Treatment of experimental animals with specific antibody or immunocompetent lymphoid cells directed against certain circulating proteins can lead to suppression of production of these proteins. Suppression has also been accomplished in vitro with tissue culture systems. Immunoglobulin allotypes, idiotypes and isotypes as well as other related substances such as complement components have been suppressed by various investigators. Although these systems may not be completely analogous to one another, they all appear to utilize specific antibody, suppressor cells and secondary soluble suppressor factors. The proposed studies will extend the work in this area by examining molecular aspects of the intracellular and extracellular mechanisms involved in suppression. Using cDNA probes for C4 and other complement components, specific mRNA will be quantitated during suppression and after recovery from suppression. If the mRNA is reduced in approximate proportion to the protein levels, experiments will determine if mRNA is reduced because of decreased transcription or decreased stability. If the mRNA levels are the same in suppressed and unsuppressed cells, then experiments will determine if the mRNA has a decreased rate of translation or if the complement component undergoes different intracellular processing. Other experiments will further define the phenotypes of lymphoid cells required for suppression and their soluble suppressor factors will be more precisely characterized. Suppression may play an important role in a) host defenses against viral diseases, b) pathogenesis of some autoimmune disorders and c) some types of immune therapy. Antibodies directed against viral products have been shown to reduce the levels of these products in infected cells. Suppression could therefore be an important mechanism by which the host regulates virus replication. Specific autoantibodies have been identified for many autoimmune disease states. Some of these antibodies may lead to suppression of the antigens against which they are directed and thereby play a role in the pathogenesis of the disease. Finally, antibodies against immunoglobulin idiotypes or other specific antigens have been used in the treatment of B cell lympomas or other tumors, and antibodies to the IL-2 receptor have prolonged transplant survival in animal models. Suppression may be one of the mechanisms by which a therapeutic response was achieved. A better understanding of the molecular mechanisms of suppression in our experimental systems will lead to a better understanding of its possible relevance to host defense, pathogenesis of disease and immunotherapy of some diseases.
| Goldman, M B; Knovich, M A; Goldman, J N (1991) Immunologic control of C3 gene expression in tissue macrophages. J Immunol 147:4248-55 |
