Intraocular trafficking of lymphocytes in locally induced experimental autoimmune uveoretinitis (EAU)

Experimental autoimmune uveoretinitis (EAU) was induced in naive Lewis rats by intravitreal adoptive transfer of 10(6) long-term S-antigen (S-Ag)-specific syngeneic T-lymphocyte lines of helper/inducer phenotype (ThS). These cells were stimulated with the T-cell mitogen concanavalin A (Con A) in culture for 48 hr and subsequently labeled with tritiated thymidine. Lymph node cells (LNC) cultured in parallel were used as controls. Histopathology and light microscopic autoradiography of the ocular tissue was performed at several time points to analyze the cell migration in relation to the development of EAU. The disappearance of both types of lymphocytes from the vitreous was similar and large numbers of host leukocytes were attracted into the vitreous. However, significantly more S-Ag-specific cells penetrated the retina and induced EAU (P less than 0.008). These results suggest that the development of EAU by intravitreal injection of S-Ag-specific T lymphocytes occurs by the migration of antigen-specific cells into the retina and recognition of the specific antigen, with subsequent release of soluble mediators that interact with the host effector cells, ultimately leading to specific photoreceptor damage.     

Inhibition of experimental autoimmune uveitis by retinal photoreceptor antigens coupled to spleen cells.

Experimental autoimmune uveitis (EAU) and experimental autoimmune pinealitis (EAP) are CD4+ T cell-mediated inflammatory diseases of the uveal tract and retina of the eye and of the pineal gland. EAU and EAP can be induced by several retinal autoantigens including S-antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP). In this study we investigated the effect of intravenous administration of S-Ag and IRBP coupled to syngeneic spleen cells on the development of EAU and EAP. Injection of S-Ag or IRBP coupled to spleen cells 5 days prior to immunization with native S-Ag or IRBP, respectively, was effective in preventing the induction of EAU and EAP in LEW rats. Conversely, LEW rats receiving S-Ag-coupled spleen cells and challenged with IRBP or LEW rats receiving IRBP-coupled spleen cells and challenged with S-Ag developed a severe EAU within 10 days to 2 weeks following immunization, as did all control animals receiving sham-coupled spleen cells and challenged with the two retinal antigens. The results show that the administration of retinal autoantigens coupled to spleen cells effectively protects against the development of EAU when animals are subsequently challenged with the tolerizing antigen but not when challenged with another unrelated pathogenic retinal autoantigen.     

Kinetics of T-lymphocyte subsets in the eyes of Lewis rats with experimental autoimmune uveitis

The kinetic changes of T-lymphocyte subtypes in the eyes of Lewis rats which developed experimental autoimmune uveitis (EAU) were studied. Lymphoid cells were the majority of the ocular inflammatory cells in different stages of the disease. As EAU proceeds, there is an increase in the relative number of OX-8 (suppressor/cytotoxic) T cells, and the decrease of W3/25 (helper/inducer) T cells. These findings were also observed in the animals with EAU and partially treated with corticosteroids or cyclosporine. The kinetics may reflect the role of immunoregulation of the inflammatory response in autoimmune diseases.     

Uveitogenic potential of lymphocytes sensitized to interphotoreceptor retinoid-binding protein

In our previous study rats immunized with bovine retinal interphotoreceptor retinoid-binding protein (IRBP) were found to develop inflammation in the eye and the pineal gland. This inflammatory disease was distinct in several aspects from experimental autoimmune uveoretinitis (EAU) induced by the retinal S-antigen (S-Ag). The current study examined the adoptive transfer of IRBP-induced EAU. We established that lymphocytes from IRBP immunized donor rats were capable of transferring EAU after in vitro stimulation with either IRBP (lymph node or spleen cells) or concanavalin A (spleen cells only). Recipients of these cells developed uveoretinitis and pinealitis identical to the actively induced disease. As compared with the S-Ag system, recipients of IRBP sensitized cells developed disease earlier, and smaller numbers of cells were needed to transfer EAU. Development of inflammation was directly related to a cellular response to the specific retinal antigen used for sensitization. Moreover, the unique nature of ocular inflammation was reestablished in the IRBP system: high proportions of polymorphonuclear leukocytes were found in the inflamed tissue of certain recipients despite a lack of a humoral response to the specific antigen. In contrast to the eye, only mononuclear leukocytes comprised the inflammation in the pineal gland.     

T cell lines mediating experimental autoimmune uveoretinitis (EAU) in the rat

Long-term S-antigen (S-Ag)-specific T lymphocyte lines were derived from the lymph nodes of immunized Lewis rats that had been pretreated with low-dose cyclophosphamide. The protocol consisted of functional selection by alternating cycles of stimulation with S-Ag presented on syngeneic accessory cells and proliferation in IL 2-containing spleen-conditioned medium, coupled with early phenotypic selection for cells bearing the helper/inducer membrane marker (W3/25), by panning on antibody-coated plastic dishes. This protocol consistently resulted in the rapid generation of in vivo functional cell lines capable of mediating experimental autoimmune uveoretinitis (EAU) when transferred into naive rats at 5 to 10 X 10(6) cells/rat systemically or 1 to 2 X 10(6) cells/rat intravitreally. The disease appeared within 6 to 8 days, usually with minimal anterior chamber involvement, and was often unilateral. Pathologic changes resembled those seen in EAU induced by active immunization. The disease could be transferred without concomitant formation of serum antibodies. The uveitogenic line cells were negative for Ia antigen and positive for the W3/25 membrane marker, which appeared to be stable in long-term culture. They proliferated vigorously in vitro and produced IL 2 in response to S-Ag or Con A, but not to unrelated antigens. The establishment of uveitogenic T helper lymphocyte lines will permit the analysis of the cellular mechanisms involved in EAU in a more defined system than has been available.     

Liposome-Encapsulated Clodronate Retards the Development of Experimental Autoimmune Uveitis

Abstract

A study was undertaken to determine if the intravenous injection of liposome-encapsulated dichloromethylene diphosphonate (C1₂MDP; Clodronat), a treatment known to deplete monocytes, as well as liver and spleen macrophages, would reduce the number of macrophages in the retina of animals with experimental autoimmune uveitis (EAU) and decrease the severity of the disease. EAU was induced in Lewis rats by immunization with S-antigen (S-Ag). Monocytes and macrophages were depleted via an intravenous injection of Cl₂MDP encapsulated in liposomes. Control groups included rats that received no S-Ag (n= 18), S-Ag and no treatment (n=23), S-Ag and free drug (n = 20), or empty liposomes (n=14). Treated animals received injections of the Cl₂MDP-liposomes, free drug, or empty liposomes. Animals were sacrificed at 14, 21 and 28 days post-S-Ag administration. Intravenous, Cl₂MDP-liposomes produced a statistically significant reduction in the severity of the EAU when compared to controls at both days 14 and 21 following S-Ag injection. Immunohistochemical staining with the monoclonal antibody EDI demonstrated that the severity of the ocular inflammatory response correlated with the number of EDI-positive cells in the retina. Following the cessation of treatment, treated animals developed disease that was as severe at day 28 as that of untreated animals at day 21. These results confirm the importance of monocytes and macrophages in EAU by demonstrating the correlation between the presence of EDI-positive cells in the retina and the resultant damage to the retina. Although the dosing regimen employed here did not provide a cure, strategies designed to prevent the local recruitment and/or activation of mononuclear phagocytes may prove to be useful in the treatment of EAU.     

Suppression of experimental autoimmune uveitis in rats by the oral administration of the uveitopathogenic S-antigen fragment or a cross-reactive homologous peptide.

The oral administration of S-antigen fragment (a synthetic peptide designated as peptide M and known to be uveitopathogenic for rat, guinea pig, and monkey) to Lewis rats prior to challenge with an emulsion of peptide M and CFA resulted in either a total or partial suppression of experimental autoimmune uveitis (EAU), a T cell-mediated autoimmune disease studied as a model for human uveitis and experimental autoimmune pinealitis (EPA). Both the clinical and histopathologic manifestations of the disease were suppressed in a dose-dependent manner. Pinealitis associated with EAU was also suppressed by the oral administration of peptide M. Additionally, ingestion of a fragment of baker's yeast (Saccharomyces cerevisiae) histone H3, which has five consecutive amino acids identical to peptide M and which has been found to be uveitopathogenic in Lewis rats, induced tolerance to either peptide M or synthetic histone H3 peptide. In addition, the proliferative response to peptide M was inhibited in peptide M-fed rats. The suppression of EAU and in vitro lymphocyte proliferative responses to peptide M were observed to be antigen specific, since oral feeding of a control protein (BSA) exerted no suppressive effect. Furthermore, the T cells isolated from the spleen and lymph nodes of animals rendered tolerant by oral administration of peptide M can transfer protection against EAU adoptively. These results demonstrate that the oral administration of an autoantigen or its homologous peptide initiates an antigen-specific cellular mechanism which may ameliorate EAU.     

Ocular immune privilege and the impact of intraocular inflammation

Immune privilege, a characteristic of the internal compartments of the eye, is a physiologic mechanism that is designed to provide the eye with protection against pathogens while protecting the delicate visual axis from the sight-destroying potential of immunogenic inflammation. It is assumed that the presence of intraocular inflammation is incompatible with the existence of immune privilege. The validity of this assumption has been tested in four animal models of intraocular inflammation-systemic and local endotoxin-induced uveitis (EIU), mycobacterial adjuvant-induced uveitis (MAIU), and experimental autoimmune uveitis (EAU). Immune privilege was assessed in inflamed eyes by growth of intracamerally injected allogeneic tumor cells, by the capacity to support immune deviation following intracameral injection of antigen (ovalbumin, OVA), by assaying protein, leukocyte, and selected cytokine content of aqueous humor (AqH), and by capacity of inflamed AqH to suppress T cell activation in vitro. The results indicate that, irrespective of the type of inflammation, tumor cells formed progressively growing tumors in inflamed eyes. Moreover, OVA injected into the anterior chamber of eyes inflamed by MAIU and EAU failed to induce immune deviation. AqH from inflamed eyes reflected breakdown of the blood:ocular barrier as well as transient loss of its immunosuppressive properties. Immunosuppressive microenvironments routinely reemerged in inflamed eyes, and the immunosuppressive agent present under these circumstances in AqH was active TGF beta2. It is concluded that immune privilege is surprisingly resistant to abolition by intraocular inflammation, and that maintenance of immune privilege in the face of ongoing inflammation depends upon the emergence of progressive and partially different immunosuppressive mechanisms.     

Abrogation of anti-retinal autoimmunity in IL-10 transgenic mice due to reduced T cell priming and inhibition of disease effector mechanisms

Experimental autoimmune uveitis (EAU) induced by immunization of animals with retinal Ags is a model for human uveitis. The immunosuppressive cytokine IL-10 regulates EAU susceptibility and may be a factor in genetic resistance to EAU. To further elucidate the regulatory role of endogenous IL-10 in the mouse model of EAU, we examined transgenic (Tg) mice expressing IL-10 either in activated T cells (inducible) or in macrophages (constitutive). These IL-10-Tg mice and non-Tg wild-type controls were immunized with a uveitogenic regimen of the retinal Ag interphotoreceptor retinoid-binding protein. Constitutive expression of IL-10 in macrophages abrogated disease and reduced Ag-specific immunological responses. These mice had detectable levels of IL-10 in sera and in ocular extracts. In contrast, expression of IL-10 in activated T cells only partially protected from EAU and marginally reduced Ag-specific responses. All IL-10-Tg lines showed suppression of Ag-specific effector cytokines. APC from Tg mice constitutively expressing IL-10 in macrophages exhibited decreased ability to prime naive T cells, however, Ag presentation to already primed T cells was not compromised. Importantly, IL-10-Tg mice that received interphotoreceptor retinoid-binding protein-specific uveitogenic T cells from wild-type donors were protected from EAU. We suggest that constitutively produced endogenous IL-10 ameliorates the development of EAU by suppressing de novo priming of Ag-specific T cells and inhibiting the recruitment and/or function of inflammatory leukocytes, rather than by inhibiting local Ag presentation within the eye.     

Immunoregulatory role of ocular macrophages: the macrophages produce RANTES to suppress experimental autoimmune uveitis

Murine experimental autoimmune uveitis (EAU) is a model of human uveitis. Ocular-infiltrating macrophages play a crucial role in the generation of tissue damage in EAU. In fact, several chemokines are actually produced in the inflamed eye. The aim of this study was to elucidate the role of ocular macrophage-derived chemokines in EAU. C57BL/6 mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20, and the EAU severity was scored at multiple time points based on microscopic fundus observations (retinal vascular dilatation and exudates) and histological examinations. The peak inflammatory response was observed 1 wk (day 16) after the beginning of macrophage infiltration to the eye (day 9). Ocular-infiltrating cells were enriched or depleted of macrophages by magnetic beads and analyzed by real-time RT-PCR for chemokine mRNA production. We found that only the macrophage-enriched cells from the eye produced RANTES, and thus proposed that macrophage-derived RANTES facilitated the ocular inflammations. In contrast to our postulate, neutralization of RANTES by specific Ab in vivo on days 9 and 13 exacerbated EAU. We also found that the ratio of ocular CD4/CD8 T cells was markedly increased after treatment. As a result, RANTES neutralization might exacerbate EAU by modulating the type of T cell subsets recruited to the eye. In conclusion, our data provide insight into the immunoregulatory role of macrophages and RANTES in the pathogenesis of ocular inflammation. Not all macrophage-derived chemokines cause local inflammation, since RANTES produced by ocular macrophages appears to suppress EAU.     

IRBP-specific Th1 cells from peripheral blood were predominant in the experimental autoimmune uveitis

Experimental autoimmune uveitis (EAU) is a Th1-cell-mediated autoimmune disease. In this study, the correlation between IRBP-specific Th1 cells in PBLs and the histological grading in the eyes was evaluated kinetically during EAU induction. EAU was induced in B10.A mice with IRBP immunization and the eyes were enucleated for histological examination on days 0, 3, 7, 15, and 21 after immunization. To determine the Th1-cell-mediated immune response, Th1 cytokines (IL-12p40 and IFN-gamma) were measured by RT-PCR in inflamed eyes. At mean time, CD4(+) and IFN-gamma(+) double positive T cells (Th1 cells) from PBLs were analyzed by flow cytometry. The level of the IRBP-specific Th1 cells was significantly increased and kinetically changed during EAU induction, but the cells reached peak time early before the disease was onset. Those IRBP-specific Th1 cells in the PBLs were evidence for EAU disease, but its peak time was different from EAU disease in the eyes. Our data suggested that it is very important to collect blood from patients at a suitable time point and the Th1 cells measured by flow cytometry are good marker for disease diagnosis.     

Antigen-specific accumulation of naïve, memory and effector CD4 T cells during anterior uveitis monitored by intravital microscopy

Uveitis is an immune-mediated ocular disease and a leading cause of blindness. We characterized a novel model of uveitis with intravital microscopy. Transfer of ovalbumin-specific T cells from DO11.10 spleen to BALB/c recipients and subsequent challenge with ovalbumin in the anterior chamber of the eye resulted in anterior uveitis. Antigen-specificity was verified by injection of irrelevant antigen and transfer of T cells with a different specificity. Subsets of CD4 T cells, including naive (DO11.10 RAG(-/-)) and in vitro-activated Th2 effector CD4 T cells, infiltrated anterior segment tissues early in the inflammation. Memory-like CD44(high) CD4 T cells from unprimed transgenic mice and in vitro-activated Th1 effector CD4 T cells accumulated to larger numbers than naive or Th2 effector cells at 48 and 72 h. Of these, the alpha(2)-integrin+CD4 unprimed T cells entered the eye more efficiently, and antibody to alpha(2)-integrin markedly inhibited the inflammatory response. Intravital microscopy revealed the early arrival and antigen-specific accumulation of CD4 T cells in inflamed tissue and should be helpful in understanding T cell migration to other organs.     

Dynamics of Intraocular IFN-γ, IL-17 and IL-10-Producing Cell Populations during Relapsing and Monophasic Rat Experimental Autoimmune Uveitis

A major limitation of most animal models of autoimmune diseases is that they do not reproduce the chronic or relapsing-remitting pattern characteristic of many human autoimmune diseases. This problem has been overcome in our rat models of experimentally induced monophasic or relapsing-remitting autoimmune uveitis (EAU), which depend on the inducing antigen peptides from retinal S-Antigen (monophasic EAU) or interphotoreceptor retinoid-binding protein (relapsing EAU). These models enable us to compare autoreactive and regulatory T cell populations. Intraocular, but not peripheral T cells differ in their cytokine profiles (IFN-γ, IL-17 and IL-10) at distinct time points during monophasic or relapsing EAU. Only intraocular T cells concomitantly produced IFN-γ, IL-17 and/or IL-10. Monophasic EAU presented rising numbers of cells expressing IFN-γ and IL-17 (Th1/Th17) and cells expressing IL-10 or Foxp3. During relapsing uveitis an increase of intraocular IFN-γ+ cells and a concomitant decrease of IL-17+ cells was detected, while IL-10+ populations remained stable. Foxp3+ cells and cells expressing IL-10, even in combination with IFN-γ or IL-17, increased during the resolution of monophasic EAU, suggesting a regulatory role for these T cells. In general, cells producing multiple cytokines increased in monophasic and decreased in relapsing EAU. The distinct appearance of certain intraocular populations with characteristics of regulatory cells points to a differential influence of the ocular environment on T cells that induce acute and monophasic or relapsing disease. Here we provide evidence that different autoantigens can elicit distinct and differently regulated immune responses. IFN-γ, but not IL-17 seems to be the key player in relapsing-remitting uveitis, as shown by increased, synchronized relapses after intraocular application of IFN-γ. We demonstrated dynamic changes of the cytokine pattern during monophasic and relapsing-remitting disease with strongly increasing IL-10 expression in intraocular T cells during monophasic uveitis.     

Identification of a uveitopathogenic and lymphocyte proliferation site in bovine S-antigen

S-antigen is a well-characterized retinal protein that is highly pathogenic for the induction of experimental autoimmune uveitis (EAU), a severe inflammatory disease of the eye and the pineal gland. EAU was observed following the immunization of Lewis rats with various doses (50 to 200 micrograms) of a small synthetic peptide, peptide N (22 amino acids in length), which corresponds to amino acid positions 281 to 302 in bovine S-antigen. Peptide N consistently induced an EAU that was identical to the disease caused by native S-antigen. Clinically, the disease that developed in the eye was characterized by iris and pericorneal hyperemia, followed by inflammatory exudates in the anterior chamber and vitreous. Histopathologically, a severe inflammatory response was observed that resulted in the complete destruction of the photoreceptor cell layer of the retina. In addition, animals with ocular inflammatory disease had an associated pinealitis characterized by a lymphocytic infiltration of the pineal gland. Furthermore, draining lymph node cells of rats immunized with peptide N showed strong in vitro proliferative responses toward peptide N as measured by [3H]thymidine uptake. Our results indicate that several synthetic peptides, which correspond to the amino acid sequence of bovine S-antigen, are capable of inducing an EAU and, as such, suggest that multiple uveitopathogenic sites may be present in the molecule.     

A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens

Experimental autoimmune uveoretinitis (EAU) is an organ-specific, T lymphocyte-mediated autoimmune disease, which serves as a model for several human ocular inflammations of an apparently autoimmune nature. EAU pathology in some rodents and in monkeys can readily be induced by immunization with several different retinal proteins; however, advancing research into the cellular mechanisms of this disease has raised the need for an EAU model in an immunologically and genetically well defined species. We report here the induction of EAU in the mouse, which has hitherto been considered a species refractory to EAU, with two retinal Ag, the retinal soluble Ag and the interphotoreceptor retinoid-binding protein. Although all the mouse strains tested exhibited lymphocyte responses and antibody titers to both retinal Ag, EAU was inducible in only some of the strains, and the uveitogenic responses to retinal soluble Ag and interphotoreceptor retinoid-binding protein appeared to be mutually exclusive. The EAU model in mice was found to differ in several respects from the EAU model in other rodent species. Induction of the disease was achieved with a relatively high dose of Ag and an intensified immunization protocol, and the onset of disease was later, the duration was longer, and the course was less acute. Anterior segment involvement was slight or nonexistent, and damage to the retina and uvea was of a focal rather than of a diffuse nature. Murine EAU appeared to approximate some types of human uveitis more closely than the EAU models described in other rodent species with respect to its pathologic manifestations as well as its more chronic course. The relatively longer duration of the active stage of disease in murine EAU should facilitate therapeutic intervention in established disease, which was not feasible in the more acute models of EAU. The extensive knowledge of the immunologic parameters of the mouse and the availability of genetically defined strains should be of great value in the study of cellular mechanisms and immunogenetics of ocular autoimmune disease.     

Identification of a potent new pathogenic site in human retinal S-antigen which induces experimental autoimmune uveoretinitis in LEW rats

Experimental autoimmune uveoretinitis (EAU) is a T cell-mediated autoimmune disease of the eye which can be induced in LEW rats by immunization with either human or bovine S-antigen (S-Ag). In previous reports, two nonimmunodominant pathogenic sites were found using synthetic peptides corresponding to conserved sequences at amino acid residues 303-314 and 286-297 of the bovine sequence. In this report, a 20-residue synthetic peptide encompassing amino acids 343-362 located near the C-terminus was found to be highly immunopathogenic in LEW rats. The onset of EAU was observed at as early as 8 days when high doses of a peptide-encompassing residues 343-362 were used. EAU was elicited with as little as 0.5 microgram of peptide per animal. Smaller peptides from this region were also tested for uveitogenicity, further refining the site to 13 amino acids. Uveitogenic T cell lines were made to this site in two ways; first, by the in vitro selection of a bulk T cell line raised to human S-Ag with peptide 343-362. Second, by the in vitro selection of a peptide-specific line from an animal immunized with peptide 352-364, which corresponds to the minimal uveitogenic site. Both of these lines adoptively transferred EAU to LEW rats, further establishing the pathogenicity of this site. A proliferative site distinct from, but overlapping, the uveitogenic site was also found. The potent uveitopathogenicity of peptides from this region indicates that it is a major pathogenic site responsible for EAU induced in LEW rats by immunization with human S-Ag.     

Amelioration of Experimental Autoimmune Uveitis by Leflunomide in Lewis Rats

Purpose

To investigate the efficacy of leflunomide in experimental autoimmune uveitis (EAU) in rats.

Methods

Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to generate EAU. Rats received three dose of leflunomide through intragastric administration (prevention or treatment protocols) after immunization at three separate doses (3 mg/kg/d; 6 mg/kg/d; 12 mg/kg/d). Cyclosporin A was administered as a positive) control. Rats were euthanized during peak disease activity (day 14 or 15). Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d14) and histopathological evaluation of enucleated eyes after experimental termination. The expression levels of inflammatory cytokines in the serum were quantified by ELISA. Eyeball of rats were harvested and mRNA expression of interleukin 17 (IL17) and IFN-γ were quantified through RT-PCR. Intracellular expression of interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. The effects of leflunomide inhibition on immune responses in rats were investigated in isolated lymphocytes.

Results

Histopathological and clinical data revealed severe intraocular inflammation in the immunized rat. Inflammation reached its peak on day 14 in this EAU model. Treatment with leflunomide significantly prevented and treated EAU-induced ocular inflammation and decreased clinical and pathological scores compared to vehicle-treated eyes. Gene expression of IL17 and IFN-γwas markedly reduced in leflunomide-treated eyes. Leflunomide significantly decreased the serum levels of IL17 and IFN-γ. The study of IL17+ T cells in peripheral blood and spleen by flow cytometry showed a decreased number of Th17 cell in rats of leflunomide prevented group. Lymphocytes from animals treated with leflunomide had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals.

Conclusions

Oral administration of leflunomide effectively suppressed IRBP-induced uveitis in rats. These results suggest that leflunomide may be potentially clinical application in uveitis.     

Systemic expression of rat soluble retinal antigen induces resistance to experimental autoimmune uveoretinitis.

To assess the role of sequestration in the maintenance of the immune privilege of the retina, retrovirally mediated gene transfer was used to express a defined, specific retinal autoantigen, rat soluble retinal Ag (S-Ag), in a systemic, nonsequestered manner. In this study we report the stable, long term transduction of rat retinal S-Ag into PBMC. Tolerance to S-Ag was assayed by challenging the S-Ag chimeric animals with S-Ag peptides in CFA and monitoring the time course and severity of experimental autoimmune uveoretinitis (EAU). The resulting data showed a correlation between the incidence of S-Ag chimerism and the loss of susceptibility to EAU. The development of resistance to EAU induction supports the hypothesis that Ag sequestration contributes to retinal immune privilege.     

研究报告: 实验性自身免疫性葡萄膜炎模型中肝脏免疫系统紊乱的研究

葡萄膜炎是一种反复发作的炎症性疾病,可导致免疫系统功能障碍和多器官损伤．然而,葡萄膜炎是否导致肝功能损害尚不十分清楚．本文通过运用流式分析技术和激光共聚焦成像技术,研究了实验性自身免疫葡萄膜炎模型的肝脏病理和功能变化．结果显示肝损伤可出现在葡萄膜炎的炎症后期并与眼损伤程度相关．并且CD3⁺ CD4⁺ T细胞、CD3^- NK1.1⁺ DX5^- NK细胞、和CD11b⁺ F4/80^- ly6c⁺ 细胞在感染的眼睛和肝脏中增加．将CD3⁺ CD4⁺ T细胞回输给炎症的小鼠后,眼睛和肝脏的病理损伤加重．此外,在炎症的小鼠中可见血管扩张,大量淋巴细胞浸润到炎症的眼和肝脏的血管周围．总之,我们的研究结果提示,肝损伤可以发生在小鼠葡萄膜炎模型中,这种损伤可能与通过外周循环浸润到肝脏的CD3⁺ CD4⁺ T细胞有关．