org/10.1128/jvi.00677-07.
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ABSTRACT Infection of mice with cytopathic foot-and-mouth disease virus (FMDV) induces a rapid and specific thymus-independent (TI) neutralizing antibody response that promptly clears the virus. Herein, it is shown that FMDV-infected dendritic cells (DCs) directly stimulate splenic innate-like CD9+ B lymphocytes to rapidly (3 days) produce neutralizing anti-FMDV immunoglobulin M antibodies without T-lymphocyte collaboration. In contrast, neither follicular (CD9−) B lymphocytes from the spleen nor B lymphocytes from lymph nodes efficiently respond to stimulation with FMDV-infected DCs. The production of these protective neutralizing antibodies is dependent on DC-derived interleukin-6 (IL-6) and on CD9+ cell-derived IL-10 secretion. In comparison, DCs loaded with UV-inactivated FMDV are significantly less efficient in directly stimulating B lymphocytes to secrete TI antibodies. A critical role of the spleen in the early production of anti-FMDV antibodies in infected mice was also demonstrated in vivo. Indeed, either splenectomy or functional disruption of the marginal zone of the spleen delays and reduces the magnitude of the TI anti-FMDV antibody response in infected mice. Together, these results indicate that in addition to virus localization, the FMDV-mediated modulation of DC functionality is a key parameter that collaborates in the induction of a rapid and protective TI antibody response against this virus.
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Homann, Dirk, Antoinette Tishon, Dietmar P. Berger, William O. Weigle, Matthias G. von Herrath та Michael B. A. Oldstone. "Evidence for an Underlying CD4 Helper and CD8 T-Cell Defect in B-Cell-Deficient Mice: Failure To Clear Persistent Virus Infection after Adoptive Immunotherapy with Virus-Specific Memory Cells from μMT/μMT Mice". Journal of Virology 72, № 11 (1998): 9208–16. http://dx.doi.org/10.1128/jvi.72.11.9208-9216.1998.
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ABSTRACT Adoptive transfer of virus-specific memory lymphocytes can be used to identify factors and mechanisms involved in the clearance of persistent virus infections. To analyze the role of B cells in clearing persistent infection with lymphocytic choriomeningitis virus (LCMV), we used B-cell-deficient μMT/μMT (B−/−) mice. B−/− mice controlled an acute LCMV infection with the same kinetics and efficiency as B-cell-competent (B+/+) mice via virus-specific, major histocompatibility complex (MHC) class I-restricted CD8+cytotoxic T lymphocytes (CTL). CTL from B−/− and B+/+ mice were equivalent in affinity to known LCMV CTL epitopes and had similar CTL precursor frequencies (pCTL). Adoptive transfer of memory cells from B+/+ mice led to virus clearance from persistently infected B+/+ recipients even after in vitro depletion of B cells, indicating that B cells or immunoglobulins are not required in the transfer population. In contrast, transfer of memory splenocytes from B−/− mice failed to clear virus. Control of virus was restored neither by transferring higher numbers of pCTL nor by supplementing B−/− memory splenocytes with LCMV-immune B cells or immune sera. Instead, B−/− mice were found to have a profound CD4 helper defect. Furthermore, compared to cultured splenocytes from B+/+ mice, those from B−/− mice secreted less gamma interferon (IFN-γ) and interleukin 2, with differences most pronounced for CD8 T cells. While emphasizing the importance of CD4 T-cell help and IFN-γ in the control of persistent infections, the CD4 T-helper and CD8 T-cell defects in B−/− mice suggest that B cells contribute to the induction of competent T effector cells.
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Fagarasan, Sidonia, Reiko Shinkura, Tadashi Kamata та ін. "Alymphoplasia (aly)-Type Nuclear Factor κB–Inducing Kinase (Nik) Causes Defects in Secondary Lymphoid Tissue Chemokine Receptor Signaling and Homing of Peritoneal Cells to the Gut-Associated Lymphatic Tissue System". Journal of Experimental Medicine 191, № 9 (2000): 1477–86. http://dx.doi.org/10.1084/jem.191.9.1477.
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Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor κB–inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/+ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2−/− mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.
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Zhong, Xuemei, Chunyan Bai, and Thomas L. Rothstein. "Suppression of Negative Immune Regulators PD-1 and PD-L1 Expression on Lymphocytes by Inflammatory Cytokines." Blood 104, no. 11 (2004): 2663. http://dx.doi.org/10.1182/blood.v104.11.2663.2663.
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Abstract The strength and duration of lymphocyte activation is determined by the net effect of positive and negative regulatory co-signaling molecules. The inhibitory receptor PD-1 and its ligand PD-L1 are both expressed on activated lymphocytes. Mice deficient of PD-1 or PD-L1 demonstrate lymphocyte hyperactivity and are prone to autoimmunity. We have shown that the expression and function of PD-1 on activated B lymphocytes can be down-regulated by certain inflammatory cytokines, rendering them resistant to PD-L1 mediated suppression. Here we further report that both PD-1 and PD-L1 expression on activated T lymphocytes can be down-regulated in a similar fashion. Thus, in addition to stimulating positive regulators, inflammatory cytokines may boost immune responses and break self-tolerance by inhibiting a negative regulator on T and B lymphocytes. Our findings may indicate a potential mechanism for the link between chronic inflammation and autoimmunity.
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Tadayon, Sina, Johannes Dunkel, Akira Takeda, et al. "Clever-1 contributes to lymphocyte entry into the spleen via the red pulp." Science Immunology 4, no. 33 (2019): eaat0297. http://dx.doi.org/10.1126/sciimmunol.aat0297.
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Lymphocytes recirculate continuously between the blood and lymphoid organs, a process that is of fundamental importance for proper functioning of the immune system. The molecular mechanisms underlying lymphocyte trafficking to the spleen remain an enigma. Here, we show that lymphocytes enter the spleen preferentially from vessels in the red pulp rather than the marginal sinus or the vasculature in the white pulp. Ex vivo adhesion assays in mice and humans, together with genetic ablation of Clever-1 in mice, indicate that CD8+T cell and B220+B cell homing to the spleen via the red pulp is Clever-1 dependent. Moreover, absence of Clever-1 leads to down-regulation of the B cell attractant chemokine, CXCL13, on spleen endothelium. CXCL13 is known to guide B cell trafficking to lymphoid organs, and its lack may contribute to the observed decrease in B cell trafficking into the spleen as well. In summary, this study identifies Clever-1 as an important molecule controlling lymphocyte entry into the spleen, along with a critical role for the splenic red pulp in this regulated trafficking. Furthermore, the results demonstrate that location-specific homing-associated molecules guide lymphocyte entry into the spleen.
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Okada, Seiji, Hideki Harada, and Shinya Suzu. "Enhanced Human Hematopoietic Cell Engraftment and T Lymphocyte Development in NOD/Scid/Jak-3 Null Mice." Blood 108, no. 11 (2006): 5143. http://dx.doi.org/10.1182/blood.v108.11.5143.5143.
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Abstract Xenotransplantation of human cells into immunodeficient mice has been used to develop models of human hematopoiesis and immune function. In this study, we generated the NOD/Scid mice with null mutation of Jak-3 (NOD/Scid/Jak-3 null) by 10 backcross mating of C57/BL6-Jak-3 null mice and NOD/Scid mice. NOD/Scid/Jak-3 null mice had NK and NKT cells as well as mature T and B lymphocytes. NK activity was not also detected in this mice. Intrahepatic injection of CD34+ human cord blood cells into irradiated (2.0Gy) newborn NOD/Scid/Jak-3 null mice led to de novo development of B and T lymphocytes. In addition to the high engraftment rate of human hematopoietic cells, multilineage cell differentiation including T cell lineage was obserbed. T lymphocyte appeared in peripheral blood as early as 8 weeks after transplantation and it was increased in number thereafter. Both naive and memory phenotype CD4 and CD8 T lymphocytes were detected 12 weeks after transplantation. Plasma cells were detected in the bone marrow 20 weeks after transplantation. Furthermore the engrafted mice were infected with HIV. Our model mice provide a valuable model to study not only development and function of human hematopoeitic and immune system but also the immune response to the cancer and infectious disease such as HIV.
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Inaoki, Makoto, Shinichi Sato, Bennett C. Weintraub, Christopher C. Goodnow, and Thomas F. Tedder. "CD19-Regulated Signaling Thresholds Control Peripheral Tolerance and Autoantibody Production in B Lymphocytes." Journal of Experimental Medicine 186, no. 11 (1997): 1923–31. http://dx.doi.org/10.1084/jem.186.11.1923.
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The CD19 cell surface molecule regulates signal transduction events critical for B lymphocyte development and humoral immunity. Increasing the density of CD19 expression renders B lymphocytes hyper-responsive to transmembrane signals, and transgenic mice that overexpress CD19 have increased levels of autoantibodies. The role of CD19 in tolerance regulation and autoantibody generation was therefore examined by crossing mice that overexpress a human CD19 transgene with transgenic mice expressing a model autoantigen (soluble hen egg lysozyme, sHEL) and high-affinity HEL-specific IgMa and IgDa (IgHEL) antigen receptors. In this model of peripheral tolerance, B cells in sHEL/IgHEL double-transgenic mice are functionally anergic and do not produce autoantibodies. However, it was found that overexpression of CD19 in sHEL/IgHEL double-transgenic mice resulted in a breakdown of peripheral tolerance and the production of anti-HEL antibodies at levels similar to those observed in IgHEL mice lacking the sHEL autoantigen. Therefore, altered signaling thresholds due to CD19 overexpression resulted in the breakdown of peripheral tolerance. Thus, CD19 overexpression shifts the balance between tolerance and immunity to autoimmunity by augmenting antigen receptor signaling.
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Portnoï, D., A. Freitas, D. Holmberg, A. Bandeira, and A. Coutinho. "Immunocompetent autoreactive B lymphocytes are activated cycling cells in normal mice." Journal of Experimental Medicine 164, no. 1 (1986): 25–35. http://dx.doi.org/10.1084/jem.164.1.25.
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Frequencies of B cell clonal precursors producing antibodies that react with mouse thyroglobulin, mouse erythrocytes, beef hemoglobin, KLH, and sheep erythrocytes were determined by limiting dilution analyses among small, resting lymphocytes, and among large activated cells from normal adult mice. While frequencies of clones reacting with external antigens were equally distributed in large and small B cells, most, if not all, autoreactive B lymphocytes were found in the large cell fraction. Analysis of antithyroglobulin hybridomas isolated from normal mice revealed dissociation constants ranging from 10(-6) to 5-6 X 10(-7). Treatment of normal donors with antimitotic drugs dramatically decreases the frequencies of autoreactive B cells, but not those of B lymphocytes reacting with external antigenic molecules. Taken together, these experiments show that immunocompetent, autoreactive B lymphocytes are activated and cycling cells in the peripheral lymphoid tissues of normal individuals.
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Hibbs, Margaret L., Kenneth W. Harder, Jane Armes, et al. "Sustained Activation of Lyn Tyrosine Kinase In Vivo Leads to Autoimmunity." Journal of Experimental Medicine 196, no. 12 (2002): 1593–604. http://dx.doi.org/10.1084/jem.20020515.
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Genetic ablation of the Lyn tyrosine kinase has revealed unique inhibitory roles in B lymphocyte signaling. We now report the consequences of sustained activation of Lyn in vivo using a targeted gain-of-function mutation (Lynup/up mice). Lynup/up mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. Lynup/up B cells are characterized by the constitutive phosphorylation of negative regulators of B cell antigen receptor (BCR) signaling including CD22, SHP-1, and SHIP-1, and display attributes of lymphocytes rendered tolerant by constitutive engagement of the antigen receptor. However, exaggerated positive signaling is also apparent as evidenced by the constitutive phosphorylation of Syk and phospholipase Cγ2 in resting Lynup/up B cells. Similarly, Lynup/up B cells show a heightened calcium flux in response to BCR stimulation. Surprisingly, Lynup/up mice develop circulating autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting that enhanced positive signaling eventually overrides constitutive negative signaling. These studies highlight the difficulty in maintaining tolerance in the face of chronic stimulation and emphasize the pivotal role of Lyn in B cell signaling.
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Lis, Magdalena, Marianna Szczypka, Agnieszka Suszko-Pawłowska, Anna Sokół-Łętowska, Alicja Kucharska, and Bożena Obmińska-Mrukowicz. "Hawthorn (Crataegus monogyna) Phenolic Extract Modulates Lymphocyte Subsets and Humoral Immune Response in Mice." Planta Medica 86, no. 02 (2019): 160–68. http://dx.doi.org/10.1055/a-1045-5437.
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AbstractThis study investigated the effect of hawthorn (Crataegus monogyna) phenolic extract on lymphocyte subsets in the lymphoid organs in nonimmunized mice and on humoral immune response in sheep red blood cell-immunized mice. Hawthorn phenolic extract (50, 100, 200 mg/kg) was administered orally five or ten times. Sheep red blood cells were injected 24 h after administration of the last extract dose. The lymphocyte subsets were assessed 24 and 72 h after the last dose. Humoral immune response was determined 4 and 7 days after immunization. Five doses of the extract decreased the percentage of CD4−CD8− and CD4+ thymocytes but elevated the percentage of CD4+CD8+ and CD8+ thymic cells. The extract increased the total number, percentage, and absolute count of T and B splenocytes. When administered five times, it lowered the percentage of T lymphocytes, but boosted the population of B lymphocytes of mesenteric lymph nodes (after 24 h). However, a rise in the population of T lymphocytes was observed 72 h after five and ten doses. The extract administered ten times elevated the number of plaque-forming cells and total anti-sheep red blood cell hemagglutinin titer but reduced the 2-ME-resistant antibody titer (day 7). At the same time, five doses of the extract increased antibody titers. Considering its impact on lymphocyte subsets and humoral immune response, hawthorn extract may be used as an immunomodulator.
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Osman, Mohammad, Janice Russell та D. Neil Granger. "Lymphocyte-derived interferon-γ mediates ischemia-reperfusion-induced leukocyte and platelet adhesion in intestinal microcirculation". American Journal of Physiology-Gastrointestinal and Liver Physiology 296, № 3 (2009): G659—G663. http://dx.doi.org/10.1152/ajpgi.90495.2008.
Full textAbstract:
Although previous studies have implicated lymphocytes in the gut microvascular and inflammatory responses to ischemia-reperfusion (I/R), the lymphocyte population and lymphocyte-derived products that mediate these responses have not been defined. Platelet and leukocyte adhesion was measured in intestinal postcapillary venules of wild-type (WT) mice and mice genetically deficient in either CD4+ T cells (CD4−/−), CD8+ T cells (CD8−/−), B cells (B cell−/−), or interferon-γ (IFN-γ−/−) subjected to 45 min of ischemia and 4 h of reperfusion. The I/R-induced platelet and leukocyte recruitment responses were also evaluated following adoptive transfer of WT splenocytes into CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. WT mice exposed to gut I/R exhibited significant increases in the adhesion of both platelets and leukocytes, compared with sham-WT mice. These blood cell adhesion responses to I/R were greatly attenuated in CD4−/−, CD8−/−, B cell−/−, and IFN-γ−/− mice. Adoptive transfer of WT splenocytes restored the WT responses to I/R in all mutants except the B cell−/− mice. These findings implicate both T and B cells and lymphocyte-derived IFN-γ as mediators of the proinflammatory and prothrombogenic phenotype assumed by intestinal microvessels after I/R.
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Johnson, Victor J., Jeffrey S. Reynolds, Wei Wang, Kara Fluharty, and Berran Yucesoy. "Inhalation of Ortho-Phthalaldehyde Vapor Causes Respiratory Sensitization in Mice." Journal of Allergy 2011 (July 14, 2011): 1–12. http://dx.doi.org/10.1155/2011/751052.
Full textAbstract:
Ortho-Phthalaldehyde (OPA) has been approved for high-level sterilization of heat-sensitive medical instruments and is increasingly being used as a replacement in the healthcare industry for glutaraldehyde, a known sensitizer. Numerous case reports have been published indicating workers and patients experiencing respiratory problems, anaphylaxis, skin reactivity, and systemic antibody production. Our laboratory previously demonstrated that OPA is a dermal sensitizer in mice. The goal of the present study was to determine if OPA is a respiratory sensitizer following inhalation exposure. Mice were exposed to OPA vapor and airway and lymph nodes were examined for cytokine gene expression and alterations in lymphocyte populations. Inhalation of OPA for 3 days resulted in a concentration-dependent increase in lymphocyte proliferation, mainly B lymphocytes, in the draining lymph nodes. A secondary challenge of mice with OPA resulted in a dramatic increase in the population of B lymphocytes expressing IgE. Expression of Th2 (IL-4, IL-5, and IL-13) and anti/proinflammatory (IL-10, TNFα, and IL-1β) cytokine genes was upregulated in the lymph nodes and the nasal mucosa. Mice exposed to the higher concentrations of OPA-produced OPA-specific IgG1 antibodies indicating systemic sensitization. These findings provide evidence that OPA has the potential to cause respiratory sensitization in mice.
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Cao, Xuefang, Paula A. Revell, William J. Grossman, Dori A. Thomas, Zhi Hong Lu, and Timothy J. Ley. "Orphan Granzymes Downstream from Granzyme B Are Important for Tumor Clearance In Vivo and in Vitro." Blood 104, no. 11 (2004): 2653. http://dx.doi.org/10.1182/blood.v104.11.2653.2653.
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Abstract Cytotoxic lymphocytes (Natural Killer cells and Cytotoxic T lymphocytes) can utilize the perforin/granzyme pathway as a major mechanism to kill pathogen-infected cells and tumor cells. Perforin is responsible for delivering and/or trafficking the granzymes (a family of neutral serine proteases) to the target cells. In the target cell cytoplasm and nucleus, the granzymes deliver the lethal hits. Granzymes A and B are the best characterized granzymes, and they can cleave a variety of important protein substrates to execute the target cells. However, some tumors and viruses have developed potent granzyme inhibitors that may allow them to evade cytotoxic lymphocyte-induced death. Interestingly, additional granzyme genes downstream from granzyme B (C, F, G, and D) on murine chromosome 14 are also expressed in cytotoxic lymphocytes, and are referred to as “orphans” since their functions have not been defined. We have developed two kinds of granzyme B knockout mice in the 129/SvJ background (H-2b) and examined their expression of granzyme B and orphan granzymes using quantitative RT-PCR and Western Blotting. In the first mouse (Gzm B−/−/+PGK-neo) a PGK-neo cassette was retained in the granzyme B gene, which caused a neighborhood effect, with significantly reduced expression of orphan granzymes C and F in cytotoxic lymphocytes (this mouse is referred to as “B cluster” deficient); In the second mouse (Gzm B−/−/ΔPGK-neo) the PGK-neo cassette was removed by Cre/loxP technology, which restored expression of granzymes C and F in cytotoxic lymphocytes (referred to as “B only” deficient). Both mutations completely abolish granzyme B expression. Using a Flow-based Killing Assay (FloKA), we have examined the cytotoxic functions of lymphocytes derived from mixed lymphocyte reactions (MLR) and 10-day lymphokine activated killer (LAK) cultures. We have found that granzyme B cluster-deficient cytotoxic lymphocytes (H-2b) generated by MLR kill allogeneic P815 or TA-3 tumor cells (H-2d) less efficiently than those deficient for granzyme B only (e.g. P815 killing at 3 hours, WT: 35%±1%, B only-deficient: 24%±5%, B cluster-deficient: 14%±3%, p&lt;0.001). The reduction in granzyme B cluster-deficient killing is also seen with LAK cells against YAC-1 and RMA-S target cells (e.g. RMA-S killing at 4 hours, WT: 26%±1%, B only-deficient: 24%±1%, B cluster-deficient: 18%±1%, p&lt;0.001). These results suggest that both allogeneic CTL and LAK cells require orphan granzymes (C and/or F) for optimal tumor cell killing. The defects in cytotoxicity detected by the FloKA assay have been confirmed to be biologically relevant (Revell et al, Blood2003, 102 (11): 1022) since granzyme B cluster-deficient mice cleared P815 cells less efficiently than either WT or granzyme B only-deficient mice (p&lt;0.02). These studies suggest that the orphan granzymes are important for cytotoxic lymphocyte functions, and that they may provide a source of functional redundancy that would help protect from pathogens or tumor cells that express inhibitors of granzyme A or B.
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Sedger, Lisa M., Arna Katewa, Ann K. Pettersen, et al. "Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice." Blood 115, no. 16 (2010): 3258–68. http://dx.doi.org/10.1182/blood-2009-11-255497.
Full textAbstract:
Abstract To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3+CD4−CD8−B220+ T cells, CD4+ and CD8+ T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4+ and CD8+ T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-γ once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease.
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Henning, Golo, Lars Ohl, Tobias Junt, et al. "CC Chemokine Receptor 7–dependent and –independent Pathways for Lymphocyte Homing." Journal of Experimental Medicine 194, no. 12 (2001): 1875–81. http://dx.doi.org/10.1084/jem.194.12.1875.
Full textAbstract:
Cognate interaction of chemokine receptor CCR7 on lymphocytes with its ligands CCL19 and CCL21 expressed on high endothelial venules (HEVs) is essential for effective migration of T and B cells across HEVs into secondary lymphoid organs. Plt mice, which lack expression of CCL19 and CCL21-ser, both ligands for CCR7 on HEVs, as well as CCR7-deficient mice, have a defective cell migration and reduced homing of lymphocytes. FTY720, a novel immunosuppressant, causes a reduction of lymphocytes in peripheral blood and tissues and their sequestration into lymphoid tissues. In this study we demonstrate that FTY720 rescues the homing defect in both CCR7−/− mice and plt mice. After FTY720 treatment, the number of CD4+ and CD8+ T cells as well as B cells in peripheral blood is reduced while pertussis toxin–sensitive homing into peripheral lymph nodes, mesenteric lymph node, and Peyer's patches is increased. Immunohistology demonstrates that FTY720 enables these cells to enter lymphoid tissue through HEVs. Thus, our data suggest an alternative G-αi-dependent, CCR7-CCL19/CCL21-independent mechanism for lymphocyte homing through HEVs which is strongly augmented in the presence of FTY720.
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Moulin, Véronique, Fabienne Andris, Kris Thielemans, Charlie Maliszewski, Jacques Urbain, and Muriel Moser. "B Lymphocytes Regulate Dendritic Cell (Dc) Function in Vivo." Journal of Experimental Medicine 192, no. 4 (2000): 475–82. http://dx.doi.org/10.1084/jem.192.4.475.
Full textAbstract:
Increasing evidence indicates that dendritic cells (DCs) are the antigen-presenting cells of the primary immune response. However, several reports suggest that B lymphocytes could be required for optimal T cell sensitization. We compared the immune responses of wild-type and B cell-deficient (μMT) mice, induced by antigen emulsified in adjuvant or pulsed on splenic dendritic cells. Our data show that lymph node cells from both control and μMT animals were primed, but each released distinct cytokine profiles. Lymph node T cells from control animals secreted interferon (IFN)-γ, interleukin (IL)-2, and IL-4, whereas those from μMT mice produced IFN-γ and IL-2 but no IL-4. To test whether B cells may influence the T helper cell type 1 (Th1)/Th2 balance by affecting the function of DCs, we immunized mice by transferring antigen-pulsed DCs from wild-type or mutant mice. Injection of control DCs induced the secretion of IL-4, IFN-γ, and IL-2, whereas administration of DCs from μMT animals failed to sensitize cells to produce IL-4. Analysis of IL-12 production revealed that DCs from μMT mice produce higher levels of IL-12p70 than do DCs from wild-type animals. These data suggest that B lymphocytes regulate the capacity of DCs to promote IL-4 secretion, possibly by downregulating their secretion of IL-12, thereby favoring the induction of a nonpolarized immune response.
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Hu, Yiguo, Thomas Sproule, Cong Peng, et al. "Immunodominant Minor Histocompatibility Antigen-Specific T Lymphocytes Eradicate BCR-ABL-Induced B-ALL and CML without Causing Graft-Versus-Host Disease in Mice." Blood 108, no. 11 (2006): 3686. http://dx.doi.org/10.1182/blood.v108.11.3686.3686.
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Abstract Adoptive immunotherapy of human Philadelphia chromosome-positive (Ph+) leukemia has not been effective due to difficulties of identifying tumor-specific antigens for the disease. It has been reported that T lymphocytes activated by some minor histocompatibility antigens (mHAs) can efficiently treat mice receiving HL4 cells (a leukemia cell line) without causing graft-versus-host disease (GVHD). We investigated whether this anti-mHA immunotherapeutic strategy is applicable to treating Ph+ leukemia that includes B-ALL (B-cell acute lymphoblastic leukemia) and CML (chronic myeloid leukemia). Because the mHA, H60, is an immunodominant mHA among H7, H28, and H58 in mice (Choi et al, Immunity 17:593–603, 2002), we tested whether H60 can serve as an immunotherapeutic target in the treatment of B-ALL and CML in our retroviral bone marrow transduction/transplantation disease models (Li et al, J Exp Med189:1399–1412, 1999). We used C57BL/6-H60 congenic mouse splenocytes to immunize wild type C57BL/6 (B6) mice that do not have the H60 gene, and the activated T lymphocytes from the immunized B6 mice were injected into mice with BCR-ABL-induced B-ALL or CML (3×107 cells/mouse). We found that H60-specific T lymphocytes at a single dose completely eliminated leukemic cells within 10 days after the injection of the cells and cured B-ALL and CML, however, in mice receiving donor bone marrow cells transduced with empty vector and treated with H60-specific T lymphocytes, the non-BCR-ABL-expressing donor marrow cells lasted for more than 4 weeks, suggesting that H60-activated T lymphocytes have much stronger inhibitory effect on BCR-ABL-expressing leukemic cells than on normal marrow cells. In contrast, leukemia mice receiving naïve T lymphocytes died within 3 to 4 weeks post BCR-ABL induction of leukemia. Six months later, no residual leukemia cells were detected in the spleen and bone morrow of the leukemia mice receiving H60-activated T lymphocytes. In addition, no GVHD was observed in the mice. We also use H7/H28/H60 triple congenic B6 mice in our study, and found that H7/H28/H60-primed T lymphocytes were more effective in elimination of leukemia cells in mice compared with when the single H60 antigen was used in similar experiment. Especially, the H7/H28/H60-primed T lymphocytes were highly effective in treating B-ALL mice, and did not induce GVHD. These results indicate that mHAs are promising targets for immunotherapy of BCR-ABL-induced B-ALL and CML.
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Ishihara, Katsuhiko, Kay Medina, Shin-Ichi Hayashi, et al. "Stromal-Cell and Cytokine-Dependent Lymphocyte Clones Which Span the Pre-B- to B-Cell Transition." Developmental Immunology 1, no. 3 (1991): 149–61. http://dx.doi.org/10.1155/1991/79721.
Full textAbstract:
Five stromal-cell-dependent lymphocyte clones are described that correspond to late pre-B or early B-cell stages of differentiation.They are useful for determining the molecular requirements for pre-B replication, for studying the stromal cells that supply those factors, and for delineating the final sequence of differentiation events as newly formed lymphocytes prepare to exit the bone marrow. The efficiency of lymphocyte growth at limiting dilution varied substantially on different stromal-cell clones and may reflect functional heterogeneity of stromal cells. Most lymphocyte clones were similar to uncloned lymphocytes from Whitlock-Witte cultures in that they responded only transiently to interleukin-7 (IL-7) and then died, unless maintained on a stromal-cell clone. One unusual lymphocyte clone (2E8) was propagated for more than 1 year in IL-7 alone and was selectively responsive to that cytokine. Most of the lymphocyte clones were not tumorigenic in immunodeficient mice. However, one pre-B clone (1A9)’grew autonomously in culture when held at high density, responded to conditioned medium from a number of cell lines, and was tumorigenic. Tumors derived from this clone were infiltrated by stromal cells and lymphocytes taken from the tumors' retained characteristics of the original clone. Ly-6 antigens were inducible on 2E8 and 1A9 cells, but the lymphocytes were otherwise arrested in differentiation. The 2E8 cells had rearranged and expressedκlight-chain genes but displayed them on the surface along with surrogate light chains andμheavy chains. Thus, expression of authentic Tight chain need not coincide with termination of surrogate light-chain utilization in newly formed B cells. Several glycoproteins have recently been demonstrated to be associated with surface immunoglobulin (Ig) on mature B-lineage cells and plasma-cell tumors. We now show that one member of this family (approximately 33 kD) was associated with theμ+surrogate light-chain complex on the 1A9 pre-B-cell clone. When compared to mature B lymphomas, fewer bands coprecipitated with the surface-labeled Ig isolated from pre-B- and early B-cell lines, suggesting that components of the antigen receptor are sequentially acquired during development. The normal replication and differentiation of pre-B cells is probably regulated by complex interactions with multiple cytokines and matrix components of the marrow microenvironment. Cloned lymphocyte lines that are dependent on stromal cells should continue to be important tools for molecular definition of those interactions.
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Santidrián, Antonio F., Diana M. González-Gironès, Daniel Iglesias-Serret, et al. "AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells." Blood 116, no. 16 (2010): 3023–32. http://dx.doi.org/10.1182/blood-2010-05-283960.
Full textAbstract:
Abstract 5-Aminoimidazole-4-carboxamide riboside or acadesine (AICAR) induces apoptosis in chronic lymphocytic leukemia (CLL) cells. A clinical study of AICAR is currently being performed in patients with this disease. Here, we have analyzed the mechanisms involved in AICAR-induced apoptosis in CLL cells in which it activates its only well-known molecular target, adenosine monophosphate-activated protein kinase (AMPK). However, AMPK activation with phenformin or A-769662 failed to induce apoptosis in CLL cells and AICAR also potently induced apoptosis in B lymphocytes from Ampkα1−/− mice, demonstrating an AMPK-independent mechanism of cell death. Importantly, AICAR induced apoptosis irrespective of the tumor suppressor TP53 or ataxia telangiectasia mutated (ATM) status via induction of the mitochondrial pathway. Apoptosis was preceded by an increase in mRNA and protein levels of proapoptotic BCL-2 family proteins of the BH3-only subgroup, including BIM, NOXA, and PUMA in CLL cells. Strikingly, B lymphocytes from Noxa−/− or Bim−/− mice were partially protected from the cytotoxic effects of AICAR. Consistently, B cells from Noxa−/−/Bim−/− mice resisted induction of apoptosis by AICAR as potently as B lymphocytes overexpressing transgenic BCL-2. These findings support the notion that AICAR is an interesting alternative therapeutic option for CLL patients with impaired p53 function and resistance to conventional chemotherapy.