Background.

To clarify the controversial results in the literature regarding the role of donor-specific transfusion (DST) on allograft survival, we have examined the influence of the following on DST-induced allograft survival in a 2C transgenic mouse model: varying the time between DST and transplantation; the role of MHC disparities between donor and recipient; whether tolerance induced by DST spreads to skin allografts expressing other alloantigens; and whether cyclosporine (CsA) treatment could further modulate skin allograft tolerance after DST.

Methods and Results.

The studies were performed in both 2C anti-L d (MHC class I) transgenic and normal (nontransgenic) mice. Our data demonstrate that a single infusion of L d-mismatched lymphocytes 7 days before transplantation leads to permanent acceptance of donor-specific skin allografts in both transgenic (58/58) and nontransgenic (8/8) mice in the absence of any other nonspecific immunosuppressive treatment. Pretransplantation DST from donors mismatched for more than one MHC antigen (Ag) has no beneficial effect on subsequent donor skin allograft survival. However, L d plus multiple minor histocompatibility (mH) Ag-mismatched DST induced permanent acceptance of donor-specific skin allografts. Tolerance induced by one-locus L d-mismatched DST spreads to skin allografts expressing either two-locus L d or one-locus L d plus multiple mH Ags. Administration of CsA after DST diminished skin allograft survival, rather than enhancing it, suggesting that tolerance in this model system is established by an active immunological process sensitive to CsA.

Conclusions.

(1) Pretransplantation infusion of L d-mismatched lymphocytes in the presence or absence of multiple mH mismatches induces permanent survival of donor-specific skin allografts.(2) CsA abrogates DST-induced transplantation tolerance.