Abstract
Depletion of T cell subsets with monoclonal antibody (mAb) permits analysis of cellular events mediating allograft destruction. MAb OX-19 and mAb OX-8 were used singly and in combination together with a short pretransplant course of cyclosporine A (CsA) to deplete OX-19+ cells (all T cells) and OX-8+ cells (cytotoxic/ suppressor and NK cells), respectively, in diabetic Lewis (Lew) recipients of a Wistar Furth (WF) pancreatic allograft. Depletion of lymph node T cell subsets was assessed at rejection (blood sugar > 250 mg/dl) by flow cytometry. Untreated Lew recipients (Group 1) rapidly rejected their allograft (11.5 ± 2.5 days). MAb OX-19 administration on the day prior to surgery (Day −1), on the day of surgery (Day 0), and alternate days thereafter until rejection (Group 2) prolonged graft survival (15.0 ± 1.6 days, P < 0.05). MAb OX-19 administration on alternate days beginning 14 days prior to transplantation (Day −14) until rejection (Group 3) further prolonged graft survival (22.6 ± 3.4 days, P < 0.01). At rejection large numbers of OX-19+ cells were present in both groups. Administration of mAb OX-8 alone (Group 4) failed to prolong graft survival despite marked depletion of OX-8+ cells at rejection. Administration of mAb OX-19 from Day −14 together with CsA (15 mg/kg) from Days −14 to −8 inclusive (Group 5) resulted in a marked and sustained depletion of OX-19+ cells at rejection but only a modest prolongation of graft survival (27.6 ± 6.0 days, P = 0.11). CsA alone from Days −14 to −8 failed to prolong graft survival. CsA from Days −14 to −8 together with administration of mAb OX-19 from Day −14 and mAb OX-8 from Day −1 until rejection (Group 6) resulted in virtual elimination of all OX-19+ and OX-8+ cells with resultant prolongation of graft survival (30.7 ± 7.9 days, P < 0.05 vs Group 3). These data indicate that elimination of both OX-19+ and OX-8+ cells with appropriate mAb in combination with a short pretransplant course of CsA most effectively prolonged pancreatic allograft survival. CsA potentiated mAb OX-19 resulting in a sustained depletion of OX-19+ cells. That late rejection occurred in the absence of OX-19+ and OX-8+ cells suggests that other phenotypically distinct cells can mediate allograft destruction. However, localization of OX-19+ and OX-8+ cells within the graft cannot be excluded.
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