LONG TERM (10 MONTH) PIG ISLET XENOGRAFT (PIX) TOLERANCE USING MEASURED-TOTAL LYMPHOID IRRADIATION, SPLENECTOMY SHORT TERM RABBIT ANTITHYMOCYTE GLOBULIN AND DEOXYSPERGUALIN WITHOUT CHRONIC IMMUNOSUPPRESSION

Abstract

320 Tolerance of pig islet xenografts without chronic immunosuppression is an attractive protocol for islet transplantation since allograft islets are in short supply and chronic immunosuppression induced morbidity and mortality is not an acceptable trade off for diabetic morbidity, especially in the juvenile age group when islet replacement should be performed ideally. In this study, 30 Lewis Rats (STZ diabetes) were transplanted with 2000 pig islet xenografts (PIX). All 30 animals had measured-total lymphoid irradiation with implanted quantitative radiosensors, splenectomy, a 3-day course of rabbit-antithymocyte globulin and deoxyspergualin (21 days at 2.5 mg/kg). The incidence of early graft loss was 0% and all pig islet xenografts survived 200 days or more. The mean pig islet xenograft survival, as determined by euglycemia and differential radioimmunoassay (All animals had circulating Pig Insulin @ 300 days) was 302 +/-42 days with euglycemia to 14 months in 23 animals.In addition, nephrectomy of the host to remove the functioning islet tissue produced a return of the diabetic state in 9 animals. This long term function and tolerance of pig islet xenograft was associated with minimal changes in T cell reactivity assayed by MLC and CML testing. In contrast, studies of anti donor CDC and ADCC showed a complete antibody block in long term function and tolerance in 10 animals (1:8 and 1:128) A separate Control group who rejected their PIX early had high levels of CDC and ADCC to donor (1:64 and 1:1024, p<0.05). The long term function and tolerance of PIX was associated closely with a block of anti-donor CDC and ADCC antibodies. The superior long term function and tolerance appears due to the unique immunosuppression which permits variations in the measured-total lymphoid irradiation to deliver uniform measured doses of TLI as well as short term effective anti-B cell suppression with splenectomy and rabbit-antithymocyte globulin-deoxyspergualin short-term treatment. Animals remained in a robust state of health presumably because they were off all drug immunosuppression for over 9 months. This suppressive regimen seems superior to all others we have tested because of the length of islet survival and the excellent health of the animal and suggests that Chronic Immunosuppression with Drugs is the major debilitating effect of multiple agent suppressive protocols.