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OBJECTIVE--The ~45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes-associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Iddg.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3. RESEARCH DESIGN AND METHODS--We used a reductionist approach that involves comparing the fate of a type 1 diabetes-relevant autoreactive [CD8.sup.+] T-cell population, specific for residues 206-214 of islet-specific glucose 6 phosphatase catalytic subunit-related protein ([IGRP.sub.206-214]), in noncongenic versus B10 Idd9-congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Iddg.2, and Idd9.3) T-cell receptor (TCR)-transgenic (8.3) NOD mice. RESULTS--Most of the protective effect of Idd9 against 8.3-[CD8.sup.+] T-cell-enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive [CD8.sup.+] T-cells. Studies in T- and B-cell-deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell-independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the [FoxP3.sup.+] [CD4.sup.+] [CD25.sup.+] T-cell subset in both TCR-transgenic and nontransgenic mice. CONCLUSIONS--A gene(s) within Idd9.1 regulates the development and function of [FoxP3.sup.+] [CD4.sup.+] [CD25.sup.+] regulatory T-cells and, in turn, the activation of [CD8.sup.+] effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential., Type 1 diabetes in both humans and nonobese diabetic (NOD) mice is the result of a complex T-cell-mediated autoimmune process against the pancreatic β-cells. Putative poorly defined environmental triggers conspire [...]

OBJECTIVE--NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade-based tolerance protocols have failed in prolonging islet allograft survival in NOD mice. RESEARCH DESIGN AND METHODS--To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes. RESULTS--The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD x CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/[6.H2.sup.g7] x CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival. CONCLUSIONS--II2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process. Diabetes 58: 165-173, 2009, The NOD mouse is a model of type 1-like autoimmune diabetes and is used to study costimulation blockade-based transplantation tolerance within the context of autoimmunity (1-4). However, costimulation blockade protocols [...]

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 NOD-derived chromosome 3 loci shortens islet xenograft survival in tolerized C57BL/6 mice. Islet xenograft survival is longer in tolerized NOD.CD4a / and (NOD x C57BL/6)F1 mice than in NOD mice but still much shorter than in C57BL/6 mice. Skin xenograft survival in (NOD x 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., The NOD mouse is an excellent model of human type 1 diabetes (1,2). It develops insulitis and diabetes that are T-cell dependent, with both the CD[4.sup.+] and CD[8.sup.+] T-cell subsets [...]

NOD mice develop type 1 autoimmune diabetes and exhibit genetically dominant resistance to transplantation tolerance induction. These two phenotypes are genetically separable. Costimulation blockade fails to prolong skin allograft survival in (NOD x C57BL/6)F1 mice and in NOD-related strains made diabetes-resistant by congenic introduction of protective major histocompatibility complex (MHC) or non-MHC Idd region genes. Here, we tested the hypothesis that the genetic basis for the resistance of NOD mice to skin allograft tolerance also applies to islet allografts. Surprisingly, costimulation blockade induced permanent islet allograft survival in (NOD x C57BL/6)F1 mice but not in NOD mice. After costimulation blockade, islet allograft survival was prolonged in diabetes-resistant NOD.B6 Idd3 mice and shortened in diabetes-free C57BL/6 mice congenic for the NOD Idd3 variant. Islet allograft tolerance could hot be induced in diabetes-resistant NOD.B10 Idd5 and NOD.B10 Idd9 mice. The data demonstrate that 1) NOD mice resist islet allograft tolerance induction; 2) unlike skin allografts, resistance to islet allograft tolerance is a genetically recessive trait; 3) an Idd3 region gene(s) is an important determinant of islet allograft tolerance induction; and 4) there may be overlap in the mechanism by which the ldd3 resistance locus improves self-tolerance and the induction of allotolerance., Replacement of insulin-producing islets of Langerhans by transplantation can cure human type 1 diabetes (1), but recipients require lifelong immunosuppression. Researchers have focused on developing alternatives to immunosuppression, using animal [...]

Genes affecting autoimmune type 1 diabetes susceptibility in the nonobese diabetic (NOD) mouse (Idd loci) have been mapped using a congenic strain breeding strategy. In the present study, we used a combination of BAC clone contig construction, polymorphism analysis of DNA from congenic strains, and sequence mining of the human orthologous region to generate an integrated map of the Idd10 region on mouse chromosome 3. We found seven genes and one pseudogene in the 950-kb Idd10 region. Although all seven genes in the interval are Idd10 candidates, we suggest the gene encoding the EWI immunoglobulin subfamily member EWI-101 (Cd101) as the most likely Idd10 candidate because of the previously reported immune-associated properties of the human CD101 molecule. Additional support for the candidacy of Cd101 is the presence of 17 exonic single-neucleotide polymorphisms that differ between the NOD and B6 sequences, 10 causing amino acid substitutions in the predicted CD101 protein. Four of these 10 substitutions are nonconservative, 2 of which could potentially alter N-linked glycosylation. Considering our results together with those previous reports that antibodies recognizing human CD101 modulate human T-cell and dendritic cell function, there is now justification to test whether the alteration of CD101 function affects autoimmune islet destruction., The NOD is increasingly recognized as an accurate and informative model of type 1 diabetes in humans. The diabetes phenotype in the NOD mouse, as found in the human disease, [...]

Susceptibility to diabetes in humans and nonobese diabetic (NOD) mice is believed to arise from the combined effect of multiple genetic loci, resulting in immune-mediated destruction of the insulin-secreting β-cells. Insulin autoantibodies (IAAs) are often present in humans for years, and in NOD mice for weeks, before the onset of diabetes. We have evaluated the expression of IAAs in NOD mice and in diabetes-resistant NOD congenic strains to characterize the association of autoantibody expression with insulitis and diabetes. In NOD congenic strains with genes that contribute to protection from insulitis and diabetes (Idd3, Idd5, Idd10, and Idd18), the prevalence of IAAs is reduced relative to NOD mice. In contrast, NOD.B10 Idd9 mice have a high prevalence of IAA and a high degree of insulitis, despite a nearly complete resistance to diabetes. These data indicate that IAA expression is a phenotype that is associated with insulitis and correlates with overall disease progression in some strains of congenic mice but not in others. It is likely that patients with type 1 diabetes will also show non-major histocompatibility complex genetically determined variation in expression of autoantibodies and progression to diabetes., Over the past two decades, progress has been made in our understanding of the immunopathogenesis and natural history of type 1 diabetes. Type 1 diabetes is considered by many investigators [...]

The loss of self-tolerance leading to autoimmune type 1 diabetes in the NOD mouse model involves at least 19 genetic loci. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CD154 antibody. Hypothesizing that these two abnormalities might be related, we investigated whether they could be uncoupled through a genetic approach. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. These data indicate that single or multiple combinations of evaluated Idd loci that dramatically reduce diabetes frequency do not correct resistance to peripheral transplantation tolerance induced by costimulation blockade. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes., The nonobese diabetic (NOD) mouse is widely used to model human type 1 diabetes (1). Disease in NOD mice is characterized by T-cell dependent autoimmune destruction of β-cells (2). NOD [...]

As many of the linked chromosome regions that predispose to type 1 diabetes in the NOD mouse have been dissected, it has become apparent that the initially observed effect is in fact attributable to several loci. One such cluster of loci on distal chromosome 3, originally described as Idd10, is now known to comprise three separate loci, Idd10, Idd17, and Idd18. Although these loci have a significant combined effect on diabetes development, their individual effects are barely detectable when diabetes is used as a read-out, which makes fine-mapping them by use of a conventional congenic approach impractical. In this study, we demonstrate that it is possible to map loci, with modest effects, to regions small enough for systematic gene identification by capitalizing on the fact that the combined loci provide more profound, measurable protection. We have mapped the Idd10 and Idd18 loci to 1.3- and 2.0-cM intervals, respectively, by holding the Idd3 allele constant. In addition, we have excluded Csf1 and Nras as candidates for both loci. Diabetes 50:2633-2637, 2001, The nonobese diabetic (NOD) mouse is a spontaneous animal model of human type 1 diabetes. As is the case in the human disease, development of diabetes in the NOD mouse [...]

Currently, 16 loci that contribute to the development of IDDM in the NOD mouse have been mapped by linkage analysis. To fine map these loci, we used congenic mapping. Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene. Segregation analysis of the known variations within this interval indicated that only one variant, a serine-to-proline substitution at position 6 of the mature interleukin-2 (IL-2) protein, consistently segregates with IDDM in crosses between NOD and a series of nondiabetic mouse strains. These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium., Linkage analysis and congenic strain mapping have localized 16 loci (Idd1-16) that contribute to the development of IDDM in the NOD mouse (1,2). The presence of two loci, Idd3 and [...]

Chromosome locations of non-major histocompatibility complex (MHC) genes contributing to insulin-dependent diabetes mellitus (IDDM) in mice have been determined by outcrossing NOD mice to other inbred strains congenic for the NOD MHC haplotype ([H2.sup.g7]). At least nine non-MHC IDDM susceptibility genes (Idd) were previously identified at first backcross (BC1) after outcross of NOD to C57BL/10.[H2.sup.g7] congenic mice (B10.H2g7). We investigated whether the same set of Idd loci segregated with IDDM susceptibility after outcross of NOD to NON.[H2.sup.g7] congenic mice. Since the outcrosses to [NON.H2.sup.g7] and B10.[H2.sup.g7] were performed in the same vivarium, direct comparisons were made of the chromosomal locations and relative strengths of Idd alleles in diabetic progeny from the two different outcrosses. In comparison with the NOD x B10.[H2.sup.g7] outcross, the NOD x NON.[H2.sup.g7] outcross produced significantly higher IDDM frequencies in F1, F2, and BC1 generations. The high F2 diabetes frequency allowed evaluation of the effects of homozygous expression of both the susceptibility and the resistance allele at Idd loci. This analysis demonstrated that no single non-MHC Idd locus was essential for the onset of diabetes in this cross. After outcross to NON.[H2.sup.g7], Idd4 (chromosome [Chr] 11), Idd5 (Chr 1), and Idd8 (Chr 14) did not segregate with IDDM in either the BC1 or the F2 generation. Diabetogenic NOD-derived alleles at Idd2 (Chr 9), Idd3 (Chr 3), and Idd10 (Chr 3) were segregating in the BC1. An NON-derived allele contributing to susceptibility on Chr 7 (Idd7) was also detected. Dominant traits, detectable only in the F2 cross, were encoded by Chr 4 (Idd9) and two newly mapped loci on Chr 13 (Idd14) and 5 (Idd15). A third dominant trait was encoded by Chr 6 (possibly Idd6), but here, in contrast to Idd9, Idd14, and Idd15, the NON allele was diabetogenic. Stepwise logistic regression analysis of the BC1 and F2 data confirmed that the ability to identify certainty of the non-MHC Idd loci was contingent on the extent of homozygosity for NOD background genes. This study shows that the diabetogenic phenotype can be achieved through the actions of variable combinations of MEIC-unlinked genes and a diabetogenic MHC haplotype. Diabetes 44: 1186-1196, 1995, The NOD mouse is susceptible to T-cell-mediated autoimmune insulin-dependent diabetes mellitus (IDDM). Previously, chromosome regions containing Idd susceptibility genes have been mapped by outcrossing NOD/Lt with the related but diabetes-resistant [...]

The role of [CD8.sup.+] T-cells in the development of diabetes in the nonobese diabetic (NOD) mouse remains controversial. Although it is widely agreed that class II--restricted [CD4.sup.+] T-cells are essential [...]

Combining congenic strain strategy with microarray gene expression gives us an insight into the identity and action of six murine T1D susceptibility loci. The framework for measuring differential gene expression that provides us an indepth into the microarray gene is discussed.

A genome scan for B10-derived loci that reduce the frequency of diabetes and insulitis in NOD mice demonstrated a large region (34 cM) of linkage on the proximal end of [...]

Members of the tumor necrosis factor receptor superfamily play an important role in the initiation, expansion, and termination of an immune response. It has recently been demonstrated that one member [...]