Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat

Islet transplantation for the treatment of autoimmune diabetes is more diff icult because of the additional barrier presented by the autoimmunity. We t ested the ability of hamster anti-rat CD154 to prevent recurrence of diabet es in renal subcapsular islet isografts In DR-BE (RT1uu) rats with establis hed autoimmune diabetes. Experimental animals with established diabetes rec eived intravenous injections of 15 mg/kg anti-CD154 on a specified schedule starting 2 days before renal subcapsular transplantation of an islet isogr aft, Control animals received either saline or hamster IgG, Plasma glucose levels >250 mg/dl over 3 days were used to indicate the recurrence of diabe tes. Rats that received saline (n = 5) or control antibody (n = 3) had a re currence of diabetes 6-11 days after transplantation. Histological examinat ion of islet isografts from these rats showed complete destruction of the i nsulin-producing portion of the isograft with residual cells positive for g lucagon. Recipient rats that received anti-CD154 at the 15-mg/kg dosage (n = 6) did not have a recurrence of diabetes for 308-461 days after transplan tation. Islet isografts removed from the rats showed low levels of insulin immunoreactivity, high levels of insulin mRNA, and focal infiltration with lymphocytes but no evidence of islet destruction. Mean peak antibody concen tration was 266 mu g/ml and returned to undetectable levels by 67-88 days a fter transplantation. Rats that received anti-CD154 starting at 4-7 days af ter transplantation had a recurrence of diabetes within 11 days of the iso- transplantation. Therefore, anti-CD154 as the sole immunomodulator prevente d the recurrence of diabetes in islet isografts in rats with established au toimmune diabetes. This suggests that CD40/CD154 blockade is effective in p reventing the insulitis or the effector phase of autoimmune diabetes.