Autoimmune Diabetes and Resistance to Xenograft Transplantation Tolerance in NOD Mice

Abstract

Costimulation blockade induces prolonged rat islet and skin xenograft survival in C57BL/6 mice. Nonobese diabetic (NOD) mice, which are used to model human autoimmune diabetes, are resistant to costimulation blockade-induced allograft tolerance. We tested the hypothesis that NOD mice would also be resistant to costimulation blockade-induced rat xenograft tolerance. We report that rat islet xenograft survival is short in spontaneously diabetic NOD mice treated with a tolerizing regimen of donor-specific transfusion and anti-CD154 antibody. Rat islet xenograft survival is only marginally longer in chemically diabetic NOD mice treated with costimulation blockade but is prolonged further in NOD Idd congenic mice bearing C57-derived chromosome 3 loci. Reciprocally, the presence of NODderived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4aϪ/Ϫ and (NOD ؋ C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD ؋ C57BL/6)F1 mice treated with costimulation blockade is short, suggesting a strong genetic resistance to skin xenograft tolerance induction. We conclude that the resistance of NOD mice to xenograft tolerance induction involves some mechanisms that also participate in the expression of autoimmunity and other mechanisms that are distinct. Diabetes 54:107-115, 2005

Development of Either Split Tolerance or Robust Tolerance along with Humoral Tolerance to Donor and Third-Party Alloantigens in Nonmyeloablative Mixed Chimeras

“…Moreover, we tried a number of induction protocols to generate chimerism in NOD mice (our unpublished observations), but with the exception of the protocol reported in this study, we were unable to achieve stable mixed chimerism, thus preventing us from assessing split tolerance. This is clearly consistent with the known tolerance resistance of NOD mice (21)(22)(23) and indicates that greater requirements must be met for chimerism induction in the NOD model. However, it does not appear that the level of chimerism by itself explains the rejection of donor islets in NOD but not B6 chimeras, as even a very low-level chimerism (1-3%) was sufficient to prevent rejection of fully mismatched donor islets in B6 mice (Figs.…”

“…Indeed, our NOD recipients could be more resistant to chimerism-induced tolerance of islets due to islet autoimmunity (31) and their known resistance to tolerance induction strategies (21)(22)(23). However, although islet-specific autoimmunity could lead to donor islet rejection by chimeras, as suggested in a previous study (32), the lack of syngeneic islet rejection in our study indicated that autoimmunity could not explain the split tolerance.…”

“…As B6 chimeras maintained donor B cells and other donor MHC class II-expressing cells while lacking alloantibodies, this suggests that NOD chimeras failed to become tolerant to donor class II but not donor class I (donor T cells persisted); studies on the specificity of the alloantibodies produced should help clarify this issue. We therefore propose that the "toleranceresistant" phenotype of the NOD mouse (21)(22)(23) prevented the MR1-based chimerism induction protocol from generating complete tolerance of Ags in donor hematopoietic cells; a sufficient number of anti-donor CD4 T cells likely remained responsive and induced split tolerance. This seems to be a likely possibility, since CD4 T cells appear to play a prominent role in the immune reactivity of NOD mice (33)(34)(35).…”

“…In addition, potential host resistance to tolerance induction, or a general defect in self-tolerance, could lead to a state of split tolerance with or without involvement of donor tissue-specific Ags. We investigated whether this might be the case with NOD mice, whose background possesses the genetically dissociable traits of tolerance resistance (21)(22)(23) and autoimmune-mediated ␤ cell destruction (24). Since chimerism is viewed to be a potential approach toward islet transplantation tolerance in type 1 diabetics, the potential for increased split tolerance in the NOD mouse model of human type 1 diabetes therefore requires full evaluation.…”

The IL-2/CD25 Pathway Determines Susceptibility to T1D in Humans and NOD Mice

“…These observations are consistent with the development of T1D in NOD mice associated with reduced IL-2 levels [18,19], and furthermore, Idd3 alleles are known to affect the development of a number of other autoimmune diseases, including autoimmune ovarian dysgenesis [31], experimental autoimmune encephalomyelitis [32], and Sjögren's syndrome-associated manifestations [33,34]. In addition, experiments utilizing Idd3 congenic mouse strains demonstrated that mice with Idd3 susceptibility alleles have reduced sensitivity to tolerance induction to allogeneic [35] and xenogeneic [36] islet grafts. Similarly, protective alleles at Idd3 and Idd5 facilitated islet-antigen specific tolerance as compared with NOD mice; the proliferation of autoreactive CD8 + T cells was greatly reduced in the pancreatic lymph nodes (PLNs) upon activation by cross-presented islet antigens and migration to the islets appeared to be eliminated [37].…”