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Antibodies: barriers to islet cell transplantation

Lorenzo Piemonti¹, Matthew J. Everly³, Paola Maffi¹, Rita Nano¹, Raffaella Melzi¹, Alessia Mercalli¹, Valeria Sordi¹, Francesca Poli², Massimo Cardillo², Mario Scalamogna², Vito Lampasona¹, Antonio Secchi¹, Paul I. Terasaki³

¹San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute; ²Organ and Tissue Transplantation Immunology, Fondazione Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, IRCCS, Milan, Italy; ³Terasaki Foundation Laboratory, Los Angeles, CA, United States

Background: HLA antibodies have been shown to have a deleterious effect on most organ transplants. Based on this it is also possible that donor specific HLA antibodies (DSA) are a major cause of function loss in islet cell transplant (ICT) recipients. In addition anti-GAD (GADA), anti ZnT8 (ZnT8A) and anti-IA2 (IA2A) autoantibodies (AutoAb) may also lead to poor outcomes in islet recipients. Herein we describe the association between antibodies (allo- and auto-) and outcomes in ICT patients.

Methods: ICT patients (n=44, 37 Islet Transplant Alone and 7 Islet after Kidney Transplant) between 2001 and 2010 were studied. Sera (n=385) were serially collected from the date of transplant and tested for DSA (via single antigen beads), GADA, ZNT8A and IA2A.

Results: The median survival of transplant from first islet cell infusion (Tx) was 441±216 days. Insulin independence, partial function and early graft loss were achieved in 48% (21/44), 32% (14/44) and 20% (9/44) of recipients, respectively. Regarding DSA, 27% (12/44) of the patients became positive post-transplant (isotype: 4/12 IgG, 3/12 IgM, 5/12 IgG and IgM). Regarding AutoAb, 36% (16/44) showed a significant rise post-transplant (8/16 GADA; 5/16 ZnT8A; 2/16 GADA and IA2A; 1/16 GADA, IA2A and ZnT8A). The median time of Ab appearance was 14±3, 16±1, 28±2, 90±73 and 189±59 days post Tx for GADA,IA2-A, DSA IgM, ZnTA and DSA IgG, respectively. The probability to develop DSA was associated with the number of donor and mismatches while the probability to develop AutoAb was associated with the absence of rapamycin treatment. Of major importance it was found that development of DSA and/or AutoAb was significantly associated with loss of islet function (p <0.005).

Conclusion: The development of DSA and AutoAb after Tx is highly associated with failure. This data suggests that monitoring these antibodies in ICT patients is important and that treatment to remove these antibodies may benefit outcomes.