Graft rejection in a congenic panel of rats with defined immune response genes for class I antigens. II: Quantitative aspects of Ir gene function in a full-haplotype mismatch

Previous studies have shown that the Ir-gene-controlled rejection of rl tissues by c/u responder and non-rejection by c low responders does not extend to tissues expressing a full a haplotype mismatch. However, antibody responses and liver graft rejection are both defective in low responders, even across a full haplotype barrier. We have therefore used a titrated adoptive transfer assay to search for quantitative differences in the responsiveness of c and c/u animals to a organ grafts. We first established that a heart graft rejection could be ablated in both recipient strains with whole-body irradiation and could be restored with syngeneic cells. Titration of restorative cells revealed that 5 times as many c cells were required to restore graft rejection in c recipients as c/u cells were required in c/u recipients. Use of cells from primed donors showed that in both c/u and c animals these cells had undergone about a 5-fold increase in potency, showing that there was no failure of proliferation and differentiation in the low responder after contact with antigens. Cross-transfer experiments were done to attempt to localize the defect in low-responder animals either to a failure of low-responder antigen-presenting cells (APC) to trigger a response or a defect in the responsiveness of alloreactive cells toward the a antigens. In these experiments c cells were obtained from radiation chimeras of the c---c/u type. These cells were used to restore graft rejection in c/u irradiated recipients. Similar experiments employing c/u cells obtained from c/u---c chimeras and given to irradiated c recipients were also done. These showed that c cells from chimeras were marginally less potent than c/u cells from chimeras. In contrast when cross-transfer of c/u cells to c animals bearing a nonrejected rl heart was done, no rejection was seen even when antigen presenting cells were cotransferred. The conclusions from this series of experiments were that quantitatively small defects were present in both repertoire and antigen presentation, and that these quantitative defects in aggregate were probably sufficient to explain the documented low responsiveness of c animals to the a haplotype. The failure of high-responder c/u cells to secure rejection of rl tissues in the low-responder c environment suggests that presentation of isolated class I differences in host APCs is mandatory for rejection to occur and is highly defective in the c animal.