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Biomedical subjects

I Gery

Publications and source records attributed to I Gery.

At least 73 records · Page 4Linked to original sources
PubMed1991

FK506 treatment of S-antigen induced uveitis in primates.

FK506 is a new immunosuppressive agent which has been found more potent than cyclosporine based on the dosage. FK506 was examined here for its effect on the development of uveitis in primates immunized with S-antigen. FK506 successfully inhibited uveitis in monkeys, even when administered three weeks after the first immunization, at the time when the immunopathogenic mechanism of uveitis is assumed to be developed. All four monkeys injected with 0.5 mg/kg/day of FK506 did not develop uveitis, 2 out of 4 treated with the 0.25 mg and 3 out of 4 of those receiving the 0.125 mg also did not develop disease. FK506 suppressed to some extent the cellular and humoral immune responses to S-antigen. The main side effect of FK506 was weight loss. We consider that this drug may be considered as a new potential therapeutic agent for immune-mediated ocular disease in humans.

Animals↗
PubMed1991

Trials of vaccination against experimental autoimmune uveoretinitis with a T-cell receptor peptide.

T lymphocytes which mediate several experimental autoimmune diseases, including encephalomyelitis (EAE) and uveoretinitis (EAU) in Lewis rats, preferentially utilize V beta 8 gene product in their receptor. Vaccination against a V beta 8.2-derived peptide was reported to inhibit EAE induction and we report here on the effect of vaccination with this peptide on the development of EAU. Experimental rats were pretreated with the V beta 8.2 peptide, emulsified in adjuvant (CFA), whereas control animals were untreated or injected with saline in CFA. Rats of all groups were immunized 30 or 40 days later with the immunopathogenic antigen, emulsified in Mycobacterium-enriched CFA. Vaccination with CFA emulsions containing either the V beta 8.2 peptide or saline, remarkably inhibited the development of the tested diseases, as compared to the untreated controls. Vaccination with the V beta 8.2 peptide had variable effects in this study on disease development: it inhibited the S-antigen-induced EAU more than did treatment with CFA in four out of six experiments, had a similar effect to that of CFA in one experiment and enhanced the disease in another experiment. Conversely, vaccination with the V beta 8.2 peptide slightly enhanced the EAU induced by the interphotoreceptor retinoid-binding protein (IRBP), or its dominant determinant, in three of four experiments and had no apparent effect in the fourth experiment. In addition, we could not reproduce the reported protective effect of vaccination with the V beta 8.2 peptide against induction of EAE. Vaccination with the V beta 8.2 peptide also had no clear effect on the development of humoral or cellular immune responses against S-antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Analysis of immune responses of uveitogenic synthetic peptides derived from IRBP].

We reported that R4 and R14 are uveitogenic synthetic peptides derived from bovine IRBP (interphotoreceptor retinoid-binding protein) in rats. R4 induced mild uveitis, while R14 induced severe uveitis with retinal detachment. In this experiment, a comparison of uveitogenicity, immune responses and capacity of uveitis transfer was made between R4 and R14. R14 was found to be approximately 1,000 times more uveitogenic than R4. R14 showed cross-reactivity with IRBP, original antigen, but R4 did not in lymphocytic proliferation assay and adoptive transfer experiment. Neither R4 nor R14 exhibited cross-reactivity with IRBP in antibody production in sera. Therefore, R14 is found to be an immunodominant site in the whole sequence of IRBP. It is conceivable that R14 plays an important role in uveitis induction and immune responses in rat immunized IRBP.

Amino Acid Sequence↗
PubMed1991

Unusual immunologic properties of the uveitogenic interphotoreceptor retinoid-binding protein-derived peptide R23.

Peptide R23, consisting of residues 1091-1115 of bovine interphotoreceptor retinoid-binding protein (IRBP), had some unusual immunologic properties in Lewis rats. The peptide induced experimental autoimmune uveoretinitis and pinealitis in these rats, but only at high doses. The minimal immunopathogenic dose was found to be 100 nmol/rat. On the other hand, R23 was highly immunogenic in Lewis rats, producing cellular immunity, as measured by the lymphocyte proliferation assay, with a minimal dose of 1 nmol/rat. This unusual dissociation between the uveitogenic and immunogenic activities of R23 was attributed to different sites on the peptide, stimulating either the lymphocytes which induce disease or those which vigorously proliferate in culture. The potent immunogenicity of R23 was consistent with the peptide being immunodominant, as demonstrated by its capacity to be recognized by lymphocytes sensitized against whole IRBP and to stimulate these cells in culture to proliferate and acquire uveitogenic capacity. Likewise, lymphocytes sensitized against R23 are stimulated in culture by whole IRBP. Unexpectedly, peptide R23 was inferior to whole IRBP in its capacity to stimulate uveitogenicity in R23-sensitized lymphocytes. This finding also was attributed to the preferential stimulation by R23 of the lymphocytes specific for the putative "nonuveitogenic" site on the peptide. Peptide R23 also differs from the other tested bovine IRBP-derived peptides in the specificity of its antibodies. Unlike antibodies to the other peptides, those to R23 showed a strong cross reactivity toward whole IRBP.

Amino Acid Sequence↗
PubMed1990

Cellular immune responses of patients with uveitis to retinal antigens and their fragments.

Of two patient populations totaling 82 patients, one in the United States and the other in Japan, we studied the cellular immune responses against S-antigen and interphotoreceptor retinoid binding protein as well as to fragments of each antigen. Behçet's disease, birdshot retinochoroidopathy, pars planitis, ocular sarcoid, sympathetic ophthalmia, and the Vogt-Koyanagi-Harada syndrome were diagnosed in these patients. The response profile of both antigens paralleled each other. This profile was more commonly seen in patients suffering from diseases affecting the retina. Responders reacting to both antigens or to several fragments of an antigen were present. This pattern of response was seen in 26 of the patients tested. Patients with uveitis appeared able to recognize several autoantigens. This might be a consequence of the breakdown of the blood-retinal barrier and may help perpetuate the inflammatory process. Several patients were capable of responding to more than one epitope of the same antigen, which indicates that there are major differences between the experimental model and human autoimmune diseases in the response to autoantigens. Both of these findings may to help develop new immunotherapeutic strategies in the treatment of uveitis.

Adolescent↗
PubMed1990

Stimulation in vitro of lymphocytes for induction of uveoretinitis without any significant proliferation.

Experimental autoimmune uveoretinitis can be adoptively transferred into naive recipients by lymphocytes from rats immunized with uveitogenic Ag, provided these cells are activated in vitro before being injected. The activation of sensitized lymphocytes, by the immunizing Ag, or by cross-reacting Ag, is usually accompanied by vigorous proliferation. We report, however, on a complete dissociation between the capacity of a peptide to generate uveitogenicity and to stimulate proliferation in cultured lymphocytes. This peptide, which occupies sequence 579-591 of the bovine interphotoreceptor retinoid-binding protein (IRBP), is one of the three "repeats" that exhibit partial sequence homologies with the immunodominant and highly immunogenic peptide, 1179-1191. Peptide 579-591 is nonimmunogenic and nonuveitogenic in Lewis rats and does not stimulate any significant proliferation in lymphocytes sensitized against whole IRBP, peptide 1179-1191, or another "repeat" peptide, 271-283, which is immunogenic and uveitogenic. In contrast, peptide 579-591 effectively generates uveitogenicity in the lymphocytes sensitized against these three Ag. Unlike 579-591, peptides 271-283 and 1179-1191 stimulated both proliferation and uveitogenicity in these sensitized lymphocytes. A different pattern of activities was observed with the other "repeat" peptide, 880-892. This peptide did not have any effect on the lymphocytes sensitized against IRBP, 271-283 or 1179-1191, but did stimulate both proliferation and uveitogenicity in lymphocytes sensitized against itself. The data suggest that 579-591 selectively stimulates a lymphocyte subset that is uveitogenic, but is incapable of mounting proliferative responses.

Animals↗
PubMed1990

Repeated determinants within the retinal interphotoreceptor retinoid-binding protein (IRBP): immunological properties of the repeats of an immunodominant determinant.

Interphotoreceptor retinoid-binding protein (IRBP), a glycoprotein which localizes in the retina and pineal gland, induces inflammatory changes in these organs (EAU and EAP, respectively) when injected into various mammals. We have previously identified a determinant (residues 1169-1191) in bovine IRBP which is immunodominant and highly immunogenic and immunopathogenic in Lewis rats. IRBP exhibits a fourfold repeat structure and we report here on the comparison between the active sequence 1179-1191 and its three repeat peptides. Only one of the repeats, 271-283, cross-reacted with 1179-1191 and exhibited immunodominance, albeit of a low level. Peptide 271-283 was also immunogenic and immunopathogenic in Lewis rats, but with a minimal dose approximately 100 times higher than that of 1179-1191. Peptide 880-892, a nondominant determinant, resembled 271-283 in its immunogenicity, but was markedly less immunopathogenic. No immunological activity was detected in the fourth repeat peptide, 579-591. Peptide 1179-1191 was superior to the other repeats also in its antigenicity, i.e., the capacity to stimulate presensitized lymphocytes in culture: the minimal stimulatory concentrations of 1179-1191 was greater than 1000 times lower than those of 271-283 or 880-892. Furthermore, 1179-1191 was stimulatory at concentrations lower than those of 271-283 even when tested with lymphocytes sensitized against 271-283. A correlation was also found between the immunological activities of the repeat peptides and their amphipathicity. This study thus identifies two new immunopathogenic determinants of IRBP and provides additional data to show the association between immunodominance of peptides and their various immunological activities.

Amino Acid Sequence↗
PubMed1990

Uveitis and immune responses in primates immunized with IRBP-derived synthetic peptides.

Monkeys immunized with bovine IRBP-derived synthetic peptides R4 (sequence 1158-1180) or R14 (1169-1191) developed EAU which was detected by both clinical and histological examinations. The inflammation localized mainly in the choroid, with only minor changes being noticed in the adjacent retinal tissue. EAU developed in only one of the two monkeys immunized with each of the peptides and the animals with disease also showed higher levels of cellular immunity toward the immunizing peptide than did the monkeys with no disease. The cellular immune responses, measured by the lymphocyte proliferation assay, were specific toward the immunizing peptides, with no cross responsiveness to whole IRBP. This finding suggests that the two uveitogenic peptides were non-immunodominant in the tested monkeys. In contrast, peptide R14 is highly immunodominant in the Lewis rat. Also, the fine specificity of the monkey response to R14 differed from that of the Lewis rat. The possible genetic control of the monkey susceptibility to EAU induction by the peptides is discussed and the unique finding of an autoimmune disease induction by a non-immunodominant peptide is underscored.

Amino Acid Sequence↗
PubMed1990

Immunological features of synthetic peptides derived from the retinal protein IRBP: differences between immunodominant and non-dominant peptides.

Interphotoreceptor retinoid-binding protein (IRBP) is a glycoprotein of 1264 residues (bovine) which localizes specifically in the retina and pineal gland and induces inflammatory changes in these organs (EAU and EAP, respectively) in immunized animals. We report here on differences between the immunological activities in Lewis rats of four IRBP-derived synthetic peptides. Only one of these peptides, designated R14 (residues: 1169-1191) is immunodominant, i.e., it has the capacity to stimulate lymphocytes sensitized against whole IRBP. The remaining peptides, R4 (1158-1180), R8 (1197-1209), and R12 (248-266), are non-dominant and are not recognized by IRBP-sensitized lymphocytes. R14 differed profoundly from the other peptides in its immunogenicity, inducing cellular immunity at the low dose of 0.1 nmol/rat, whereas the non-dominant peptides initiated immune responses at doses approximately 100 times higher. R14 was also superior to the non-dominant peptides in its antigenicity, as determined by the lowest concentration required to induce sensitized lymphocytes to proliferate. Responses were stimulated by R14 at a concentration of 10(-6) microM, while the three non-dominant peptides were stimulatory at the much higher concentration of 10(-1) microM. These data support the concept that immunodominance is linked to a high binding affinity of the peptide determinant to the major histocompatibility complex antigens on antigen-presenting cells.

Amino Acid Sequence↗
PubMed1990

Lymphocyte responses to peptide M and to retinal S-antigen in uveitis patients.

A synthetic amino acid, peptide M18 (18 amino acids in length which correspond to the amino acid positions 303-322 of bovine S-antigen: DTNLASSTIIKEGIDKTV), is capable of inducing experimental autoimmune uveitis in monkeys and Hartley guinea pigs as well as Lewis rats. Recently, the amino acid sequence of human S-antigen corresponding to peptide M was found to be virtually identical to that of bovine S-antigen. To investigate the role of the epitope corresponding to peptide M in human uveitis, 21 patients with uveitis were tested for proliferation of peripheral mononuclear cells against peptide M18 and bovine S-antigen. Six of the 21 patients responded to S-antigen and 4 of these 6 patients responded to peptide M18. These findings show that peptide M18 is immunogenic in man and provide additional support to the hypothesis that the amino acid sequence which corresponds to peptide M might be involved in uveitic conditions in man.

Adolescent↗
PubMed1990

Serial adoptive transfer of experimental autoimmune uveoretinitis in rats.

Experimental autoimmune uveoretinitis (EAU) and pinealitis induced by an interphotoreceptor retinoid-binding protein (IRBP)-derived peptide (R4) was serially transferred into naive recipient rats, using spleen cells from recipients of previous "orders" of transfer. The cells initiating the disease in recipients of the first order were either lymph node cells from rats immunized against peptide R4, or lymphocytes of a cell line specific toward this peptide. The serial transfer was successfully carried out through as many as four orders of sequential recipients.

Amino Acid Sequence↗
PubMed1989

Synthesis of an immunopathogenic fusion protein derived from a bovine interphotoreceptor retinoid-binding protein cDNA clone.

We have extended the cDNA sequence of bovine interphotoreceptor retinoid-binding protein (IRBP) and subcloned one of the sequenced cDNA fragments into an expression vector. The nucleotide (nt) sequences of four bovine IRBP cDNA clones have been determined. These sequences when assembled cover the 3' proximal 3629 nt of the IRBP mRNA and encode the C-terminal 551 amino acids (aa) of IRBP. This cDNA sequence validates the intron: exon boundaries predicted from the gene. A 2-kb EcoRI insert from lambda IRBP2, one of the clones sequenced, encoding the C-terminal 136 aa of IRBP was subcloned into the expression vector pWR590-1. Escherichia coli carrying this plasmid construction, pXS590-IRBP, produced a fusion protein containing 583 N-terminal aa of beta-galactosidase, three linker aa residues, 136 C-terminal aa of IRBP and possibly a number of additional C-terminal residues due to suppressed termination. This 86-kDa fusion protein, purified by detergent/chaotrope extraction followed by reverse-phase high-performance liquid chromatography, cross-reacted with anti-bovine IRBP on Western blots. This protein induced an experimental autoimmune uveo-retinitis and experimental autoimmune pinealitis in Lewis rats indistinguishable from that induced by authentic bovine IRBP. Thus, it is evident that biological activity of this region of IRBP, as manifested by immuno-pathogenicity, is retained by the fusion protein.

Amino Acid Sequence↗
PubMed1989

Identification of an immunodominant and highly immunopathogenic determinant in the retinal interphotoreceptor retinoid-binding protein (IRBP).

Interphotoreceptor retinoid-binding protein (IRBP), a glycoprotein specific for the retina and pineal gland, induces inflammatory changes in these two organs in immunized animals. We report here on the identification of an immunodominant determinant of bovine IRBP that is highly immunogenic and immunopathogenic in the Lewis rat. The peptide, which comprises the sequence 1169-1191 of bovine IRBP, was shown to be immunodominant by its capacity to stimulate lymphocytes sensitized against whole IRBP. A comparison was made between peptide 1169-1191 and another peptide, 1158-1180, which is nondominant but is immunogenic and immunopathogenic in the Lewis rat. Peptide 1169-1191 was found to be superior in its immunological capacities; the minimal dose of 1169-1191 needed to induce cellular immune response or disease in Lewis rats (0.02-0.1 nmol/rat) is congruent to 1,000 times smaller than that of 1158-1180. In addition, unlike the ocular disease induced by 1158-1180, the disease produced by 1169-1191 resembled that induced by whole IRBP in its kinetics and histopathological features. The immunological activity of 1169-1191 in the Lewis rat was localized to the 10 residues at the COOH terminus; no such activity was exhibited by the truncated peptide 1169-1188, which comprises the 20 residues at the NH2 terminus of the full peptide. The usefulness of this unique experimental system in analyzing the role of immunodominance in peptide immunogenicity and immunopathogenicity is underscored.

Amino Acid Sequence↗
PubMed1989

Rat T-cell lines specific to a nonimmunodominant determinant of a retinal protein (IRBP) produce uveoretinitis and pinealitis.

Rat lymphocyte lines were established, with specificity toward two synthetic peptides derived from the interphotoreceptor retinoid-binding protein (IRBP), which specifically localizes in the retina and pineal gland. One of the peptides, R4, is immunopathogenic, producing experimental autoimmune uveoretinitis (EAU) and pinealitis (EAP) in immunized rats, while the other peptide, R3, exhibits no detectable immunopathogenicity in rats. The cell lines carry surface markers specific for the helper/inducer subset of T-lymphocytes. When tested by the proliferation assay, the line cells demonstrated major histocompatibility-restricted vigorous responses against the immunizing (homologous) peptide, but failed to recognize the intact IRBP molecule. This finding is in line with other data indicating that peptides R3 and R4 are nonimmunodominant determinants of IRBP for the Lewis rat. Yet, the cell lines specific for R4 were highly immunopathogenic, producing EAU and EAP in naive rats at numbers as low as 0.25 x 10(6), with histopathological changes similar to those induced by active immunization with this peptide. The immunological capacity of the cell lines was further demonstrated by the finding that spleen cells from recipient rats of these lines responded well against the homologous peptides. The uniqueness of this system, in which lymphocytes specific toward a nondominant determinant are immunopathogenic, is underscored and the possible mechanisms of disease induction are discussed.

Animals↗
PubMed1989

Immune responses to peptides derived from the retinal protein IRBP: immunopathogenic determinants are not necessarily immunodominant.

Interphotoreceptor retinoid-binding protein (IRBP), a glycoprotein specific to the retina and pineal gland, induces in immunized rats inflammatory changes in these organs (EAU and EAP, respectively). We report here on the immunological activities in Lewis rats of 10 IRBP-derived peptides. Only one of these peptides (R3) was found to induce high levels of antibodies in immunized rats, as detected by ELISA. On the other hand, the majority of the tested peptides stimulated substantial cellular immune responses, measured by the lymphocyte proliferation assay. None of the tested peptides were recognized, however, by antibodies or lymphocytes from rats immunized with the whole IRBP molecule, thus indicating that these synthetic peptides are nonimmunodominant in the Lewis rat. Two of these peptides, R4 and R9 (which contains R4), were previously found to be immunopathogenic, producing EAU and EAP in immunized Lewis rats. The immune responses to peptide R4 were further examined and the data show that it induces measurable lymphocyte responses only when injected at remarkably high doses (greater than or equal to 67 microgram/rat). Yet, peptide R4 was highly antigenic when tested for stimulation of specifically sensitized lymphocytes in culture. Furthermore, lymphocytes sensitized against R4 exhibited high capacity to adoptively transfer EAU and EAP to naive recipients. The finding of immunopathogenic but nonimmunodominant peptides is discussed.

Amino Acid Sequence↗
PubMed1989

Opsin- and S-antigen-like immunoreactions in photoreceptors of the tree shrew retina.

In the tree shrew retina individual rod and cone photoreceptors can be readily identified and quantified because their perikarya are arranged in a single layer. This retina is therefore an ideal system for testing the specificity of photoreceptor-directed antibodies. Here we describe the staining properties of polyclonal antibodies against (rhod)opsin and retinal S-antigen in the tree shrew retina. The (rhod)opsin antibody exclusively and completely labelled the rod population. The antibody against S-antigen also labelled all rods and, in addition, a regularly arrayed subpopulation of cones, which we argue to be the blue-sensitive cones. In the context of our findings, the labelling of pinealocytes with these antibodies is discussed.

Animals↗
PubMed1989

Expression of Ia antigen by ocular tissues of mice treated with interferon gamma.

Intraperitoneal injections of interferon gamma (IFN-gamma) induced or enhanced the expression of Ia antigen by selected murine ocular tissues. In contrast, topical application of this lymphokine had no effect. Ia antigen expression was noted in most cellular components of the conjunctiva, iris, ciliary body, choroid and sclera of treated mice. Intense staining was also found in stromal cells of the cornea, but no Ia reactivity was detected in the corneal epithelium. The lack of staining in the corneal epithelium is in contrast to the strong reactivity in the adjacent conjunctival epithelium, as well as in the skin epithelium. There was no increase in the number of Langerhans cells in the peripheral cornea and limbus, or in their intensity of staining with the anti Ia antibodies. The pattern of Ia expression in ocular tissues of mice treated with IFN-gamma is similar to that of rats with experimental autoimmune uveoretinitis (EAU) except that Ia is expressed more regularly and with higher intensity by the retinal vascular endothelium of rats with EAU than by that of IFN-gamma-treated mice. The findings in the current study thus support the notion that IFN-gamma may be involved in immune-mediated inflammation in the eye.

Animals↗