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Effector Phase (effector + phase)
Selected AbstractsThe role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2006Yoshihiko Usui Abstract ICOS/B7RP-1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP-1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4+ T cells in the region of the retina in EAU-induced mice. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti-B7RP-1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti-B7RP-1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN-, production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP-1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU. [source] Cover Picture , Eur.EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2006The cover depicts the safranin staining of joint sections from the hind paws of arthritic mice. It illustrates the finding of Nandakumar et al. (pp. 1608,1618) that suppression of arthritis by IL-4 is dependent on IFN-,c. In their article, Nandakumar et al. investigate the role of IL-4 in the collagen antibody-induced arthritis (CAIA) disease process and demonstrate an increased frequency of arthritis in the presence of IL-4, suggesting a pro-inflammatory effect of IL-4 during the effector phase of CAIA. [source] Complement activation by both classical and alternative pathways is critical for the effector phase of arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2004Albert Hietala Abstract To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3- and factor,B (FB)-deficient (C3,/, and FB,/,) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type,II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days,7,10. Although 75% of C3,/, mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB,/, mice ranked intermediate in comparison with C3,/, and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3,/, and FB,/, mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis. [source] Astilbin suppresses delayed-type hypersensitivity by inhibiting lymphocyte migrationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2003Yu Cai This study examined the effects of astilbin, a flavanone, on delayed-type hypersensitivity reactions and its mechanisms of action on cell migration. Astilbin significantly inhibited the sheep-red-blood-cell-induced footpad reaction and picryl-chloride-induced ear dermatitis without affecting the organ weights, when administered during the effector phase but not the induction phase. The flavanone also significantly inhibited the migration to gelatin of spleen cells isolated from mice with ear dermatitis in a transwell system. Furthermore, the isolated spleen cells from normal mice were incubated with astilbin in the presence of concanavalin A, or those from mice with ear dermatitis were cultured with astilbin. In the supernatants collected, the activity of matrix metalloproteinases (MMPs) MMP-2 and MMP-9 was remarkably inhibited by astilbin. These results suggest that astilbin may inhibit delayed-type hypersensitivity reactions through selectively suppressing the lymphocyte functions, including cell migration, via down-regulating MMP activity. [source] Interferon-,-mediated activation of enterocytes in immunological control of Encephalitozoon intestinalis infectionPARASITE IMMUNOLOGY, Issue 1 2009N. CHOUDHRY SUMMARY The microsporidian Encephalitozoon intestinalis develops within intestinal epithelial cells (enterocytes) and is an important opportunistic diarrhoeal pathogen associated with AIDS. Little is known about the protective immune response against the parasite although in mice IFN-, is involved and is required to prevent dissemination of the infection to other organs. The present study was designed to establish a suitable short-term in vitro culture technique for E. intestinalis that would enable studies of the role of cytokines such as IFN-, in the effector phase of immunity. Encephalitozoon intestinalis reproduced considerably better in the murine enterocyte cell line CMT-93 than in the three human enterocyte cell lines Caco-2, HT29 and HCT-8. Treatment of CMT-93 cells with IFN-, significantly reduced parasite reproduction in a dose- and time-dependent manner. IFN-, also inhibited development of the parasite in Caco-2 cells. Neither production of NO nor Fe deprivation appeared to be involved in IFN-,-mediated parasite killing. However studies suggested that tryptophan catabolism by indoleamine 2,3-dioxygenase played an important part in inactivation of E. intestinalis. [source] Amelioration of experimental autoimmune encephalomyelitis in Lewis rats treated with fucoidanPHYTOTHERAPY RESEARCH, Issue 3 2010Heechul Kim Abstract We examined whether fucoidan affected the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in rats. EAE was induced in Lewis rats that were immunized with guinea-pig myelin basic protein (MBP) and complete Freund's adjuvant. Fucoidan (50,mg/kg, daily) was administered to rats with EAE intraperitoneally, either in the EAE induction phase from either 1 day before immunization to day 7 post-immunization (PI), or the effector phase from day 8 to 14 PI, to test which phase of rat EAE is affected by fucoidan treatment. The onset, severity and duration of EAE paralysis in the fucoidan-treated group in the days 8,14 PI-treated rats, but not in days ,1,7 PI-treated rats, were significantly delayed, suppressed and reduced, respectively, compared with the vehicle-treated controls. Treatment with fucoidan reduced the encephalitogenic response and TNF-, production during EAE. Moreover, the clinical amelioration coincided with decreased infiltration of inflammatory cells in the EAE-affected spinal cord. The ameliorative effect of fucoidan on clinical paralysis in EAE-affected rats may be mediated, in part, by the suppression of the autoreactive T cell response and inflammatory cytokine production. Copyright © 2009 John Wiley & Sons, Ltd. [source] Preferential recruitment of interferon-,,expressing TH17 cells in multiple sclerosis,ANNALS OF NEUROLOGY, Issue 3 2009Hania Kebir MSc Objective There is substantial evidence supporting the role of interferon (IFN)-,,producing T helper (TH) 1 and interleukin (IL)-17,expressing TH17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN-,,expressing TH17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS). Methods Human TH17 lymphocytes were expanded in vitro from the blood of healthy controls and relapsing MS patients using IL-23. Immune cell migration to the CNS was assessed in vitro with primary cultures of human blood,brain barrier (BBB)-derived endothelial cells, and in vivo in EAE mice. Results We demonstrate that in response to IL-23, human memory lymphocytes expand into a TH17 phenotype, with a subpopulation of cells simultaneously expressing IFN-, and IL-17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN-,,producing TH17 cells and identify numerous T lymphocytes coexpressing IL-17 and IFN-, in brain tissue of MS patients. We also find lymphocytes expressing both the TH1- and the TH17-associated transcription factors ROR,t and T-bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN-,+ TH17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE. Interpretation Our data underscore the involvement of IFN-,+ TH17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events. Ann Neurol 2009;66:390,402 [source] Deficiency of CXCR2, but not other chemokine receptors, attenuates autoantibody-mediated arthritis in a murine modelARTHRITIS & RHEUMATISM, Issue 7 2010Jonathan P. Jacobs Objective Chemokines coordinate leukocyte trafficking in homeostasis and during immune responses. Prior studies of their role in arthritis have used animal models with both an initial adaptive immune response and an inflammatory effector phase. We undertook analysis of chemokines and their receptors in the effector phase of arthritis using the K/BxN mouse serum,transfer model. Methods A time-course microarray analysis of serum-transferred arthritis was performed, examining ankle tissue, synovial fluid, and peripheral blood leukocytes. Up-regulation of chemokines was confirmed by quantitative reverse transcriptase,polymerase chain reaction. The functional relevance of chemokine induction was assessed by transferring serum into mice deficient in CCR1,7, CCR9, CXCR2, CXCR3, CXCR5, CX3CR1, CCL2, or CCL3. Further mechanistic analysis of CXCR2 involved treatment of arthritic mice with a CXCR2 antagonist, bone marrow (BM) cell transfers with CXCR2+/, and CXCR2,/, donors and recipients, flow cytometry of synovial cells, and competition experiments measuring enrichment of CXCR2-expressing neutrophils in arthritic joints of mice with mixed CXCR2+/+ and CXCR2,/, BM cells. Results Gene expression profiling revealed up-regulation of the CXCR2 ligands CXCL1, CXCL2, and CXCL5 in the joint in parallel with disease activity. CXCR2,/, mice had attenuated disease relative to CXCR2+/, littermates, as did mice receiving the CXCR2 inhibitor, while deficiency of other chemokine receptors did not affect arthritis severity. CXCR2 was required only on hematopoietic cells and was widely expressed on synovial neutrophils. CXCR2-expressing neutrophils were preferentially recruited to arthritic joints in the presence of CXCR2-deficient neutrophils. Conclusion CXCR2 (but not other chemokine receptors) is critical for the development of autoantibody-mediated arthritis, exhibiting a cell-autonomous role in neutrophil recruitment to inflamed joints. [source] Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomeraseARTHRITIS & RHEUMATISM, Issue 3 2008Keiichi Iwanami Objective To clarify the glucose-6-phosphate isomerase (GPI),specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti,interferon-, (anti-IFN,) monoclonal antibody (mAb), anti,interleukin-17 (anti,IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti,IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFN, mAb exacerbated arthritis. Neither anti,IL-17 mAb nor anti-IFN, mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti,IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase. [source] Distinct mechanisms of action of anti-CD154 in early versus late treatment of murine lupus nephritisARTHRITIS & RHEUMATISM, Issue 9 2003Sergio A. Quezada Objective Treatment with anti-CD154 antibody is known to ameliorate murine lupus nephritis when given early in the disease. The aims of this study were to identify the mechanism of this early effect, to determine whether late anti-CD154 treatment could halt established nephritis, and, if so, to examine potential mechanisms of late efficacy. Methods We studied the effects of anti-CD154 treatment on autoantibody production and immune complex deposition, renal pathology, survival, and renal cytokine and chemokine messenger RNA (mRNA) expression both in (NZB × NZW)F1 mice (BW mice) and in NZM.2410 mice. Results Early treatment with anti-CD154 produced long-term survival in BW mice, with abrogation of renal immune complex deposition for months after treatment was stopped. Late anti-CD154 treatment, started after development of nephritis, could halt disease in ,40% of mice. In some mice, proteinuria could be reversed repeatedly with sequential courses of anti-CD154 antibody. The remissions induced by late treatment with anti-CD154 occurred despite ongoing renal immune complex deposition. In preliminary studies, responding mice had rapid reductions in renal mRNA for transforming growth factor ,, interleukin-10, and tumor necrosis factor ,. Conclusion Amelioration of murine lupus by anti-CD154 therapy is mediated by distinct mechanisms in early versus late intervention. We postulate that anti-CD154 therapy prevents autoantibody production and renal immune complex deposition in the early, induction phase and limits secondary tissue damage in situ in the late, effector phase. These data demonstrate that CD40,CD154 interactions are critical for the maintenance of autoimmunity and suggest a potential role for anti-CD154 as a therapeutic agent in established human lupus. [source] | ||||||||||