AUTOIMMUNE DESTRUCTION OF ISLET GRAFTS IN THE NOD MOUSE IS RESISTANT TO 15-DEOXYSPERGUALIN BUT SENSITIVE TO ANTI-CD4 ANTIBODY

Islet allografts transplanted into Type I diabetic recipients may be d estroyed by allorejection or recurrent autoimmune diabetes. We studied islet transplantation in three murine models in order to determine th e relative sensitivity of autoimmunity and alloimmunity to two immunos uppressive agents that may be useful in clinical islet transplantation : 15-deoxyspergualin (DSG) and anti-CD4 antibody (GK 1.5), In the mode l in which only allorejection occurs (BALB/c islets transplanted into streptozotocin-induced diabetic CBA or streptozotocin-induced diabetic NOD recipients), both DSG and anti-CD4 antibody treatment led to inde finite survival of allogeneic islets (>100 days in both treatments). I n the second model in which only recurrent autoimmunity can destroy is let grafts (islets from NOD donors transplanted into spontaneously dia betic NOD recipients), only anti-CD4 treatment caused prolonged graft survival [MST 36.7 +/- 6.8 days vs 9.8 +/- 1.8 days (controls), P < 0. 0002]. Treatment with DSG did not cause any increase in graft survival (MST 12.6 +/- 5.4 days, NS). Finally, using a model in which both aut oimmunity and allorejection may occur (BALB/c to spontaneously diabeti c NOD mice), treatment with anti-CD4 caused marked graft prolongation [42.0 +/- 14.5 days vs 7.2 +/- 0.8 days (control), P < 0.002] while DS G; again did not prolong graft survival with respect to untreated reci pients (9.8 +/- 3.0, NS). We conclude that recurrent autoimmunity in t he NOD mouse involves a CD4(+) T cell that is not sensitive to DSG. An ti-CD4 antibody may be useful in human clinical islet transplantation trials because it seems to prevent both allorejection and recurrent au toimmunity. (C) 1996 Academic Press, Inc.