IL-4 and IL-10 are both required for the induction of oral tolerance. (1/1070)

Protection from the development of experimental autoimmune uveitis (EAU) can be induced by feeding mice interphotoreceptor retinoid binding protein before uveitogenic challenge with the same protein. Two different regimens are equally effective in inducing protective tolerance, although they seem to do so through different mechanisms: one involving regulatory cytokines (IL-4, IL-10, and TGF-beta), and the other with minimal involvement of cytokines. Here we studied the importance of IL-4 and IL-10 for the development of oral tolerance using mice genetically engineered to lack either one or both of these cytokines. In these animals we were able to protect against EAU only through the regimen inducing cytokine-independent tolerance. When these animals were fed a regimen that in the wild-type animal is thought to predominantly induce regulatory cells and is associated with cytokine secretion, they were not protected from EAU. Interestingly, both regimens were associated with reduced IL-2 production and proliferation in response to interphotoreceptor retinoid binding protein. These findings indicate that both IL-4 and IL-10 are required for induction of protective oral tolerance dependent on regulatory cytokines, and that one cytokine cannot substitute for the other in this process. These data also underscore the fact that oral tolerance, manifested as suppression of proliferation and IL-2 production, is not synonymous with protection from disease.  (+info)

Pregnancy ameliorates induction and expression of experimental autoimmune uveitis. (2/1070)

Female patients suffering from autoimmune uveitis are reported to experience a temporary remission during pregnancy. Experimental autoimmune uveitis (EAU) is a model for human uveitis. Here we examine the effect of pregnancy on the development of EAU and its associated immunological responses. Susceptible C57BL/6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP). EAU scores and Ag-specific responses were evaluated 21 days later. Mice immunized during pregnancy developed significantly less EAU than nonpregnant controls. Their lymph node cells and splenocytes produced a distinct pattern of cytokines in response to IRBP: reduced IFN-gamma and IL-12 p40, but unchanged levels of TNF-alpha, IL-4, IL-5, and IL-10. Anti-IRBP Ab isotypes revealed an up-regulation of IgG1, indicating a possible Th2 bias at the humoral level. Ag-specific proliferation and delayed hypersensitivity, as well as mitogen-induced IFN-gamma production, remained undiminished, arguing against an overall immune deficit. Interestingly, pregnant mice that received an infusion of IRBP-primed lymphoid cells from nonpregnant donors also developed reduced EAU, suggesting that pregnancy suppresses not only the generation, but also the function of mature uveitogenic effector T cells. Pregnant mice at the time of immunization exhibited elevated levels of TGF-beta, but not of IL-10, in the serum. We suggest that protection from EAU during pregnancy is due primarily to a selective reduction of Ag-specific Th1 responses with only marginal enhancement of Th2 function, and that these effects may in part be secondary to elevated systemic levels of TGF-beta.  (+info)

Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity. (3/1070)

PURPOSE: Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL-10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated. METHODS: Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested. RESULTS: Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture. CONCLUSIONS: Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect.  (+info)

Mice deficient in inducible nitric oxide synthase are susceptible to experimental autoimmune uveoretinitis. (4/1070)

PURPOSE: Nitric oxide (NO) is an important mediator of inflammatory tissue damage. The present study addresses the question whether inducible nitric oxide synthase (iNOS), and consequently the ability to upregulate NO, is required to effect the pathogenesis of experimental autoimmune uveoretinitis (EAU) in mice. METHODS: Mice with a homologous disruption of the iNOS gene (iNOS KO) were evaluated for their ability to develop EAU and associated cellular responses after immunization with the interphotoreceptor retinoid-binding protein. EAU was determined by histopathology 21 days after uveitogenic immunization, and antigen-specific cellular responses were assessed by delayed type hypersensitivity and lymphocyte proliferation. RESULTS: iNOS knockout (iNOS KO) mice developed EAU with scores similar to wild-type mice and exhibited good cellular responses to the immunizing antigen. CONCLUSIONS: A functional iNOS gene is not necessary for EAU pathogenesis. Therefore, upregulation of NO is not required to mediate autoimmune tissue damage in the eye.  (+info)

Identification of genomic regions controlling experimental autoimmune uveoretinitis in rats. (5/1070)

The present study attempts to identify specific genetic loci contributing to experimental autoimmune uveoretinitis (EAU) susceptibility in F2 progeny of resistant Fischer (F344/N) and susceptible Lewis (LEW/N) inbred rats. F2 progeny of F344/N x LEW/N inbred rats were immunized with the R16 peptide of interphotoreceptor retinoid-binding protein (IRBP). A genome-wide scan was conducted using 125 simple sequence length polymorphism markers in selected F2 animals that developed severe eye disease or remained unaffected to identify phenotype:genotype co-segregation. The F2 population (n = 1287) demonstrated a wide range of histologically assessed EAU scores (assessed on a scale of 0-4). The disease incidence and severity were not consistent with a simple Mendelian inheritance model. Of the F2 hybrid rats, 60% developed EAU, implying the existence of a potent susceptibility locus with incomplete penetrance associated with the LEW genome or a more complex polygenic model of inheritance. Two genomic regions, on chromosomes 4 and 12, showed strong genetic linkage to the EAU phenotype (P < 0.0016), suggesting the presence of susceptibility loci in these chromosomal regions. In conclusion, we have identified two genomic candidate intervals from D4Arb8 to D4Mit17 on chromosome 4 and from the chromosome end to D12Arb8 on chromosome 12, that appear to influence EAU susceptibility in LEW/F344 rats. Further analysis of these genomic regions may lead to identification of the susceptibility genes and to characterization of their function.  (+info)

Iris crystals in chronic uveitis. (6/1070)

AIMS: To analyse the unusual physical sign of iris crystals occurring in patients with uveitis. METHODS: Demographic details and clinical features were documented in 24 patients with chronic uveitis and iris crystals. Plasma immunoglobulin subclasses were measured, and a histopathological review of iridectomy specimens from 33 patients with chronic uveitis was also undertaken. RESULTS: The mean age of patients was 38 years, with a slight preponderance of females. 17 patients had Fuchs' heterochromic cyclitis although a number of other uveitis entities were represented. There was no correlation between severity of clinical signs and presence of iris crystals. Over a mean follow up period of 15 months no significant change in the number, size, or position of the crystals was seen except in four patients who underwent intraocular surgery. Only three patients had raised plasma IgG1. The review of the histology of iridectomy specimens failed to show evidence of Russell body formation in any patient. CONCLUSIONS: Iris crystals appear to be rare but may be underreported as they are small and can easily be missed. They are likely to be associated with disease processes in which there is active immunoglobulin production within the anterior chamber, such as Fuchs' heterochromic cyclitis.  (+info)

Immunopathology of pineal glands from horses with uveitis. (7/1070)

PURPOSE: Pinealitis accompanying uveitis is well established in laboratory models of experimental autoimmune uveoretinitis. In naturally occurring uveitis, pinealitis has been demonstrated in the pineal gland from a mare with active uveitis and is suspected in some human uveitides. We have evaluated pineal glands from horses with various stages of uveitis for signs of immunopathology accompanying spontaneous uveitis. METHODS: Pineal glands from 10 horses with uveitis and from 13 horses without uveitis were evaluated for histochemical (H&E, collagen) and immunohistochemical (MHC class II antigen expression, infiltration of T and B lymphocytes, and glial fibrillary acidic protein (GFAP) and vimentin upregulation) evidence of inflammation. RESULTS: Septal areas of pineal glands from horses with uveitis had clusters of MHC class II antigen-expressing cells, T lymphocytes, and enhanced collagen deposition. These changes were not as readily observed in pineal glands from horses without uveitis. B lymphocytes were detected only in the pineal gland from the one mare with active uveitis in which T and B lymphocytes were organized into follicles. No differences in GFAP or vimentin immunoreactivity were noted in pineal glands from horses with or without uveitis. CONCLUSIONS: These pineal gland changes suggest that the pinealitis associated with equine uveitis is transient just as the uveitis of these horses is recurrent. Study of pineal glands from horses with clinically documented uveitis allows demonstration of subtle pineal changes associated with natural uveitis. Similar changes would be difficult to document in human patient populations.  (+info)

Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. (8/1070)

To evaluate the safety and potential therapeutic activity of humanized anti-IL-2 receptor mAb (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior noninfectious uveitis, a nonrandomized, open-label, pilot study was performed. Patients with uveitis were treated with a minimum of 20 mg of prednisone, cyclosporine, antimetabolites, or any combination of these agents were eligible. Patients were weaned off their systemic immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-IL-2 receptor antibody therapy, given intravenously with intervals of up to 4 weeks in lieu of standard immunosuppressive therapy, appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in 8 of 10 patients treated over a 12-month period, with noted improvements in visual acuity. One patient met a primary endpoint with a loss of vision of 10 letters or more from baseline in one eye and another patient discontinued therapy because of evidence of increased ocular inflammation. All patients were able to tolerate the study medications without the need for dose reduction. We report effective long-term use of anti-IL-2 therapy for an autoimmune indication. These initial findings would suggest that anti-IL-2 receptor therapy may be an effective therapeutic approach for uveitis and, by implication, other disorders with a predominant Th1 profile.  (+info)