IMMUNOGENETIC STUDIES OF COLLAGEN ARTHRITIS

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Collagen-induced arthritis (CIA) is a new, autoimmune model of chronic peripheral arthritis. We have observed strain differences in susceptibility to CIA and in immune response to collagen (II) among 11 inbred rat strains representing 6 RT1.A specificities. Our objectives are: 1) to delineate genetically controlled immune functions that regulate collagen-arthritis in rats. We will determine if differences in susceptibility are related to differences in the degree, type, or specificity of the immune response to collagen (II). To determine linkages, the inheritance pattern of genes controlling RT1.A allotypes, phenotypic susceptibility to CIA, and collagen-specific immune responses will be analyzed among the F1, F2, and backcross progeny of matings between susceptible and resistant, congenic strains. Resistant strains will be tested for collagen-specific suppressor cell activity by adult thymectomy and cyclophosphamide pretreatment. 2) To identify (putative) arthritogenic determinants on the collagen (II) molecule. We will compare the immune response of resistant and susceptible strains to collagen (II) fragments. We will also test these polypeptides as inducers of CIA. Antibody titers are determined by ELISA. Cellular immunity will be assessed by in vitro spleen cell proliferation assays. Antigen-specific, T-cell proliferation will be measured using sensitized peritoneal exudate T-cells purified by passage through nylon wool columns. Native type II collagens (rat, calf, chick), their cyanogen-bromide peptides, and collagenase (mammalian) produced helical fragments will be used as antigens and immunogens. 3) To establish a tissue culture model whereby the interaction of synovial cells, collagen, and collagen auto-reactive lymphoid cells can be investigated in vitro. Primary synovial cell cultures will be prepared from arthritic rat knee joint tissues. We will determine the effects of collagen (II), CNBr peptides, and collagen-activated mononuclear cells on proliferation (3H-thymidine uptake), collagenase production, and Inteleukin 2 production. The strains needed are available in our rat colony and include 4 CIA-discordant, congenic stain pairs. This study will provide information relative to the role of anti-collagen autoimmune activity in patients with rheumatoid arthritis.