The phenotype of lymphoid cells and thymic epithelium correlates with development of autoimmune insulitis in NOD in equilibrium with C57BL/6 allophenic chimeras.

Abstract

The mechanisms contributing to the development of autoimmune insulin-dependent diabetes mellitus have been analyzed in allophenic mouse chimeras of the NOD +* C57BL/6 strain combination (where NOD is nonobese diabetic). Occurrence of lymphoid cell infiltration (insulitis) in pancreatic islets was observed in the majority of such chimeras. The development of insulitis was found to correlate with major histocompatibility complex chimerism in lymphoid cells and in thymus cortical regions. Chimeras with more than 50% of C57BL/6 lymphoid cells rarely developed insulitis. Our data suggest that the correlation with the thymic cortical region is absolute. Thus, all individuals displaying NOD or NOD/ C57BL/6 thymic cortical regions developed insulitis, whereas we have not observed insulitis in chimeras with only C57BL/6 thymic cortical regions. Thus the positive selection of T cells appears to play a crucial role in the development of insulindependent diabetes mellitus.One of the best animal models of human insulin-dependent diabetes mellitus is represented by the nonobese diabetic (NOD) mouse (1). In these mice overt diabetes develops spontaneously in a majority of female mice and less frequently in male mice. As in human insulin-dependent diabetes mellitus, development of overt diabetes in NOD mice is preceded by infiltration of lymphoid cells into the pancreatic islets and is observed only after massive destruction of insulin-producing f3 cells (2).Predisposition to the disease is under polygenic control, one of the genes having been identified as the major histocompatibility complex (MHC) class II locus both in man and in the NOD mouse strain (3, 4). The involvement of MHC genes in the development of autoimmunity in NOD mice indicates that T cells play a crucial role in this process. Indeed, the disease can be transferred with cells from diabetic animals (5) requiring both CD4+ and CD8+ cells (6, 7). NOD mice express a unique I-A molecule (I-ANOi) where aspartic acid in position 57 ofthe 13 chain is replaced by serine (8). This is observed also in the HLA-DQ ,8 chain of many Caucasians with insulin-dependent diabetes mellitus (9-11). The I-E antigen is absent in the NOD strain due to a defect in I-E a chain expression (3). Recent reports showing that insulitis in NOD mice can be prevented by the introduction of I-E a chain or non-NOD I-A transgenes have supported the hypothesis that I-A and I-E expression affects development of insulitis (12-15).I-E expression is known to mediate intrathymic clonal deletion of sets of T-cell antigen receptors carrying specific 13-chain variable regions (16, 17). Based on these observations, the protective effect of I-E has been suggested to reflect negative selection through intrathymic clonal deletion of potentially hazardous T-cell clones (12, 18). However, the observation that NOD mice expressing promoter-mutated I-E a chain genes mediating intrathymic deletion of I-Ereactive T cells still develop insulitis has cast doubt about this hypothesis (19).To further investigate t...

Non‐Diabetogenic Insulitis in NOD↔BIO. GD Allophenic Mice in Spite of Permissive Class I MHC Antigens

“…Hence, NOD-allophenic mice can be used to dissect the cellular mechanisms involved in the pathogenesis of the autoimmune process. For example, we found previously that the ailophenic chimeras lacking the NOD component in thymic epithelium consistently failed to develop insulitis [24], supporting the notion that thymic positive selection of T cells is essential for development of this spontaneous, tissue-specific autoimmunity. In that experiment, however, although many NOD*-vC57BL/6 ailophenic mice showed insulitis and extensive destruction of l^ cells in the islets, none of them developed diabetes.…”

Diabetes Induction in C57BL/6 Mice Reconstituted with Lymphocytes of Nonobese Diabetic <−> C57BL/6 Mouse Embryo Aggregation Chimeras

“…We had previously observed that the proportion of NOD lymphocytes in EA chimeras correlated with the development of insulitis [ 15] and with subsequent CY‐induced diabetes [ 16]. In order to assess whether the lymphoid chimerism would also affect diabetes susceptibility in the transfer model, the chimerism was measured in the donor spleen cells at the moment of transfer, and in the spleens of the recipients at death.…”

“…The risk of graft‐versus‐host disease can therefore be excluded. NOD <−> B6 EA chimeras develop spontaneous autoimmune insulitis but are virtually resistant to IDDM [ 15]. Similar to diabetes‐free NOD male mice, the resistance in EA chimeras can be overriden by cyclophosphamide (CY) treatment [ 16].…”

The lupus-prone BXSB strain: the Yaa gene model of systemic lupus erythematosus

“…As discussed below, if the Yaa gene effect can be associated with the recognition by T helper cells of the putative Yaa-related antigen expressed on B cells, the I-A molecule may be involved in the selection or deletion of T cells with anti-Yaa specificity or in the presentation of the Yaa antigen-derived peptides. In this regard, a recent elegant study of Forsgren et al [13] is relevant. Finally, it should be emphasized that the MHC gene is not the only autosomal gene to be involved in the action of the Yaa gene, since the autoimmune accelerating activity of the Yaa gene is observed in BXSB (H-2 b) and MRL (H-2 k) mice, but not in non-autoimmune mice bearing the same H-2 haplotype, B6 (H-2 b) and CBA/J (H-2 k) [23,31].…”