Recurrent Autoimmunity Accelerates Destruction of Minor and Major Histoincompatible Islet Grafts in Nonobese Diabetic (NOD) Mice

Abstract

Recurrent autoimmunrty destroys nonobese diabetic (NOD) islet isografts, but whether recurrent autoimmunity contributes to islet graft destruction in immunocompetent allogeneic recipients is unknown. In the NOD, a single dose of streptozocin prevents or delays primary autoimmunrty, allowing the detection of alloimmunity alone in chemically diabetic hosts (streptozocin-NOD) to be compared to the combined effects of autoimmunrty and alloimmunity in spontaneously diabetic NODs (autoimmune-NOD). Islets were isolated from prediabetic NOD (H-2KdDb), nonobese resistant (NOR) (H-2KdDb), Balb/cByJ (H-2d) and B10.BR (H-2k) donors and transplanted to either the renal subcapsule or the intraportal site in autoimmune-NODs or streptozocin-NODs. MHC-matched NOR islets had indefinite graft survival in streptozocin-NODs. However, NOR islets showed graft loss at 12.6 ± 3.2 days in renal subcapsule and at 6.8 ± 0.1 days in intraportal site of autoimmune-NODs. Partially MHC-matched Balb/cByJ islet grafts failed significantly sooner in autoimmune-NODs than in streptozocin-NODs (p <0.005). Fully MHC-mismatched B10.BR islet grafts also failed sooner in autoimmune-NODs, but the difference did not reach significance (p <0.06). Although the streptozocin-NOD was functionally tolerant of MHC-matched NOR islets, NOR islets transplanted into autoimmune-NODs failed sooner than NOD islets in both renal subcapsule (12.6 ± 3.2 days vs. 26.4 ± 10.5 days, p = 0.009) and intraportal sites (6.8 ± 0.1 days vs. 11.5 ± 1.7 days, p =0.014). In the autoimmune-NODs, the intraportal site consistently showed shorter graft survival than the renal subcapsule site (NOD: p =0.009, NOR: p =0.014, Balb/cByJ: p =0.008, B10.BR: p =0.032). In conclusion, autoimmune processes facilitate the alloimmune response to minor and major histocompatibility antigens and accelerate graft destruction. The same autoimmune processes are more pronounced in the intraportal site.