Prolongation of allograft survival by repeated cycles of donor antigen and cyclosporine in rat kidney transplantation.
Combination therapy with a short course of cyclosporine (CsA) on the day prior to, to day of, and the day after transplantation and one dose of 5 mg 3M-KCl-extracted donor-soluble antigen (Ag) prolongs the survival of Buffalo (Buf, RT1b) kidney allografts in Wistar-Furth (WFu, RTu) inbred rats because of the induction of specific suppressor cells. Four systems were utilized to demonstrate suppressor cell activity in vivo. First, pooled lymphocytes from CsA-Ag-treated hosts suppressed the capacity of admixed, syngeneic WFu cells to display an in vivo mixed lymphocyte culture reaction toward donor Buf, but not third-party Brown-Norway (BN, RT1n), hosts. Second, systemic adoptive transfer two days prior to, or on the day of, transplantation of 5 x 10(8) putative suppressor cells harvested ten days after combined Ag-CsA treatment prolonged graft survival slightly but significantly from 7 to 9 days in virgin, secondary hosts. Third, admixture of 5 x 10(8) cells from Ag-CsA-treated hosts vitiated the capacity of 5 x 10(8) virgin WFu spleen cells to restore the capacity of recipients sublethally irradiated with 500 rads to reject. Buf allografts at 7.9 days rather than 16.7 days. Fourth, i.p. administration of low-dose cyclosphophamide (CY) 7 days after transplantation, a regimen known to inhibit suppressor cells, reduced the capacity of the Ag-CsA regimen to prolong graft survival. Two additional cycles of CsA therapy at 10-day intervals administered in an attempt to maintain T suppressor dominance over T helper cells prolonged median graft survival to 65 days. Similar prolongation was not achieved using donor blood transfusion as the immunogen, or using cycles of CsA alone. These findings suggest that 3M KCl donor antigen amplifies the induction of specific suppressor cells, and that CsA by virtue of helper T cell inhibition facilitates the establishment of suppressor cell dominance, eventually leading to host unresponsiveness.
D000818:Animals; D001803:Blood Transfusion; D003524:Cyclosporins / Q000008:administration & dosage*; D006085:Graft Survival / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000008:administration & dosage*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D014019:Tissue Donors
D003524:Cyclosporins; D006649:Histocompatibility Antigens; C038353:histocompatibility antigens RT, rat