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1.
Loh C Pau E Lajoie G Li TT Baglaenko Y Cheung YH Chang NH Wither JE 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(10):5845-5853
Numerous mapping studies have implicated genetic intervals from lupus-prone New Zealand Black (NZB) chromosomes 1 and 4 as contributing to lupus pathogenesis. By introgressing NZB chromosomal intervals onto a non-lupus-prone B6 background, we determined that: NZB chromosome 1 congenic mice (denoted B6.NZBc1) developed fatal autoimmune-mediated kidney disease, and NZB chromosome 4 congenic mice (denoted B6.NZBc4) exhibited a marked expansion of B1a and NKT cells in the surprising absence of autoimmunity. In this study, we sought to examine whether epistatic interactions between these two loci would affect lupus autoimmunity by generating bicongenic mice that carry both NZB chromosomal intervals. Compared with B6.NZBc1 mice, bicongenic mice demonstrated significantly decreased mortality, kidney disease, Th1-biased IgG autoantibody isotypes, and differentiation of IFN-γ-producing T cells. Furthermore, a subset of bicongenic mice exhibited a paucity of CD21(+)CD1d(+) B cells and an altered NKT cell activation profile that correlated with greater disease inhibition. Thus, NZBc4 contains suppressive epistatic modifiers that appear to inhibit the development of fatal NZBc1 autoimmunity by promoting a shift away from a proinflammatory cytokine profile, which in some mice may involve NKT cells. 相似文献
2.
Loh C Cai YC Bonventi G Lajoie G Macleod R Wither JE 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(3):1608-1617
Previous mapping studies have linked New Zealand Black (NZB) chromosome 4 to several lupus traits, including autoantibody production, splenomegaly, and glomerulonephritis. To confirm the presence of these traits, our laboratory introgressed homozygous NZB chromosome 4 intervals extending from either 114 to 149 Mb or 32 to 149 Mb onto the lupus-resistant C57BL/6 background (denoted B6.NZBc4S and B6.NZBc4L, respectively). Characterization of aged cohorts revealed that B6.NZBc4L mice exhibited a striking increase in splenic B1a and NKT cells in the absence of high titer autoantibody production and significant renal disease. Tissue-specific expansion of these subsets was also seen in the peritoneum and liver for B1a cells and in the bone marrow for NKT cells. Staining with CD1d tetramers loaded with an alpha-galactosylceramide analog (PBS57) demonstrated that the expanded NKT cell population was mainly CD1d-dependent NKT cells. The lack of both cellular phenotypes in B6.NZBc4S mice demonstrates that the genetic polymorphism(s) that result in these phenotypes are on the proximal region of NZB chromosome 4. This study confirms the presence of a locus that promotes the expansion of B1a cells and newly identifies a region that promotes CD1d-restricted NKT cell expansion on NZB chromosome 4. Taken together, the data indicate that neither an expansion of B1a cells and/nor NKT cells is sufficient to promote autoantibody production and ultimately, renal disease. 相似文献
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Tadafumi Yokoyama Ayumi Yoshizaki Karen L. Simon Martha R. Kirby Stacie M. Anderson Fabio Candotti 《PloS one》2015,10(10)
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by recurrent infections, thrombocytopenia, eczema, and high incidence of malignancy and autoimmunity. The cellular mechanisms underlying autoimmune complications in WAS have been extensively studied; however, they remain incompletely defined. We investigated the characteristics of IL-10-producing CD19+CD1dhighCD5+ B cells (CD1dhighCD5+ Breg) obtained from Was gene knockout (WKO) mice and found that their numbers were significantly lower in these mice compared to wild type (WT) controls. Moreover, we found a significant age-dependent reduction of the percentage of IL-10-expressing cells in WKO CD1dhighCD5+ Breg cells as compared to age-matched WT control mice. CD1dhighCD5+ Breg cells from older WKO mice did not suppress the in vitro production of inflammatory cytokines from activated CD4+ T cells. Interestingly, CD1dhighCD5+ Breg cells from older WKO mice displayed a basal activated phenotype which may prevent normal cellular responses, among which is the expression of IL-10. These defects may contribute to the susceptibility to autoimmunity with age in patients with WAS. 相似文献
5.
Bo Tang Wei Wu Xiaowei Wei Yang Li Gang Ren Wenhai Fan 《The Journal of biological chemistry》2014,289(50):34595-34600
Therapeutic outcomes of glioma are currently not encouraging. Tumor tolerance plays an important role in the pathogenesis of glioma. It is reported that micro RNAs (miR) are associated with tumor development. This study aims to investigate the role of miR-92a in the development of tolerant natural killer T (NKT) cells. In this study, U87 cells (a human glioma cell line) and primary glioma cells were prepared. The assessment of miR-92a was performed by real time RT-PCR. The expression of interleukin (IL)-10 and IL-6 in NKT cells was evaluated by flow cytometry. Results showed that abundant IL-6+ IL-10+ NKT cells were detected in glioma tissue. Cultures of glioma cells and NKT cells induced the expression of IL-6 and IL-10 in NKT cells. Glioma cells expressed miR-92a; the latter played a critical role in the induction of IL-6 and IL-10 expression in NKT cells. The expression of the antitumor molecules, including perforin, Fas ligand, and interferon-γ, was significantly attenuated compared with control NKT cells. The IL-6+ IL-10+ NKT cells showed less capability in the induction of apoptosis in glioma cells, but showed the immune suppressor functions on CD8+ T cell activities. We conclude that glioma-derived miR-92a induces IL-6+ IL-10+ NKT cells; this fraction of NKT cells can suppress cytotoxic CD8+ T cells. 相似文献
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Xiaoqian Yu Yuhua Wang Jiang Lin Yang Hu Toshihisa Kawai Martin A. Taubman Xiaozhe Han 《PloS one》2016,11(11)
Innate-like B lymphocytes play an important role in innate immunity in periodontal disease through Toll-like receptor (TLR) signaling. However, it is unknown how innate-like B cell apoptosis is affected by the periodontal infection-associated innate signals. This study is to determine the effects of two major TLR ligands, lipopolysaccharide (LPS) and CpG-oligodeoxynucleotides (CpG-ODN), on innate-like B cell apoptosis. Spleen B cells were isolated from wild type (WT), TLR2 knockout (KO) and TLR4 KO mice and cultured with E. coli LPS alone, P. gingivalis LPS alone, or combined with CpG-ODN for 2 days. B cell apoptosis and expressions of specific apoptosis-related genes were analyzed by flow cytometry and real-time PCR respectively. P. gingivalis LPS, but not E. coli LPS, reduced the percentage of AnnexinV+/7-AAD- cells within IgMhighCD23lowCD43-CD93- marginal zone (MZ) B cell sub-population and IgMhighCD23lowCD43+CD93+ innate response activator (IRA) B cell sub-population in WT but not TLR2KO or TLR4KO mice. CpG-ODN combined with P. gingivalis LPS further reduced the percentage of AnnexinV+/7-AAD- cells within MZ B cells and IRA B cells in WT but not TLR2 KO or TLR4 KO mice. Pro-apoptotic CASP4, CASP9 and Dapk1 were significantly down-regulated in P. gingivalis LPS- and CpG-ODN-treated B cells from WT but not TLR2 KO or TLR4 KO mice. Anti-apoptotic IL-10 was significantly up-regulated in P. gingivalis LPS- and CpG-ODN-treated B cells from WT and TLR2 KO but not TLR4 KO mice. These results suggested that both TLR2 and TLR4 signaling are required for P. gingivalis LPS-induced, CpG-ODN-enhanced suppression of innate-like B cell apoptosis. 相似文献
8.
There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to
stimulate CD8+ T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL
tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent
tumor-specific CD8+ T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8+ T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL
lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8+ CD44hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15
following vaccination did not secrete increased levels of tumor-specific TNF-α or IFN-γ or have enhanced C6VL-specific CTL
activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing
vaccinated mice. Thus, while activated- and memory-phenotype CD8+ T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8+ T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic
model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8+ T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively
transferred transgenic CD8+ T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and
activity of preexisting tumor-specific CD8+ T cells. 相似文献
9.
Background
Understanding the induction of immune regulatory cells upon helminth infection is important for understanding the control of autoimmunity and allergic inflammation in helminth infection. Babesia microti, an intraerythrocytic protozoan of the genus Babesia, is a major cause of the emerging human disease babesiosis, an asymptomatic malaria-like disease. We examined the influence of acute B. microti infection on the development of regulatory B cells together with regulatory T cells.Principal Findings
Our data demonstrate that B cells stimulated in vitro with B. microti produce interleukin (IL)-10. This cytokine is also secreted by B cells isolated from B. microti-infected mice in response to lipopolysaccharide stimulation. In addition, high levels of IL-10 were detected in the serum of mice after infection with B. microti. The frequency of IL-10-producing CD1dhighCD5+ regulatory B cells (Bregs) and CD4+CD25+FoxP3+ T cells increased during the course of B. microti infection. Furthermore, adoptive transfer of IL-10-producing B cells induced by B. microti infection led to increased susceptibility of recipient mice to infection with B. microti. In contrast, experiments with B cell-deficient (µMT) mice demonstrated that lack of B cells enhances susceptibility to B. microti infection.Conclusions
This study is the first demonstration of the expansion of Bregs following infection by an intraerythrocytic protozoan parasite. These data suggest that B. microti infection in mice provides an excellent model for studying Breg-mediated immune responses and begins to elucidate the mechanism by which helminth infection regulates autoimmunity and allergic inflammation. 相似文献10.
Christine M. Coquery Nekeithia S. Wade William M. Loo Jason M. Kinchen Kelly M. Cox Chao Jiang Kenneth S. Tung Loren D. Erickson 《PloS one》2014,9(7)
Despite increased frequencies of neutrophils found in autoimmune diseases such as systemic lupus erythematosus (SLE), how they contribute to disease pathogenesis and the mechanisms that affect the accumulation of neutrophils are poorly understood. The aim of this study was to identify factors in autoantibody-mediated autoimmunity that controls the accumulation of spleen resident neutrophils and to determine whether neutrophils contribute to abnormal B cell responses. Increased levels of the cytokine BAFF have been linked to loss of B cell tolerance in autoimmunity, but the cellular source responsible for excess BAFF is unknown. B cell maturation antigen (BCMA) is a receptor for BAFF and is critical for the survival of bone marrow plasma cells. Paradoxically, BCMA deficiency exacerbates the formation of autoantibody-secreting plasma cells in spleens of lupus-prone mice and the reasons for this effect are not understood. Here we analyzed the phenotype, localization and function of neutrophils in spleens of healthy mice and congenic lupus-prone mice, and compared mice sufficient or deficient in BCMA expression. Neutrophils were found to be significantly increased in frequency and activation status in spleens of lupus-prone mice when BCMA was absent. Furthermore, neutrophils localized within T cell zones and enhanced CD4+ T cell proliferation and IFNγ production through the production of BAFF. Reduced BAFF and IFNγ serum levels, decreased frequencies of IFNγ-producing T cells, germinal center B cells, and autoantibody production after neutrophil depletion indicated the involvement of neutrophils in these autoimmune traits. Thus, we have identified a novel role for BCMA to control excess BAFF production in murine lupus through restraining the accumulation of BAFF-producing neutrophils. Our data suggests that devising therapeutic strategies to reduce neutrophils in autoimmunity may decrease BAFF levels and ameliorate disease. 相似文献
11.
Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases. 相似文献
12.
Haijun Zhao Zhifeng Li Shiting Xie Yiming Luo Yong Zhou Manman Deng Hanyan Zeng Jintao Zhao Lian Yu Bing Xu 《Experimental cell research》2019,374(1):69-75
Type I natural killer T (NKT) cells are attractive candidates for cancer immunotherapy. In this study, we examined the characteristics of type I NKT cells in patients with adult B-cell acute lymphoblastic leukemia (ALL). We first identified type I NKT cells as Vα24-Jα18 and Vβ11 double-positive CD3+ lymphocytes. Using this method, we found that the adult B-cell ALL patients presented significantly lower level of type I NKT cells than the age- and sex-matching control subjects. The expression of IL-21 by type I NKT cells was then examined using intracellular flow cytometry, which showed that with α-GalCer stimulation, the adult B-cell ALL patients presented significantly lower level of IL-21+ type I NKT cells than control subjects. By both flow cytometry and ELISA, we found that the vast majority of IL-21-expressing type I NKT cells expressed IL-21R, which was also reduced in adult B-cell ALL patients. Using an in vitro co-culture system, we demonstrated that IL-21R+, but not IL-21R-, type I NKT cells could promote the IFN-γ, granzyme B, and perforin expression by CD8 T cells in an IL-21-dependent fashion. This type I NKT cell-mediated stimulatory effect was reduced in adult B-cell ALL patients than in control subjects. In addition, we observed a positive correlation between the frequency of IL-21R+ type I NKT cells and the frequencies of IFN-γ-, granzyme B-, and perforin-expressing circulating CD8 T cells in adult B-cell ALL patients directly ex vivo. Overall, this study identified an IL-21-related impairment in type I NKT cells from adult B-cell ALL patients. 相似文献
13.
David A Horwitz 《Arthritis research & therapy》2008,10(6):227
Regulatory/suppressor T cells (Tregs) maintain immunologic homeo-stasis and prevent autoimmunity. In this article, past studies
and recent studies of Tregs in mouse models for lupus and of human systemic lupus erythematosus are reviewed concentrating
on CD4+CD25+Foxp3+ Tregs. These cells consist of thymus-derived, natural Tregs and peripherally induced Tregs that are similar phenotypically
and functionally. These Tregs are decreased in young lupus-prone mice, but are present in normal numbers in mice with established
disease. In humans, most workers report CD4+Tregs are decreased in subjects with active systemic lupus erythematosus, but the cells increase with treatment and clinical
improvement. The role of immunogenic and tolerogenic dendritic cells in controlling Tregs is discussed, along with new strategies
to normalize Treg function in systemic lupus erythematosus. 相似文献
14.
Akihiro Tsukahara Hiroki Kawamura Tsuneo Iiai Tetsuya Moroda Susumu Suzuki Takashi Tada Masahiro Minagawa Nobuyuki Musha Katsuyoshi Hatakeyama Toru Abo 《Microbiology and immunology》1998,42(6):447-456
When C57BL/6 (B6) mice were irradiated (9 Gy) and received bone marrow (BM) cells of B6-lpr/lpr mouse origin (i.e., lpr→B6), all mice died within 6 days. In the irradiated B6 mice, radioresistant CD3? IL-2Rβ+ NK cells and IL-2Rβ CD3int cells (i.e., CD3int cells of extrathymic origin) remained, especially in the liver. There were two subsets, NK1.1+ and NK1.1?, among the IL-2Rβ+ CD3int cells. However, the NK1.1+ subset (i.e., NK1.1+ T cells) was much more radioresistant, and the majority of CD3int cells belonged to this subset in irradiated mice. The expansion of lymphocytes from injected BM cells did not occur in the irradiated B6 mice. However, such expansion did take place in irradiated B6-lpr/lpr mice injected with both BM cells of B6-lpr/lpr and B6 origin. As a result, the mice subjected to BM cells survived. Irradiated B6 mice were treated in vivo with anti-NK1.1 mAb or anti-asialoGM1 antibody to eliminate NK cells alone or both NK cells and NK1.1+ T cells. When irradiated B6 mice were pretreated with anti-NK1.1 mAb, the mice could survive. These results suggest that intact NK1.1+ T cells of extrathymic origin may recognize abnormal BM cells with the lpr gene and inhibit the expansion of lymphocytes, including abnormal double-negative CD4?8? cells, in B6-lpr/lpr mice. To inhibit the expansion of lymphocytes, mechanisms other than Fas ligand/Fas molecules on extrathymic T cells may be responsible. 相似文献
15.
Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and
natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways
can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT
cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine
production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study
whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8+ OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8+ cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8+ T cells were adoptively transferred into PD-L1−/− recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1−/− mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated
with increased trafficking of antigen-presenting cells and CD8+ T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells
amplifies an anti-tumor response when coupled with DC vaccination. 相似文献
16.
Linsen L Thewissen M Baeten K Somers V Geusens P Raus J Stinissen P 《Arthritis research & therapy》2005,7(3):R493-R502
Natural killer T (NKT) cells have been implicated in the regulatory immune mechanisms that control autoimmunity. However,
their precise role in the pathogenesis of rheumatoid arthritis (RA) remains unclear. The frequency, cytokine profile and heterogeneity
of NKT cells were studied in peripheral blood mononuclear cells (PBMCs) from 23 RA patients and 22 healthy control individuals,
including paired PBMC–synovial fluid samples from seven and paired PBMC–synovial tissue samples from four RA patients. Flow
cytometry revealed a decreased frequency of NKT cells in PBMCs from RA patients. NKT cells were present in paired synovial
fluid and synovial tissue samples. Based on the reactivity of PBMC-derived NKT cells toward α-galactosylceramide, RA patients
could be divided into responders (53.8%) and nonresponders (46.2%). However, NKT cells isolated from synovial fluid from both
responders and nonresponders expanded upon stimulation with α-galactosylceramide. Analysis of the cytokine profile of CD4+ and CD4- PBMC derived NKT cell lines from RA patients revealed a significantly reduced number of IL-4 producing cells. In contrast,
synovial fluid derived NKT cell lines exhibited a Th0-like phenotype, which was comparable to that in healthy control individuals.
This suggests that synovial fluid NKT cells are functional, even in patients with nonresponding NKT cells in their blood.
We conclude that, because the number of Vα24+Vβ11+CD3+ NKT cells is decreased and the cytokine profile of blood-derived NKT cells is biased toward a Th1-like phenotype in RA patients,
NKT cells might be functionally related to resistance or progression of RA. Providing a local boost to the regulatory potential
of NKT cells might represent a useful candidate therapy for RA. 相似文献
17.
Lele Guo Wen Liu Tingting Lu Wenjie Guo Jian Gao Qiong Luo Xuefeng Wu Yang Sun Xudong Wu Yan Shen Qiang Xu 《PloS one》2015,10(4)
Treatment of systemic lupus erythematosus (SLE), a chronic inflammatory disease, involves the long-term use of immunosuppressive agents with significant side effects. New therapeutic approaches are being explored to find better treatment possibilities. In this study, age-matched female MRL/lpr mice were treated orally with a natural flavonoid astilbin. Astilbin administration started either at week 8 or week 12 of age though week 20. In the early treatment regimen, the treatment with astilbin reduced splenomegaly / lymphomegaly, autoantibody production and ameliorated lupus nephitis. Several serum cytokines were significantly decreased upon treatment including IFN-g, IL-17A, IL-1b, TNF-a and IL-6. Both spleen CD44hiCD62Llo activated T cells and CD138+B220- plasma cells greatly declined. Furthermore, astilbin treatment resulted in decreased mitochondrial membrane potential in activated T cells and downregulated expression of the co-stimulatory molecules CD80 and CD86 on LPS stimulated B cells. Similar but less profound effectiveness was observed in the mice with established disease in the late treatment regimen. These results indicate that the natural product astilbin can mitigate disease development in lupus-prone mice by decreasing functional activated T and B cells. 相似文献
18.
Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in the prevention of autoimmune myasthenia 总被引:7,自引:0,他引:7
Liu R La Cava A Bai XF Jee Y Price M Campagnolo DI Christadoss P Vollmer TL Van Kaer L Shi FD 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(12):7898-7904
CD1d-restricted NKT cells and CD4+CD25+ regulatory T (Treg) cells are thymus-derived subsets of regulatory T cells that have an important role in the maintenance of self-tolerance. Whether NKT cells and Treg cells cooperate functionally in the regulation of autoimmunity is not known. We have explored this possibility in experimental autoimmune myasthenia gravis (EAMG), an animal model of human myasthenia gravis, induced by immunization of C57BL/6 mice with the autoantigen acetylcholine receptor. We have demonstrated that activation of NKT cells by a synthetic glycolipid agonist of NKT cells, alpha-galactosylceramide (alpha-GalCer), inhibits the development of EAMG. alpha-GalCer administration in EAMG mice increased the size of the Treg cell compartment, and augmented the expression of foxp3 and the potency of CD4+CD25+ cells to inhibit proliferation of autoreactive T cells. Furthermore, alpha-GalCer promoted NKT cells to transcribe the IL-2 gene and produce IL-2 protein. Depletion of CD25+ cells or neutralization of IL-2 reduced the therapeutic effect of alpha-GalCer in this model. Thus, alpha-GalCer-activated NKT cells can induce expansion of CD4+CD25+ Treg cells, which in turn mediate the therapeutic effects of alpha-GalCer in EAMG. Induced cooperation of NKT cells and Treg cells may serve as a superior strategy to treat autoimmune disease. 相似文献
19.
Naeem K. Patil Liming Luan Julia K. Bohannon Yin Guo Antonio Hernandez Benjamin Fensterheim Edward R. Sherwood 《PloS one》2016,11(2)
Background
Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection.Methods
Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed.Results
Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival.Conclusion
Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15 SA does not augment host resistance to burn wound sepsis in mice despite inducing proliferation and activation of lymphocyte subsets. 相似文献20.
Baschuk N Utermöhlen O Gugel R Warnecke G Karow U Paulsen D Brombacher F Krönke M Deppert W 《Cancer immunology, immunotherapy : CII》2007,56(10):1625-1636
In this report we analyzed the impact of interleukin-4 (IL-4) on tumor-associated simian virus 40 (SV40) large T-antigen (TAg)-specific CD8+ cytotoxic T cells during rejection of syngeneic SV40 transformed mKSA tumor cells in BALB/c mice. Strikingly, challenge of naïve mice with low doses of mKSA tumor cells revealed a CD8+ T cell-dependent prolonged survival time of naïve IL-4?/? mice. In mice immunized with SV40 TAg we observed in IL-4?/? mice, or in wild type mice treated with neutralizing anti-IL-4 monoclonal antibody, a strongly enhanced TAg-specific cytotoxicity of tumor associated CD8+ T cells. The enhanced cytotoxicity in IL-4?/? mice was accompanied by a significant increase in the fraction of CD8+ tumor associated T-cells expressing the cytotoxic effector molecules granzyme A and B and in granzyme B-specific enzymatic activity. The data suggest that endogenous IL-4 can suppress the generation of CD8+ CTL expressing cytotoxic effector molecules especially when the antigen induces only a very weak CTL response. 相似文献