The Role of Autoimmunity in Islet Allograft Destruction Major Histocompatibility Complex Class II Matching Is Necessary for Autoimmune Destruction of Allogeneic Islet Transplants After T-Cell Costimulatory Blockade Leila Makhlouf, 1 Koji Kishimoto, 1 Rex N. Smith, 2 Reza Abdi, 1 Maria Koulmanda, 3 Henry J. Winn, 3 Hugh Auchincloss, Jr., 3 and Mohamed H. Sayegh 1,4 Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent auto- immunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac trans- plants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)- matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recip- ients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with bet- ter MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allo- grafts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4 and CD8 T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation. Diabetes 51: 3202–3210, 2002 I slet transplants for patients with type 1 diabetes potentially face two distinct types of immune de- struction: one generated by the allogeneic response to foreign tissues and the other generated by the recurrence of the tissue-specific autoimmune process that caused the disease in the first place. Indeed, previous reports showed that human islets from genetically identi- cal twins (1) or cadaver donors (2) were subject to recurrent autoimmunity. Several other findings have sug- gested that recurrent autoimmunity might be responsible for destruction of xenogeneic (3) and allogeneic (3– 6) islets. In interesting studies by Woehrle et al. (7) and Markmann et al. (8) in BB rats, precultured major histo- compatibility complex (MHC)-mismatched islets were not subject to recurrent autoimmunity, and the survival was significantly better for MHC-mismatched grafts than for MHC-matched grafts. Furthermore, until recently, human islet transplants have generally been notably unsuccessful compared with other types of transplants in patients with type 1 diabetes (9). In addition, several investigators have found that strategies that induce long-term survival of allogeneic islets in ordinary mice have been less success- ful when used in NOD mice that have developed sponta- neous autoimmune diabetes (5,10,11). In these cases, the assumption has been that the existence of the autoimmune process in NOD mice was responsible for the failure of the tolerance-induction strategies. On the other hand, other evidence has not supported the idea that recurrent autoimmunity plays a role in the destruction of islets transplanted from genetically dispar- ate donors (12). First, although the results of clinical islet transplantation have often been poor, survival rates for whole-organ pancreas transplants are similar to those of kidneys (13), and even islet transplantation has been very successful recently when performed with newer immuno- suppressive protocols (14). Second, it has been shown that xenogeneic islets survive for longer periods than synge- neic islets in diabetic NOD mice when they have been treated with a variety of immunomodulating therapies (15). Finally, Markees et al. (16) recently reported that the resistance of NOD mice to tolerance induction applies to tissues other than islets, suggesting that this resistance may not necessarily reflect recurrent tissue-specific auto- From the 1 Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; the 2 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; the 3 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and the 4 Nephrology Division, Children’s Hospital, Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Mohamed H. Sayegh, MD, Laboratory Immunogenetics and Transplantation, Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115. E-mail: msayegh@rics.bwh.harvard.edu. Received for publication 21 March 2002 and accepted in revised form 8 August 2002. MHC, major histocompatibility complex; MST, mean survival time. 3202 DIABETES, VOL. 51, NOVEMBER 2002