The role of humoral immunity in graft rejection in the rat model remains controversial. Passive transfer of cytotoxic alloantibody (CAA) has resulted either in hyperacute rejection or in graft enhancement. This study examines the effect of transfer of CAA on cardiac allograft survival in three rat strain combinations that are fully mismatched at the major histocompatibility (MHC) loci. Strain-specific immune responsiveness in donorrecipient pairs varied from low (Lewis-to-ACI) to high (ACI-to-Lewis) as measured by mixed lymphocyte reactions. CAA was obtained from rats sensitized by three successive skin grafts at weekly intervals. Group 1 (high responder recipients), which consisted of Lewis rats presensitized to ACI and had a lymphocytotoxicity titer of 1:512 to 1:2048, rejected ACI cardiac allografts in 10.8±7.2 hr compared with 6.5±0.5 days in naive controls (P<0.001). Injection of 1 ml of high-titer CAA into naive Lewis rats immediately after ACI cardiac grafting led to hyperacute rejection of ACI hearts in 2.1±0.8 hr while 1 ml of CAA followed by 2 ml of guinea pig complement (GPC) resulted in even faster rejection (mean survival time (MST) of 23.8±4.7 min). Injection of 2 ml GPC alone or in combination with 1 ml naive Lewis serum had no effect on graft survival. Multiple pretransplant injections of 1 ml of CAA on days —3, —2, —1, and 0 relative to transplantation resulted in significant prolongation of allograft survival (MST of 10.3± 0.3 days; P<0.01). In group 2 (intermediate responder recipients), where Lewis rats were presensitized to WF strain and where cytotoxicity titer was 1:16 to 1:256, the recipients rejected WF hearts in 23.8±5.8 hr compared with 6.8±0.8 days in unsensitized control recipients (PcO.OOl). Injection of 1 ml of Lewis anti-WF CAA resulted in prolonged graft survival of 9.7±3.5 days, while injection of 1 ml of CAA followed by 2 ml of GPC caused hyperacute rejection in 104±61.7 min. Pretransplant injections of CAA on days —3, —2, —1, and 0 resulted in enhancement, with an MST of 16.3±1.3 days (P<0.01). In group 3 (low responder recipients), ACI presensitized to Lewis developed a cytotoxicity titer of 1:2 to 1:32 and rejected Lewis hearts in 5.3±0.4 days compared with 10.6±1.0 days in naive recipients. Injection of 1 ml of ACI-anti-Lewis CAA prolonged Lewis hearts to 19.8±1.8 days (P<0.001), while the addition of 2 ml GPC did not cause accelerated rejection but resulted in continued prolongation of graft survival (MST of 18.2±2.8 days). This study demonstrates that hyperacute rejection and enhancement of allografts are phenomena the balance of which can be influenced by the MHC differences between the rat strains, strainspecific responsiveness, rat complement system, and the potency of the transferred CAA as measured by antidonor lymphocytotoxicity titer.
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