NATURE OF THE SUPPRESSOR CELLS MEDIATING PROLONGED GRAFT SURVIVAL AFTER ADMINISTRATION OF EXTRACTED HISTOCOMPATIBILITY ANTIGEN AND CYCLOSPORINE

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Abstract
Antigen-specific suppressor T cells are induced by donor histocompatibility antigen extracted from spleen cells with 3M KCl combined with cyclosporine (Ag-CsA). A single i.v. injection of 5 mg 3 M-KCl-extracted donor Buffalo (Buf, RT1b) antigen (Ag) combined with a three day course of CsA prolonged renal allograft survival in Wistar-Furth (WFu, RT1u) hosts to a greater extent (MST 26.5 days) than CsA alone (MST 11.8 days). Peripheral blood lymphocytes (PBL) or spleen cells harvested from Ag-CsA-treated recipients 10 days after transplantation inhibited the mixed lymphocyte reaction (MLR) between normal responder WFu cells and irradiated Buf cells (55.6% and 64.4% suppression, respectively, P < 0.025), but not 3rd-party Brown-Norway (BN, RT1n) stimulator cells (13.6% and -18.3% suppression, respectively, NS). The suppressor effect was not mediated by cytolytic cells; there was neither primary nor secondary cytolytic activity against 51Cr-labeled Con-A blastoid Buf cells. The suppressor cells were neither adherent to plastic dishes nor to nylon-wool columns. PBL irradiated with 800 rads, but not 1500 rads, suppressed the MLR. A single injection of cyclophosphamide (CY, 25 mg/kg) seven days after transplantation abrogated the suppression induced by Ag-CsA treatment. PBL from Ag-CsA recipients failed to suppress the MLR, if depleted either of all T cells by treatment with monoclonal antibody (Mab) W3/13 HLK (pan T cells; % suppression -15.8), or of cytotoxic/suppressor cells with Mab OX-8 (-19.3% suppression) together with rabbit antimouse Ig and complement. PBL treated with the Mab W3/25 (helper) showed suppressor cell activity (+56.4%, P < 0.001) similar to untreated cells (62.4%, P < 0.001). Adoptive transfer of suppressor T cells purified from pooled lymphocytes by rosetting using Mab significant prolonged the survival of donor-specific, but not 3rd-party, test grafts in naive secondary hosts. These studies demonstrated antigen-specific suppressor T cells mediate the longterm unresponsiveness induced by the Ag-CsA regimen.