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Biomedical subjects

I Gery

Publications and source records attributed to I Gery.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effect of gallium nitrate on experimental autoimmune uveitis.

Gallium nitrate (GN) has been shown to inhibit T cell-mediated inflammatory disease. The purpose of our study was to test the effect of gallium nitrate (GN) on experimental autoimmune uveitis (EAU). Experimental autoimmune uveitis was induced in male Lewis rats immunized with retinal S-antigen. Rats received subcutaneous injections of GN or saline one day prior to immunization and 1, 4, 7, 10, 13, 16, and 19 days after immunization. Ocular inflammation was graded clinically and histologically by masked observers, and in vitro assays of cell-mediated and humoral immunity were performed. GN significantly inhibited the development of EAU graded clinically (P = 0.001) and histologically (P = 0.002). Treatment with GN also resulted in a small (30-41%) decrease in the lymphocyte responses to retinal S-Antigen and a small (12-37%) reduction in antibody production to S-antigen. These data show that GN suppresses the development of EAU, and inhibits both lymphocyte proliferative responses to antigen and antibody production.

Animals↗
PubMed1997

Treatment of uveitis by oral administration of retinal antigens: results of a phase I/II randomized masked trial.

PURPOSE: To evaluate the effect and safety of the oral administration of retinal antigens as a treatment of ocular inflammation. METHODS: In a phase I/II randomized masked trial, patients with endogenous uveitis who were dependent on immunosuppressive agents were randomly assigned to receive either retinal S antigen alone (10 patients), retinal S antigen and a mixture of soluble retinal antigens (10 patients), a mixture of soluble retinal antigens alone (10 patients), or placebo (15 patients). An attempt was then made to taper patients completely off their standard immunosuppressive therapy over an 8 week period. The primary study endpoint was time to ocular inflammatory attack. The secondary study endpoint was the ability to taper patients completely off their immunosuppressive or cytotoxic medication within 8 weeks. RESULTS: Time to development of the main study endpoint was not statistically significantly different for any of the four treatment groups. However, the group receiving the purified S antigen alone appeared to be tapered off their immunosuppressive medication more successfully compared with patients given placebo (P = .08), whereas all the other groups appeared to do worse than did those receiving placebo. No toxic effects attributable to any treatment were observed. CONCLUSIONS: This phase I/II study is the first to test the use of orally administered S antigen in the treatment of uveitis. Although not statistically significant, patients given S antigen were more likely to be tapered off their chronically administered systemic immunosuppressive therapy than were the other groups tested.

Administration, Oral↗
PubMed1997

Immunomodulatory effects of linomide in animals immunized with immunopathogenic retinal antigens: dissociation between different immune functions.

Linomide (LS-2616, quinoline-3-carboxamide) has been reported to exert a diverse range of effects on the immune system. On one hand, this drug was found to stimulate the immune system and to enhance activities such as DTH or allograft rejection. On the other hand, linomide was shown to inhibit the induction of experimental autoimmune encephalomyelitis and myasthenia gravis, as well as the development of diabetes in non-obese diabetic (NOD) mice. Here we report the effects of linomide in animals immunized with uveitogenic retinal antigens. Treatment with linomide completely inhibited the development of experimental autoimmune uveoretinitis (EAU) in mice immunized with interphotoreceptor retinoid-binding protein and markedly suppressed EAU in rats immunized with S-antigen (S-Ag). In addition, linomide-treated rats exhibited reduced antibody production and lymphocyte proliferative response to S-Ag. In contrast to these suppressive activities, linomide treatment did not affect the development of adoptively transferred EAU in rats and moderately enhanced the DTH reactions to S-Ag in immunized rats in which EAU and other immune responses to this antigen were suppressed.

Adjuvants, Immunologic↗
PubMed1997

Permissive recognition of immunodominant determinants of the retinal S-antigen in different rat strains, primates and humans.

The majority of antigenic peptides exhibit restriction in their interaction with the MHC molecules on antigen-presenting cells of different haplotypes. Certain peptides, however, are "permissive': they bind strongly to different MHC molecules and are selected as the immunodominant epitopes by animals using these MHC gene products. Here we show for the first time that several peptides from four regions of the sequence of human S-antigen (H-SAg), a retinal-specific protein, demonstrate high levels of permissiveness. Each of these peptides was found to be immunodominant in at least some of four inbred rat strains and five cynomolgus monkeys, immunized with whole H-SAg. Moreover, some of these peptides were recognized by lymphocytes from four normal controls and four patients with uveitis who responded against the H-SAg molecule. On the other hand, the permissive peptides stimulated marginal or no response in cultures of Lewis rats injected with adjuvant alone, or rat and human cell lines specific to other antigens, thus demonstrating that these peptides do not carry any non-specific mitogenic activity. One peptide, 29, which was found immunodominant in the monkeys, the uveitis patients and Lewis rats, is highly immunopathogenic in this rat strain. No good correlation between immunodominance and immunopathogenicity was found with other H-SAg peptides. The finding of cross-species permissiveness among peptides of H-SAg and similar observations with myelin proteins suggest that permissiveness could be quite prevalent among peptides of immunopathogenic antigens.

Adult↗
PubMed1996

Intraocular inflammatory disease (uveitis) and the use of oral tolerance: a status report.

Intraocular inflammatory disease, or uveitis, is a disorder that mostly affects children and young adults. It is the cause of about 10% of the severe visual handicap in the United States. Many of the severe, sight-threatening uveitic conditions are thought to be driven by putative autoimmune mechanisms, often with high-dose oral prednisone use as treatment, along with cytotoxic agents, antimetabolites, and cyclosporine adjunctively. The feeding of the uveitogenic retinal S-Ag to rats immunized with the same antigen resulted in clinical protection. A pilot study in which two patients, one with pars planitis and the other with Behcet's disease, were fed with the retinal S-Ag resulted in these patients' immunosuppressive medication being decreased and/or stopped. The trial also provided us with information concerning dosage and expected immune responses. A randomized, masked study looking at the effect of feeding retinal antigens to uveitis patients is ongoing.

Administration, Oral↗
PubMed1996

Human lymphocyte responses against epitopes of a self antigen: a follow-up at different time points.

This study was aimed at examining the changes that may occur with time in the lymphocyte responses of an individual against peptide determinants of self antigens. Peripheral blood lymphocytes were collected from the same donor at seven different time points during a 10-month period and tested for their proliferative responses against whole human S-antigen and 40 overlapping peptides derived from the sequence of this uveitogenic retinal protein. Lymphocytes collected at different dates varied in their responsiveness to all tested antigens, as well as in the pattern of their response against individual peptides. The latter variability was expressed by differences in the hierarchical order of the most stimulatory peptides for lymphocytes collected at the seven time points. Despite the variability in their stimulatory capacity, six of the peptides exhibited their immunodominance by eliciting proliferation in lymphocytes collected at all time points. Our results thus indicate that data collected from a single sample of blood may be insufficient to accurately assess the level of cellular response to autologous antigens.

Amino Acid Sequence↗
PubMed1996

CD8 T-cells are not essential for the induction of "low-dose" oral tolerance.

To examine whether CD8 T-cells are essential for the induction of "low-dose" oral tolerance, we tested animals deficient in CD8 T-cells, i.e., Lewis rats in which CD8 cells were eliminated by injections of specific antibodies and beta 2m(-/-) mice in which the CD8 cells are scarce and poorly functional. Oral tolerance was induced in the rats by repeated feedings with the uveitogenic retinal S-antigen, while in the mice the fed antigen was ovalbumin. Feeding reduced in both species the specific cellular immune response, measured by the lymphocyte proliferation assay. In the rats, this treatment also inhibited the development of the inflammatory eye disease, experimental autoimmune uveoretinitis. In addition, the levels of specific antibodies in the fed animals were moderately lower than those in their controls. Both the CD8-depleted rats and the beta 2m(-/-) mice resembled their normal controls in demonstrating reduced immune responses following feeding with the corresponding antigen. This observation thus indicates that CD8 T-cells are not essential for the induction of low-dose oral tolerance.

Administration, Oral↗
PubMed1996

Reduced susceptibility to IL-1 and endotoxin in transgenic mice expressing IL-1 in their lens.

To learn about the effects of chronic exposure to IL-1 we generated a transgenic (Tg) mouse line that expresses human IL-1 beta under the control of the lens alpha-A crystallin promoter. Expression of human IL-1 beta was restricted to the eye; neither the protein nor its mRNA were detected in various other organs of the Tg mice. The Tg mice develop severe ocular inflammation shortly after birth, which affects the lens and other eye tissues and apparently allows the release of IL-1 into the circulation. Here we report that the Tg mice exhibit decreased responsiveness to IL-1 and lipopolysaccharide (LPS), as compared to their wild-type littermate controls: (1) when injected with IL-1 the Tg mice produced lower levels of serum amyloid A than their controls; (2) thymocytes of the Tg mice responded less vigorously in culture to stimulation with IL-1; and (3) Tg mice showed lower morbidity and mortality than their controls when injected with toxic amounts of LPS. These data suggest that chronic exposure to IL-1 in the Tg mice induces partial resistance to this cytokine, analogous to the reduced responsiveness to IL-1 in animals pretreated with this proinflammatory cytokine.

Animals↗
PubMed1995

Periocular inflammation in mice with experimental systemic lupus erythematosus. A new experimental blepharitis and its modulation.

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal anti-DNA Ab, bearing a major Id 16/6Id. Immunized mice initially produce Abs to 16/6Id, DNA and nuclear Ags, and subsequently develop various clinical manifestations including leukopenia and renal immune complex disease. MHC class I Ags play a critical role in the induction and progression of experimental SLE. The present study reports that ocular changes also occur in mice with experimental SLE. The ocular disease is characterized by bilateral subacute and chronic inflammation of the eyelids (blepharitis) with immune complex IgG deposition and hypertrophic meibomian glands. The severity of ocular changes was strain dependent: most severe in 129 mice, less intense in BALB/c animals and only minimal in C3H.SW mice. No blepharitis developed in mice deficient in MHC class I expression. Further, the disease was strongly inhibited in BALB/c mice treated with methimazole, an agent that has been shown to repress transcription of MHC class I. In these cases, there was no IgG deposition and a decreased infiltration of inflammatory cells in the eyelids. These observations thus suggest that, similar to the observation with experimental SLE, MHC class I is critical in the onset of this experimental autoimmune blepharitis. The new experimental eye disease described here provides an animal model for chronic blepharitis in humans, a common condition for which such a model has been sought.

Animals↗
PubMed1995

Inhibition of experimental autoimmune uveoretinitis by mycophenolate mofetil, an inhibitor of purine metabolism.

Mycophenolate mofetil (MM), an inhibitor of purine metabolism, was found to effectively inhibit the development of experimental autoimmune uveoretinitis (EAU) induced by S-antigen (SAg) in Lewis rats. MM completely inhibited EAU development in the majority of rats when administered daily, on days 0-13, at a dose of 30 mg kg-1 day-1. The drug was less effective, however, when given on days 7-20: minimal disease inhibition was achieved with the drug at 30 mg kg-1 day-1, although at 60 mg kg-1 day-1 the drug inhibited EAU development in most treated rats during the period of its administration. MM also completely inhibited in most treated rats the development of EAU adoptively transferred by SAg-sensitized lymphocytes, thus depicting its capacity to inhibit the efferent limb of the immune response. Treatment with MM also suppressed the cellular and humoral immune responses against SAg, with a good correlation being observed between the inhibition of these responses and suppression of EAU in the different groups of rats. MM is currently being examined for its immunosuppressive effects in humans and the data recorded here thus suggest this compound may be useful in treatment of immune-mediated uveitic conditions.

Animals↗
PubMed1994

A pathogenic autoimmune process targeted at a surrogate epitope.

Immunization with the retinal interphotoreceptor retinoid-binding protein (IRBP) induces in a variety of animals an inflammatory eye disease, experimental autoimmune uveoretinitis (EAU). We have previously shown that sequence 1181-1191 of bovine IRBP (BOV 1181-1191) is immunodominant and highly uveitogenic and immunogenic in Lewis rats. Sequence 1181-1191 of the rat IRBP (RAT 1181-1191) differs from BOV 1181-1191 by two residues, at positions 1188 and 1190, that are pivotal for the immunological activity of the bovine epitope. Here we show that, unlike its bovine homologue, RAT 1181-1191 did not induce EAU or an immune response in Lewis rats. The immunological inactivity of RAT 1181-1191 in Lewis rats is due at least in part to its poor affinity toward the antigen-presenting cells of these rats, as shown by its failure to compete with binding of BOV 1181-1191 to Lewis adherent spleen cells. Moreover, unlike all other known autologous homologues of immunopathogenic epitopes, RAT 1181-1191 was not recognized by lymphocytes sensitized against BOV 1181-1191 and failed to stimulate proliferation, uveitogenic capacity or signal transduction in these cells. These findings thus suggest that RAT 1181-1191 is not a likely target for lymphocytes sensitized against BOV 1181-1191 in the process in which these cells recognize IRBP in the rat eye and trigger the inflammatory reaction of EAU. Our data further suggest that the target for the disease-inducing lymphocytes is sequence 273-283 of the rat IRBP: (a) sequence 273-283 is highly conserved and is identical in the bovine and rat proteins; (b) determinant 273-283 is a "repeat" of 1181-1191 in the fourfold structure of IRBP and shares seven residues with BOV 1181-1191; (c) rat peptide 273-283 is recognized by lymphocytes sensitized against BOV 1181-1191 and stimulates them for proliferation and for acquisition of uveitogenicity; and (d) moreover, sequence 273-283 is superior to BOV 1181-1191 in its capacity to generate uveitogenicity in lymphocytes sensitized against this bovine peptide. The present study thus describes for the first time a system in which an autologous homologue of an immunopathogenic epitope is inactive and a "surrogate" determinant apparently serves as the target for lymphocytes sensitized against the immunopathogenic peptide.

Amino Acid Sequence↗
PubMed1994

Immune responses against self-TCR peptides.

Vaccination of rats against the TCR peptide V beta 8.2 (39-59) was reported to inhibit the immunopathogenic process of EAE. Analysis of the immune response to this peptide and several related TCR peptides yielded the following findings: (i) Lewis rats immunized in vivo and challenged in vitro responded with vigorous lymphocyte proliferative responses to peptide V beta 8.2 (39-59) and to three other rat TCR peptides, V beta 8.3 (15-32), V beta 8.3 (39-59), and V beta 14 (39-59). On the other hand, two other rat peptides, V beta 8.2 (18-38) and V beta 8.3 (62-76), were poorly immunogenic. (ii) Rat peptide V beta 8.2 (39-59) was found more immunogenic than its mouse homolog, in both Lewis rats and B10.A mice. A moderate level of cross-reactivity was observed between these two peptide homologs. (iii) Rats of different genetic makeups varied in their response to peptide V beta 8.2 (39-59). A similar pattern of response of the different rats was found with another TCR peptide, V beta 14 (39-59). Hybrids between high and low responder rat strains resembled the high responders in their response to the TCR peptides. (iv) Sensitized lymph node cells as well as lymphocytes of a cell line specific for peptide V beta 8.2 (39-59) failed to respond to T cells that express the V beta 8.2 gene product. This observation is interpreted to indicate that peptide V beta 8.2 (39-59) is a cryptic determinant of the V beta 8.2 protein. Moreover, the data suggest that lymphocytes proliferating against peptide V beta 8.2 (39-59) may not be responsible for the reported inhibition of EAE in rats vaccinated with this peptide.

Amino Acid Sequence↗
PubMed1994

Autoimmunity in the eye and its regulation.

Recent studies have provided new information concerning the development of autoimmune-mediated intraocular inflammation (uveitis) and the mechanisms that suppress this sight-robbing process. Newly collected data have led to several interesting advances: the discovery of additional uveitogenic antigens and novel uveitogenic reactions; dissection of the early steps of the pathogenic process; identification of the subsets of lymphocytes that selectively accumulate in the inflamed eye; analysis of the development of tolerance against sequestered antigens in the eye; elucidation of the cellular and molecular events of the anterior chamber-associated immune deviation, the major immunoregulatory mechanism in the eye; the capacity of this mechanism to inhibit and even treat uveitis; and examination of the mechanisms whereby oral tolerance inhibits ocular inflammation.

Amino Acid Sequence↗
PubMed1994

Experimental melanin-protein-induced uveitis in the Lewis rat. Immunopathologic processes.

PURPOSE: To study the immunopathology of experimental melanin-protein-induced uveitis in the Lewis rat. METHODS: Rats were immunized with bovine ocular melanin protein. The kinetics of experimental melanin-protein-induced uveitis was studied by clinical examination and immunopathology. Cellular and humoral responses were evaluated by lymphocyte proliferation, delayed-type hypersensitivity, and agglutination. After clinical disease subsided, recurrent experimental uveitis was induced with a low-dose footpad injection of lipopolysaccharide. RESULTS: Experimental melanin-protein-induced uveitis was characterized by bilateral uveal infiltration mainly with lymphocytes and monocytes. Delayed-type hypersensitivity, lymphocyte proliferation, and agglutination to bovine ocular melanin protein were positive. Expressions of major histocompatibility complex class II and intercellular adhesion molecule-1 were observed before ocular infiltration. The predominantly infiltrating cells were CD4+ lymphocytes. Experimental melanin-protein-induced uveitis subsided within 1 month, spontaneously recurred within 1 week in approximately one quarter of the rats, and was inducible in most rats with 5 micrograms of lipopolysaccharide confirmed by histopathology. CONCLUSIONS: Experimental melanin-protein-induced uveitis is a T-cell-mediated autoimmune uveitis, resembling noninfectious recurrent iridocyclitis and choroiditis in humans.

Animals↗
PubMed1994

Interphotoreceptor retinoid-binding protein derived peptide can induce experimental autoimmune uveoretinitis in various rat strains.

Experimental autoimmune uveoretinitis (EAU) is an intraocular inflammatory disease model induced by retinal specific antigens such as S-antigen and interphotoreceptor retinoid-binding protein (IRBP). The present study was aimed at testing the uveitogenicity of IRBP and an IRBP-derived peptide in various strains of rats with different RT1 (major histocompatibility complex in rats) haplotypes. Immunization with IRBP induced distinct EAU in LEW (RT1l), WKAH (RT1k) W/M (RT1k), LEJ (RT1j), and BUF (RT1b) rats. IRBP also induced a low grade of EAU in SDJ (RT1u), but no disease was detected in TO rats, another strain of the RT1u haplotype. IRBP-derived peptide R16 (aa 1177-1191) induced severe EAU in LEW rats and moderate disease in the WKAH and W/M strains. Immunization with R16 also induced low levels of inflammation in eyes of 75% and 20% of LEJ and BUF rats, respectively, but this peptide did not cause any disease in SDJ and TO rats. Injection of Bordetella pertussis had minimum or no effect on the induction of EAU by peptide R16 in this study. These data thus indicate that peptide R16 can bind to various RT1 molecules in addition to RT1l. Further, our observations support the notion that certain epitopes of IRBP could be uveitogenic in humans with different HLA haplotypes.

Amino Acid Sequence↗
PubMed1994

Recoverin is highly uveitogenic in Lewis rats.

PURPOSE: Recoverin, a calcium-binding protein that selectively localizes to the retina and pineal gland, has been identified as the target for the putative pathogenic autoimmune process of cancer-associated retinopathy (CAR). The present study was aimed at testing the capacity of recoverin to induce experimental autoimmune uveoretinitis and pinealitis in Lewis rats. METHODS: Lewis rats were immunized against recombinant myristoylated recoverin by a single footpad injection of the protein, at various doses, emulsified in complete Freund's adjuvant. Development of uveoretinitis was monitored by clinical and histologic examinations, whereas pinealitis was detected by histologic examination. RESULTS: Immunization with recoverin induced severe panuveitic changes that closely resemble those induced by S-antigen (arrestin). The effect was dose-dependent, with 10 micrograms/rat the lowest immunopathogenic dose. Rats immunized with recoverin also developed pineal inflammation. CONCLUSION: Recoverin is highly immunopathogenic in Lewis rats. Although the ocular changes induced in rats differ from those seen in CAR, the data recorded here are in line with the concept that recoverin can initiate pathogenic autoimmune processes in the eye.

Animals↗