The immune system may play a role in the pathogenesis of progressive systemic sclerosis (PSS, scleroderma) through the interactions of activated T lymphocytes with dermal fibroblasts. Soluble products of activated T lymphocytes are known to modulate growth and the synthesis of connective tissue components in normal and PSS dermal fibroblas cultures. We established an in vitro model of these interactions and are engaged in identifying, characterizing, and purifying from crude T-cell supernatants the stimulatory and inhibitory factors that modulate synthesis of connective tissue components by human dermal fibroblasts. Bioassays will be established to monitor lymphokine activities. ELISA methods are being developed to measure fibroblast synthesis of collagen and fibronectin. Short-term and long-term effects of lymphokines on normal dermal fibroblasts in culture are being studied. We will clone normal and PSS dermal fibroblasts and study the synthetic characteristics of these clones to see if PSS skin yields only clones with excessive synthetic activity. The long-term effect of lymphokines on normal dermal explants and clones of fibroblasts will be evaluated in terms of stable changes in the biosynthetic patterns. Mechanisms of diminished ability of PSS lymphocytes for colony growth in agar will be explored. A demonstration that PSS T lymphocytes are reactive to the skin autoantigen will allow studies of specific, scleroderma-related immune responses. The development and expansion of autoreactive or lymphokine-releasing clones of T lymphocytes form the peripheral blood of patients with PSS will provide a confirmation of autosensitization and a source for purification of lymphokines modulating synthetic activities of fibroblasts. The availability of an in vitro model of lymphocyte-fibroblast interactions is scientifically and clinically important. In PSS and other diseases with prominent tissue fibrosis, purified lymphokines may have a therapeutic significance because of their modulatory effects of fibroblasts. Studies of conditions and mechanisms under which lymphokines regulate fibroblast activities may contribute to better understanding of a role of the immune system in the pathogenesis of PSS and of those other diseases that are characterized by fibrosis.
