Fetal pancreas allografts for reversal of diabetes in rats. II. Induction of life-term-specific unresponsiveness to pancreas allografts across nonmajor histocompatibility complex barriers.

Specific unresponsiveness to LEW whole fetal pancreases was induced in F344 rats across non-RT1 incompatibilities. Our treatment regimen was a modification of that developed by Brent and Opara and used an i.v. injection of donor liver extracts (equivalent to 250 to 500 mg wet tissues) between days -18 and -24 followed by a single i.p. injection each of procarbazine hydrochloride (one-third of the LD50 dose) and 0.5 ml of antilymphocyte serum (ALS) within a few days of transplantation. Complete and life-term (greater than 1 year) reversal of streptozotocin (SZ)-induced diabetes was observed in 13 of 16 treated recipients, while the reversal of diabetes was only transient in 2 recipients as a result of graft rejection which occurred between days 30 and 50. The remaining one recipient did not respond to the treatment. Allograft viability was confirmed by the visual observations and histological examination of tissues, by the recurrence of diabetes after the graft removal, and by the reversal of diabetes in the secondary recipients in which long-term surviving allografts were retransplanted. Specificity of the induced unresponsiveness was demonstrated by the prolonged survival times of donor-type skin but the normal rejection of third-party skin which was grafted onto the diabetes-reversed F344 recipients carrying viable LEW pancreases. Prolonged but limited survival times of donor-type skin grafts suggested that the induced unresponsiveness is specific to donor alloantigens as well as organ-specific antigens. This immunosuppressed state was transferable into ALS-treated syngeneic F344 rats by nylon-wool-nonadherent spleen cells. Thus, LEW skin grafts survived for 30 days in ALS-treated F344 rats receiving test spleen cells, while those in controls survived for 19 days. LEW pancreases surviving for more than 300 days were fully capable of eliciting rejection reaction when the grafts were retransplanted into a nonimmunosuppressed secondary F344 recipient along with the primary host kidney.