DEPENDENCE OF ACQUIRED SYSTEMIC TOLERANCE TO RAT ISLET ALLOGRAFTS INDUCED BY INTRATHYMIC SOLUBLE ALLOANTIGENS ON HOST RESPONSIVENESS, MHC DIFFERENCES, AND TRANSIENT IMMUNOSUPPRESSION IN THE HIGH RESPONDER RECIPIENT

Recent studies suggest that the adult immune system can be manipulated by intrathymic (IT) inoculation of donor Ag to accept cardiac and isl et allografts in the low responder rat combination of Lewis-to-WF. We have now extended this study to examine the effect of IT inoculation o f soluble protein Ag obtained from 3M KCl extracts of resting T cells combined with transient ALS immunosuppression on islet allograft survi val in the high responder combination of WF-to-Lewis. We first confirm ed the earlier observation that IT injection of 2 mg soluble Ag on day -7 led to permanent islet graft survival (>200 days) in the Lewis-to- WF rat combination without the use of recipient immunosuppression and found this to be true in the Lewis-to-ACI rat combination, In the high responder combination of WF-to-Lewis, unmodified Lewis rats pretreate d with IT inoculation of 2 mg soluble Ag acutely rejected WF and BN is let allografts, IT inoculation of donor Ag combined with 1 ml ALS tran sient immunosuppression on day -7 led to a modest graft prolongation [ 24.8+/-10.1 days as compared with 15.2+/-3.6 days in ALS only treated controls]. Intrathymic injection of soluble Ag on day -7 combined with 1 mi ALS on days -7 and 0 relative to allografting resulted in 100% p ermanent islet graft survival (>200 days) compared with an MST of 20.6 +/-2.3 days in ALS only-treated controls. Similar treatment led to acu te rejection of 3rd party (BN) grafts, thus demonstrating donor-specif icity. In addition, extrathymic inoculation of donor Ag in similarly i mmunosuppressed animals did not result in islet graft prolongation, on ce again confirming the importance of the thymus in tolerance inductio n. To examine them for donor-specific tolerance, long-term unresponsiv e (>120 days) Lewis recipients of renal subcapsular islets underwent n ephrectomy of the islet bearing kidneys and were challenged with intra portal donor- or third party-type islets after becoming diabetic, All the nonimmunosuppressed recipients of donor-type (WF) islets became pe rmanently normoglycemic (>100 days) while the third-party (BN) grafts were promptly rejected, with an MST of 10.6 days. These findings confi rm that acquired thymic tolerance induced by IT inoculation of soluble protein Ag in the low to moderate responder rat combinations is repro ducible in the high responder combination provided that adequate perit ransplant immunosuppression is used. This study suggests that acquired thymic tolerance in the rat model is dependent on host responsiveness to alloantigens, MHC differences between the donor-recipient pair, an d the use of transient immunosuppression in the high responder recipie nt. This model may have potential clinical application in the developm ent of strategies for specific transplantation tolerance.