title: Recurrent autoimmunity accelerates destruction of minor and major histoincompatible islet grafts in nonobese diabetic (NOD) mice.
abstract: Recurrent autoimmunity 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 autoimmunity, allowing the detection of alloimmunity alone in chemically diabetic hosts (streptozocin-NOD) to be compared to the combined effects of autoimmunity 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 in definite 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.
authors.affiliation: Division of Transplantation, University of Maryland School of Medicine, Baltimore, USA.
authors.forename: T
authors.initials: T
authors.lastname: Okitsu
authors.forename: S T
authors.initials: ST
authors.lastname: Bartlett
authors.forename: G A
authors.initials: GA
authors.lastname: Hadley
authors.forename: C B
authors.initials: CB
authors.lastname: Drachenberg
authors.forename: A C
authors.initials: AC
authors.lastname: Farney
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology / Q000502:physiology
chemical_list: D015778:Minor Histocompatibility Antigens