title: A prostaglandin-dependent immunoregulatory mechanism activated by in vivo administration of antithymocyte globulin.
abstract: The mechanism responsible for the profound and enduring immunosuppressive action of antithymocyte globulin (ATG) is not well understood. In a primate model, we found that a 5-day rabbit ATG (RATG treatment course activates a prostaglandin (PG)-dependent suppressor cell mechanism that persists for several months. Groups of normal rhesus monkey skin allograft recipients, kidney allograft recipients, or nontransplant control animals received either RATG or no immunosuppression. The peripheral blood mononuclear cell (PBMC) population was longitudinally monitored for (1) percentage of total T cells, helper cells, and suppressor/cytotoxic T cell subsets with the monoclonal antibodies Leu-5, OKT4, and CKT8, respectively, and (2) phytohemagglutinin (PHA)-induced lymphocyte proliferative responses (LPR). The nonimmunosuppressed control groups showed no significant changes in any of these parameters. In contrast, PBMCs from all RATG-treated monkeys developed a persistent imbalance in the ratio of OKT4+ and OKT8+ subsets. Their PBMCs became unresponsive to PHA and remained unresponsive (less than 20% of control level) for at least 3 months, although total T cell counts recovered within 2 to 3 weeks after cessation of RATG. Addition of PG synthetase inhibitors indomethacin. RO-20-5720, and tolmetin caused a significant, dose-dependent recovery of LPR that was completely inhibited by exogenous PGE2 at 1 X 10(-8) M. PBMCs from RATG-treated monkeys caused a dose-dependent suppression of the normal PHA response, and this suppressor cell activity was blocked by indomethacin. PHA responses of nonimmunosuppressed control groups were not increased significantly in the presence of PG synthetase inhibitors, were less sensitive to suppression by PGE2, and did not exhibit suppressor cell activity. These data suggest that the prolonged depression in LPR after RATG treatment is due to an active PG-dependent suppressor cell mechanism and provide a new concept to explain the immunosuppressive action of RATG.
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007108:Immune Tolerance / Q000187:drug effects*; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D011453:Prostaglandins / Q000494:pharmacology*; D011817:Rabbits; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000032:analysis / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000032:analysis; D013997:Time Factors; D014182:Transplantation, Autologous
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D011453:Prostaglandins