New strategies applied in the treatment of experimental autoimmune disease models involve blocking or modulation of MHC-peptide-TCR interactions either at the level of peptide-MHC interaction or, alternatively, at the level of T cell recognition. In order to identify useful competitor peptides one must be able to assess peptide-MHC interactions. Several well described autoimmune disease models exist in the Lewis rat and thus this particular rat strain provides a good model system to study the effect of competitor peptides. So far no information has been available on the peptide binding characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides by chemiluminescence. The assay is sensitive and specific. We have used this assay to determine the binding characteristics of several disease associated T cell determinants and their sequence analogues in the Lewis rat. Notably, most of the autoimmune disease associated peptide sequences tested were found to be intermediate to poor binders. Single amino acid substitutions at defined positions were sufficient to turn certain peptides into good binders. These results are relevant to the design of competitor peptides in the treatment of experimental autoimmune diseases.
Objective. To examine whether T cell reactivity toward heat-shock proteins (HSP) contributes to cartilage destruction in rheumatoid arthritis (RA).Methods. An in vitro system was used, in which human cartilage explants were cocultured with hsp60-activated synovial fluid mononuclear cells (SFMC) from patients with RA, and proteoglycan (PG) synthesis was measured.Results. The hsp60-activated SFMC suppressed cartilage PG synthesis. This effect was dependent on the production of interleukin-1 (IL-1) and tumor necrosis factor a (TNFa).Conclusion. Mycobacterial60-kd heat-shock protein can activate rheumatoid SFMC to suppress human From the
We studied the early events in athymic immunoincompetent rats after implantation with cultured thymic fragments (CTF) under the kidney capsule, with special emphasis on the settlement of lymphocytes and non-lymphoid RT1 class II elements. At 2 weeks after grafting, tissue under the kidney capsule comprises strands of keratin-positive epithelial cells from the graft, without immigrant cells. At 3 weeks, the CTF graft is populated with lymphocytes and with non-lymphoid RT1 class II-positive cells expressing the recipient haplotype (allogeneic combinations). Part of these cells bear determinants recognized by an anti-rat dendritic cell antibody. At 4 weeks the graft exhibits a completely restored thymic architecture. At the periphery, the first indications of T-cell competence generated after CTF implantation are observed 6 weeks after implantation. At 18 weeks, the peripheral thymus-dependent immune system is almost completely developed. This includes in vitro alloreactivity, even to the donor RT1 haplotype of the graft. But skin grafts of the allogeneic CTF donor haplotype are not rejected. Thus, a state of in vivo tolerance is induced under the influence of grafted epithelium, which is not due to a specific deletion of alloreactive cells. We conclude that CTF regain their original thymic architecture between 2 and 4 weeks after implantation in (allogeneic) athymic nude recipients, and that only after this restoration does peripheral thymus-dependent immune competence start to develop.
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