INDUCTION OF SPECIFIC UNRESPONSIVENESS TO RAT ISLET ALLOGRAFTS BY INTRATHYMIC UVB DONOR SPLEEN-CELLS

Recently, we showed that intrathymic (i.t.) injection of UVB-irradiate d (600 J/m(2)) spleen cells induces donor-specific unresponsiveness to cardiac allografts in the sublethally irradiated (200 rads, TBI) reci pients in the Lewis-to-ACI rat combination. This study examined if i.t . injection of UVB donor SC could induce specific unresponsiveness to neovascularized (islet) allografts in the same rat combination of Lewi s-to-ACI. Streptozotocin-induced diabetic ACI rats pretreated with sub lethal TBI (200 rads) 7 days prior to intraportal transplantation of f reshly isolated Lewis islets reject their grafts in 10.2+/-2.9 days co mpared with rejection of islets in 8.5+/-2.6 days in unmodified contro ls. Recipient pretreatment with i.t. injection of UVB donor SC combine d with sublethal TBI (200 rads) 7 days prior to islet transplantation induced indefinite graft survival (>200 days) in 3 of 7 animals. Simil ar treatment failed to prevent acute rejection of third-party (WF) isl ets, thus demonstrating donor-specificity. Treatment with sublethal TB I (200 rads) on the day of islet transplantation led to permanent graf t survival in 2 of 5 animals that received i.t. inoculation of UVB don or SC 7 days prior to islet transplantation. Conditioning of the recip ients with a sublethal TBI dose of 300 rads on the day of islet transp lantation, which alone delayed graft rejection for only 19 days, led t o indefinite graft survival (>150 days) in all animals pretreated with i.t. injection of UVB donor SC. Extrathymic inoculation of donor UVB SC via subcutaneous, intraperitoneal, intratesticular, and intravenous routes, respectively in similarly prepared animals failed to prolong islet survival, thus confirming the privileged position of the thymus in the induction of tolerance. Our findings suggest that this new stra tegy of immunomodulation with donor UVB SC is potentially useful for i nduction of donor-specific unresponsiveness.