PARTIAL T-CELL ACTIVATION AND ANERGY INDUCTION BY POLYCLONAL ANTITHYMOCYTE GLOBULIN

Background Polyclonal antithymocyte globulins have been assumed to dep lete or sequester immunocompetent T cells. We investigated the hypothe sis that anti-human thymocyte globulin (ATGAM)-mediated immunosuppress ion is delivered via nondepletive, immunologically specific actions as a consequence of simultaneous engagement of multiple T cell receptors . Methods. Purified T cells obtained from healthy volunteers or renal transplant recipients receiving their first dose of ATGAM were evaluat ed for proliferative responses and cell-mediated lympholysis. ATG;AM b inding and receptor expression were determined by Bow cytometry. Cytok ines and ATG;ABI levels were measured by enzyme-linked immunosorbent a ssay. Results. ATGAM-treated T cells showed significant dose-dependent inhibition of proliferation in vitro at concentrations comparable to those measured in patients. Effecters raised after ATGAM treatment fai led to develop cytotoxicity. Supernatant interleukin (IL)-2 levels in ATGAM-treated cultures were significantly reduced (P < 0.01 vs, contro l). IL-4 was not significantly altered. In vivo studies confirmed sign ificant ATGAM-mediated inhibition of proliferative responses. Concanav alin A and OKT3-driven proliferation were reduced 30-60% by ATGAM. Flo w cytometry showed that ATGAM recognized multiple cell surface recepto rs and resulted in markedly increased IL-2R and CD28 expression in the absence of proliferation, demonstrating partial T-cell activation. AT GAM synergized with phorbol myristate acetate to produce strong prolif eration, which suggests that it provides a calcium-based signal result ing in anergy. Conclusions. ATGAM recognizes and cross-links multiple cell surface receptors and costimulator molecules on human T cells. Si multaneous engagement by ATGAM in the context of allogeneic or mitogen ic stimulation leads to partial T-cell activation and anergy.