Granulomatous inflammation is encountered in a variety of important human pathological conditions, including lung disease, and results in enormous suffering and expense. These diseases are often associated with anergy. Despite a large and long research effort, little is known about the underlying mechanisms. We propose that lymphokines are generated by inflammatory cells within granulomatous lesions and secreted into the circulation resulting in cutaneous anergy. These hypotheses are based on previous studies from this laboratory showing that lymphokine activities including MIF, MCF and MFF can be recovered from hypersensitivity lung granulomas, that IV administration of lymphokine-rich supernatants inhibits DTH skin reactions in animals immunized to unrelated antigens and that serum MIF activity and transient anergy are concurrently present during the initial stages of granuloma formation. A model of pulmonary hypersensitivity granulomatous inflammation induced in immunized guinea pigs by IV injection of antigen-linked Sepharose beads will be used to test these hypotheses. Specific objectives include (1) attempts to determine the time course in which cutaneous anergy and serum lymphokine activities (initially MIF) occur in guinea pigs during the development of hypersensitivity granulomas, (2) attempts to passively transfer anergy to immune guineapigs with serum from guinea pigs with hypersensitivity granulomas and with aqueous extracts from pulmonary hypersensitivity granulomas, (3) physiochemical and immuno-chemical characterization of the serum and extract factor(s) responsible for anergy and comparrison of them to known lymphokines, (4) identification of the cell populations which produce the factor(s) involved in the production and maintenance of anergy and (5) initiation of efforts toward the long-term goal of producing antibodies (conventional and monoclonal) to the factors identified as being involved in the development and regulation of anergy and pulmonary hypersensitivity granulomas. These studies will help to illuminate the mechanism of anergy in granulomatous inflammation.
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