Increased collagen deposition is a clinical and histopathological feature of many rheumatoid and inflammatory diseases. Most evidence indicates that the collagen deposition is due to increased fibroblast collagen production secondary to leukokine stimulation. However, evaluation of the leukokine control of fibroblast collagen production has been limited by the lack of defined systems. Chronic graft versus host disease (cGVHD) produced by the bone marrow transplantation of H-2 identical, non-H-2 non-identical mice is a model system of increased collagen deposition. Using this model system we have identified two populations of T lymphocyte clones that control fibroblast collagen production through separate leukokines. One population of T lymphocytes produces a leukokine that stimulates fibroblast proliferation whereas the other population of T lymphocytes produces a leukokine that stimulates fibroblast collagen synthesis on a per cell basis. The clones that stimulate per cell collagen synthesis have specificity for autologous I-A. Since auto-reactive T lymphocytes are normally present in mice and humans, they may under appropriate circumstances produce leukokines that stimulate collagen production. To determine if naturally occurring autoreactive T lymphocytes produce collagen stimulating leukokines, T lymphocyte clones will be generated from autologous mixed lymphocyte reaction (AMLR) stimulated by non-T lymphocytes, activated T lymphocytes, and I-A positive fibroblasts and will be assayed for the production of collagen stimulating leukokines. Since clinically increased collagen deposition is anatomically localized, the localization may be due to tissue specific differences in the fibroblast responses. The expression of I-A by fibroblasts is found in a variety of disease states. The role of fibroblast I-A in the stimulation of the auto-reactive, I-A specific T lymphocytes will be determined. The mechanism of action of the collagen stimulating leukokines will be determined. In summary, the role of auto-reactive T lymphocytes and their leukokines in the control of fibroblast collagen production will be studied in a model system.
