It is planned to perform an in-depth analysis of interleukin-2 (IL-2) pathophysiology in human immunodeficiency syndromes (IDS). These studies will focus on the following diagnostic categories as well as on appropriate controls: (1) congenital IDS; (2) IDS of unknown etiology: (a) CVI and (b) AIDS with and without Kaposi's sarcoma; and (3) therapy/cancer-associated IDS: (a) Hodgkin's disease prior to and after therapy, (b) ovarian carcinoma prior to and after high-dose chemotherapy, (c) breast cancer prior to and on adjuvant chemotherapy, and (d) patients prior to and after allogeneic and autologous bone marrow transplantation. The in vitro studies planned will evaluate IL-2 production and response (IL-2 P/R) of total mononuclear cell fractions (PBL) as well as of isolated PBL subsets. We will investigate: (1) the molecular events leading to T-cell activation by analysis of (a) methylation patterns of the IL-2 gene, (b) IL-2m RNA blots, (c) demonstration of IL-2 in individual cells by in situ hybridization, (d) quantitation of IL-2 secreted into the culture medium, (e) IL-2 receptor (Tac) expression by immunofluorescence and in situ hybridization, and (f) expression of other cell surface structures related to T-cell activation and/or proliferation (e.g., HLA-Dr, transferrin receptor); (2) the effect of other cell types on IL-2 P/R, e.g. monocytes, NK cells, suppressor and helper T cells through mixing experiments of PBL subsets; (3) the role of other lymphokines (e.g., interferon alpha, gamma, interleukin-1) and pharmacological agents (e.g., cimetidine, indocine, cyclosporin A) on IL-2 P/R of PBL and PBL subsets; (4) the biological effect of monoclonal reagents recognizing antigens of regulatory significance in IL-2 physiology (e.g., anti IL-2, anti IL-2 receptor, OKT3, antitransferrin receptor, anti Ia, anti HLA) on IL-2 P/R of PBL and PBL subsets. Healthy volunteers will serve as controls, while patients participating in clinical trials of IL-2 will serve to investigate the in vivo significance of the in vitro experiments. It is hoped that the understanding of the molecular events regulating IL-2 and Tac expression and definition of specific defects in IDS will allow their specific modulation in vitro and eventually in vivo. (IS)
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