Search PubMed⌕ Search

Biomedical subjects

I Gery

Publications and source records attributed to I Gery.

At least 91 records · Page 5Linked to original sources
PubMed1989

An 18-mer peptide derived from the retinal S antigen induces uveitis and pinealitis in primates.

S-antigen, a photoreceptor cell protein, induces a predominantly T-cell mediated autoimmune uveitis in many vertebrate animals, including primates. Because of this activity and the finding of immune responses to S antigen in patients with uveitis, this protein has been implicated in the pathogenesis of uveitis in humans. Peptide M, an 18-amino acid component of S antigen, has previously been shown to be highly uveitopathogenic in rats and guinea pigs. We report here that peptide M is immunopathogenic in some monkeys, producing inflammatory changes in eyes and pineal glands similar to those induced by native S antigen. Monkeys with disease also developed intense immune responses to peptide M, measured by the lymphocyte proliferation assay. In addition, lymphocytes from these monkeys reacted against whole S antigen. Furthermore, lymphocytes from certain monkeys immunized with whole S antigen responded well against peptide M, thus indicating that this peptide is an immunodominant epitope in these animals. Two of the four monkeys immunized with peptide M did not develop disease. Lymphocytes from these two animals did not respond in culture against the peptide. Following immunization with the whole protein, these monkeys were capable, however, of developing cellular immunity against S antigen and one of them developed disease. The possible involvement of peptide M in the pathogenesis of uveitis in humans is discussed.

Animals↗
PubMed1989

Cryopexy enhances experimental autoimmune uveoretinitis (EAU) in rats.

Treatment of rat eyes with cryopexy enhanced the development of experimental autoimmune uveitis (EAU) in these eyes. The enhancement of EAU by cryopexy was particularly pronounced when the disease was induced by active immunization in rats of a low responder strain (Wistar Furth), or by adoptive transfer with lymphocytes sensitized against S-antigen. The disease enhancement was expressed by earlier onset of clinical symptoms and by more severe inflammatory changes. Histological examination of cryopexy-treated eyes showed focal necrosis and inflammation, confined to the affected sites. Immunohistochemical analysis of the inflammatory infiltration revealed it consists mainly of macrophages and T-lymphocytes of the helper and suppressor subsets. In addition, increased expression of class II antigens was observed in affected areas, on both inflammatory and resident ocular cells. Using electron microscopy and Evans blue angiography we could show breakdown of the blood-retinal barrier at the treated sites. Histological examination of eyes with EAU following cryopexy showed localization of the early inflammation at the injured site. The data are interpreted to suggest that the enhanced EAU in cryopexy-treated eyes is mainly due to the breakdown of the blood-retinal barrier, the accumulation of lymphoid cells and the increased expression of class II antigens, which facilitates antigen presentation.

Animals↗
PubMed1988

Effects of continuous light exposure on the rat retina and pineal gland.

We examined the effects of intense continuous light (400 ftc for 10 days) on the morphology and immunoreactivity of the rat retina and pineal gland. The light treatment caused severe degeneration in the retina, with loss of most photoreceptor cells, and produced a marked decrease in S-antigen immunoreactivity in this organ. Unlike the retina, the light treatment had minimal effects on the histological structure of the pineal gland. However, pineal glands of light-treated rats exhibited a substantial reduction in their S-antigen immunoactivity, as demonstrated immunohistochemically and quantitatively verified by the rocket immunoelectrophoresis technique: pineal glands of light exposed rats had approximately two-thirds of the S-antigen immunoactivity of the untreated controls. Light treatment was also found to reduce both uveoretinitis and pinealitis in rats immunized with S-antigen. Yet pinealitis was not affected by light exposure in rats, as they were enucleated before treatment. This study thus provides new information to support the notion that the mammalian pineal gland is directly associated with light detection by the retina.

Animals↗
PubMed1988

Differential effects of cyclosporins A and G on functional activation of a T-helper-lymphocyte line mediating experimental autoimmune uveoretinitis.

The effect and relative efficiency of cyclosporin A (CsA) and cyclosporin G (CsG) on suppressing the activation of primed autoimmune rat T-helper lymphocytes were assayed. The autoimmune T-helper cells (ThS) are a long-term line specific to the retinal soluble antigen (SAg) and can adoptively transfer experimental autoimmune uveoretinitis (EAU), after in vitro reactivation with antigen or mitogen, to naive syngeneic hosts. Antigen-driven production of interleukin-2 (IL-2) and antigen-driven proliferation were inhibited in a dose-dependent manner and to a similar extent at each of the respective cyclosporin concentrations. CsA was 8-10 times more potent than CsG, with ID50-CsA occurring at 0.5 to 2 ng/ml, and ID50-CsG at 5 to 20 ng/ml, depending on the experiment and the cyclosporin batch. Addition of exogenous lymphokines in the form of rat spleen concanavalin A (Con A)-conditioned medium (SCM) or recombinant IL-2 (but not recombinant IL-1) was able to reverse only about half of the inhibition, as measured along the linear part of the dose-response curve. Inhibition of IL-2 production was lost if a maximally inhibitory dose of cyclosporin was added to the cultures later than 8 hr after antigen stimulation, while proliferation was still suppressed to 50% by cyclosporin added as late as 12 hr and could not be restored by addition of SCM. Both cyclosporins at concentrations that blocked proliferation and IL-2 production significantly suppressed the generation of high-affinity and low-affinity IL-2 receptors by ThS in response to antigen (as assayed by direct binding of 125I-IL-2). These results suggest that CsA and CsG inhibit antigen-induced expansion of ThS by interfering with more than one activation step. In contrast, the in vitro activation of the uveitogenic potential of ThS cells, incubated with antigen in the presence of CsA or CsG and adoptively transferred into untreated recipients, was not affected by the cyclosporins. Thus, triggering of the pathogenic potential of primed autoimmune T-helper lymphocytes can take place in the presence of cyclosporin and in the absence of cellular proliferation.

Animals↗
PubMed1988

Cyclosporine-induced specific unresponsiveness to retinal soluble antigen in experimental autoimmune uveoretinitis.

Cyclosporine (CsA) was previously reported to effectively suppress the induction of experimental autoimmune uveoretinitis (EAU) in rats immunized with S-antigen. The present study provides information concerning the development of specific unresponsiveness in the CsA-treated rats. The majority of Lewis rats immunized with S-antigen and treated with CsA from Day 0 to Day 14 failed to develop EAU when reimmunized with S-antigen on Day 30. In contrast, similarly treated rats were fully susceptible to induction of experimental allergic encephalomyelitis when immunized with myelin basic protein, or even to EAU when immunized with another retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). The possible involvement of suppressor cells in establishing the unresponsiveness state was indicated by experiments both in vitro and in vivo. The enriched fractions of suppressor cells from rats unresponsive to induction of EAU by S-antigen were found to inhibit the specific mitotic response of lymphocytes to S-antigen, but had no effect on the response to IRBP. In vivo, injection of such enriched suppressor cell fractions to naive syngenic rats inhibited or delayed the development of EAU following immunization with S-antigen. It is proposed, therefore, that specific unresponsiveness plays a role in the suppression of EAU by CsA and that the unresponsiveness is mediated in part by specific suppressor cells.

Animals↗
PubMed1988

Cyanogen bromide fragments of bovine interphotoreceptor retinoid-binding protein induce experimental autoimmune uveoretinitis in Lewis rats.

Interphotoreceptor retinoid-binding protein (IRBP), a retinal specific antigen, induces experimental autoimmune uveoretinitis (EAU) when injected into Lewis rats. Here we report that certain cyanogen bromide fragments of IRBP are capable of inducing EAU. Bovine IRBP, reduced and S-carboxymethylated, was subjected to cyanogen bromide cleavage. This CNBr digest was subjected to reversed-phase high performance liquid chromatography. Three fragments were purified to apparent homogeneity. These three fragments were subjected to gas-phase amino-terminal sequencing analysis. All three yielded single sequences, confirming their purity. On the basis of this amino-terminal sequencing and sequencing of cDNAs encoding bovine IRBP, two of these sequences, named CB-58 and CB-71, were localized to the C-terminal one-third of the IRBP molecule, whereas the third, a subfragment thought to result from cleavage at a tryptophan residue and named CB-47, was localized to the N-terminal one third of the protein. CB-71 and CB-47 shared a strong homology, suggesting a putative internal gene duplication event in the evolution of IRBP. All three of these fragments when injected into Lewis rats caused moderately severe EAU with early onset at relatively low doses. The histopathologic changes induced were indistinguishable from those caused by the intact protein. It would seem, therefore, that bovine IRBP contains multiple uveitogenic sites.

Amino Acid Sequence↗
PubMed1988

Lymphocyte responses to retinal-specific antigens in uveitis patients and healthy subjects.

A modified procedure for measuring human lymphocyte responses to retinal antigens was introduced and found to be highly sensitive. The main modifications are the use of round bottom culture wells, high antigen concentrations (up to 100 micrograms/ml) and extended incubation time (up to 9 days). Using this procedure, the majority of patients with uveitis, as well as a large proportion of healthy donors were found to respond positively (S.I. greater than or equal to 2.0) toward S-antigen and interphoto-receptor retinoid-binding protein. The responses to the retinal antigens were further enhanced by enriching the cultured lymphocytes for the helper/inducer subset. The responses to the retinal antigens were inferior to those against tuberculin (PPD), in particular in subjects who had been inoculated with BCG. The "secondary" responses to PPD were always higher in magnitude, were stimulated by markedly lower concentrations of antigen and were detected earlier in culture. The notion that the responses to retinal antigen in healthy donors are "primary" in nature was further supported by the findings that (a) lymphocytes from cord blood samples resembled adult lymphocytes in their response to S-Ag and (b) healthy donor lymphocytes which were prestimulated in vitro with S-Ag reacted to this protein by a specific "secondary" fashion. The possible involvement of lymphocytes with reactivity toward retinal antigens in pathogenic autoimmune processes in the eye is discussed.

Adult↗
PubMed1988

Synthetic peptides derived from IRBP induce EAU and EAP in Lewis rats.

In an earlier study we isolated three cyanogen bromide cleavage fragments of bovine IRBP that exhibited high levels of immunopathogenicity, producing inflammatory changes in the eyes (EAU) and pineal gland (EAP) of Lewis rats. These fragments have been localized within the IRBP sequence. In order to identify these putative immunopathogenic epitopes of IRBP, nine selected peptide sequences were synthesized and tested for the induction of disease in Lewis rats. Seven of the peptides were found inactive in producing disease while two closely related peptides, designated R4 (23-mer) and R9 (27-mer) were found to reproducibly induce EAU and EAP in immunized rats. No good correlation was found between the immunopathogenicity of the nine tested peptides and their amphipathicity: peptides R4 and R9 were not predicted to form strong amphipathic helices, while peptides selected for their high predicted helical amphipathicity were not immunopathogenic. EAU induced by peptides R4 and R9 was less severe and had a longer onset time than the disease induced by whole IRBP. In addition, the inflammatory changes induced by R4 and R9 in the posterior segment of the eye were less acute than those induced by whole IRBP and included granuloma formation and perivasculitis, features which are not generally seen in rats immunized with whole IRBP. Thus, the changes induced by R4 and R9 more closely resemble those which are characteristically found in human eyes affected by certain uveitic diseases than do changes produced by the intact protein.

Amino Acid Sequence↗
PubMed1988

A cell line and clones of lymphocytes from a healthy donor, with specificity to S-antigen.

Retinal-specific antigens can induce autoimmune diseases in eyes of immunized experimental animals and are thought to be involved in certain uveitic conditions in man. We have recently found that peripheral blood lymphocytes from a large proportion of healthy donors react in culture against the retinal S-antigen (S-Ag), when tested by a modified sensitive assay. The investigation of this responsiveness was extended by isolation and characterization of a cell line and clones specific to S-Ag from the blood of a healthy donor. Characterization of the cell line and clones by flow cytometry showed that these lymphocytes carried antigens specific for helper/inducer T cells (CD3 and CD4). The response of the cell line and clones to S-Ag depended completely on added antigen-presenting cells (APC), and was MHC-restricted; no response was observed in cultures with APC carrying incompatible MHC antigens. The cell line and clones reacted to S-Ag considerably more vigorously than the freshly collected blood lymphocytes from the same donor. These data thus provide additional support to the notion that lymphocytes with reactivity toward retinal specific antigens are present in the circulation of normal donors. The possibility that such cells could be involved in pathogenic autoimmune processes in the eye is discussed.

Antigens↗
PubMed1988

S-antigen in a hereditary visual cell disease. Immunocytochemical and immunological studies.

S-antigen is a photoreceptor-specific and potentially autoantigenic protein. Using light microscopic immunocytochemistry, the localization of S-antigen was studied in the retinas of normal dogs and Irish setters affected with rod-cone dysplasia, a hereditary retinal degeneration characterized by abnormal cGMP metabolism and arrested outer segment differentiation. Normal and affected dogs were also tested for the presence of humoral and cellular immunity to S-antigen. S-antigen was present in both rods and cones during inner and outer segment differentiation, but there was an apparent loss of immunoreactivity in cones as the retina matured. The developmental appearance and localization of S-antigen in affected retinas was similar to that of normals. S-antigen immunoreactivity decreased during the early stages of rod loss (39-57 days), but was still present in photoreceptor somata in the late stages of retinal degeneration. No significant difference was found between normal and affected setters in humoral immunity to S-antigen, indicating that it probably does not stimulate autoimmunity in red 1. Because normal dog lymphocytes failed to respond when sensitized to bovine S-antigen, cellular immunity to S-antigen in this disease cannot be ruled out.

Animals↗
PubMed1987

Immunocytochemical evidence of molecular photoreceptor markers in cerebellar medulloblastomas.

With the use of antisera against bovine retinal S-antigen and bovine opsin the authors demonstrate that in cerebellar medulloblastomas certain tumor cells display immunocytochemical properties characteristic of retinal photoreceptors and pinealocytes. S-antigen-like and opsin-like immunoreactions occur in nine of 28 medulloblastomas investigated. All tumors displaying S-antigen-like immunoreactive neoplastic cells also contain opsin-like immunoreactive cells; however, the opsin-like immunoreactive cells were less frequent than the S-antigen-like immunoreactive cells throughout all positive cases. The immunoreactive cells displayed several long processes. Generally, both S-antigen and opsin-like immunoreactive cells considerably vary in number among individual tumors. The results indicate that certain neoplastic cells of medulloblastoma are capable of expression of photoreceptor-specific proteins and, thus, may be closely related to tumor cells of retinoblastoma and pineocytomas previously shown to bind antisera against retinal S-antigen and opsin. No S-antigen and opsin-like immunoreaction was found in malignant teratomas and germinomas of the pineal gland, oat cell tumors, astrocytomas, ependymomas, oligodendrogliomas, glioblastomas, gangliogliomas, gangliocytoma, ganglioneuroblastomas, neuroblastomas, and esthesioneuroblastoma.

Cerebellar Neoplasms↗
PubMed1987

Dissociation between lymphocyte activation for proliferation and for the capacity to adoptively transfer uveoretinitis.

We have shown previously that immunization with bovine interphotoreceptor retinoid-binding protein (IRBP) induces in rats severe eye disease, experimental autoimmune uveoretinitis (EAU). This study examined the uveitogenic capacity of IRBP of another species, the monkey, and tested the cross-antigenicity between these two proteins by a battery of immunological assays. Monkey IRBP was found to be approximately 20 times less uveitogenic in Lewis rats than bovine IRBP. High levels of cross-reactivity between bovine and monkey IRBP were demonstrated by antibodies as measured by the enzyme-linked immunosorbent assay, and by the radiometric ear test of delayed-type hypersensitivity, by using rats immunized with either one of the IRBP. On the other hand, lymphocytes from these rats failed to detect the cross-reactivity between the two IRBP by the proliferation response in culture. Yet, such lymphocytes did recognize the nonimmunizing IRBP when activated in culture for acquiring the capacity to adoptively transfer EAU into naive recipients. The data are discussed with regard to the limited usefulness of the lymphocyte proliferation assay for detection of immunopathogenic processes and the role of cross-reacting antigens in initiation of autoimmune responses.

Animals↗
PubMed1987

Retinal vascular endothelium expresses fibronectin and class II histocompatibility complex antigens in experimental autoimmune uveitis.

To analyze the role of the retinal vascular endothelial cells in the development of experimental autoimmune uveitis (EAU), we studied the presence of Ia antigen and FN in retinal vessels of Lewis rats immunized with retinal S antigen. Immunopathologic studies were performed on frozen tissues obtained during various stages of the disease. Our results show that Ia antigen was not present in the normal rat retina, and there was very little FN present in a few retinal vessels. One to two days prior to the histologic and clinical onset of EAU, FN was found to be increased in the retinal vessels. Ia antigen was found to be present in the retinal vessels coincident with the first signs of cellular infiltration. During the stage of maximal cellular infiltration, FN was present diffusely throughout the retina, as well as in the subretinal space, and Ia antigen was found diffusely in the cellular infiltrate. Therefore, FN and Ia antigen reflect the immunomodulation of vascular endothelial cells in EAU, which may be very important in the pathogenesis of retinal S antigen-induced uveitis. Two possible mechanisms for the role of the activation of the retinal vascular endothelium in the development of retinal inflammation in uveitis are discussed.

Animals↗
PubMed1987

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.

Animals↗
PubMed1987

Experimental autoimmune uveoretinitis (EAU) induced by retinal interphotoreceptor retinoid-binding protein (IRBP): differences between EAU induced by IRBP and by S-antigen.

Rats immunized with the retinal interphotoreceptor retinoid-binding protein (IRBP) develop an inflammatory eye disease, "experimental autoimmune uveoretinitis" (EAU). The ocular changes which characterize the EAU induced by IRBP resemble those seen in rats which develop EAU by immunization with another retinal protein, S-antigen (S-Ag). Yet, the two antigens do not cross-react antigenically and the two diseases differ by several features: At low doses (less than or equal to 4 micrograms/rat), IRBP was more uveitogenic in Lewis rats than was S-Ag, inducing disease more reproducibly and with earlier onset time. On the other hand, at higher doses (greater than or equal to 20 micrograms/rat) the disease induced by S-Ag was more severe than that induced by the same doses of IRBP. Rats of various inbred strains differed in their susceptibility to EAU induced by these two antigens. In particular, BN rats were more susceptible to IRBP-induced EAU than to the S-Ag-induced disease, while WF and RCS-rdy+ rats developed severe EAU when immunized with S-Ag but showed minimal or no ocular change when immunized with IRBP.

Animals↗
PubMed1987

Uveitis induced in primates by IRBP: humoral and cellular immune responses.

In a previous publication, we have reported that immunization with bovine interphotoreceptor retinoid-binding protein (IRBP) produces severe uveitis in monkeys. The present study further examined the uveitogenicity of IRBP and analysed the immune responses in the immunized monkeys. Uveitis developed in monkeys immunized with bovine IRBP at doses as low as 10 micrograms Kg-1 body wt. In contrast, no disease was detected in monkeys immunized with monkey IRBP at the total dose of 100 micrograms Kg-1. Serum antibodies were measured in the immunized monkeys by the enzyme-linked immunosorbent assay, while cellular immunity was determined by skin hypersensitivity and the lymphocyte mitotic reaction in culture. No humoral or cellular immune responses were detected in monkeys immunized with monkey IRBP. Monkeys immunized with bovine IRBP produced antibodies which cross-reacted well with monkey IRBP. On the other hand, these monkeys did not react with monkey IRBP by skin hypersensitivity and their lymphocytes responded in culture to this protein only when tested by a highly sensitive procedure. In contrast, significant responses of the same cells to bovine IRBP were obtained at all tested conditions. These data are interpreted to suggest that the pathogenic cellular immune responses in vivo detect cross-reactivity with this autologous ocular antigen more efficiently than most conventional laboratory tests.

Animals↗