Antigen-Based Immunotherapy Drives the Precocious Development of Autoimmunity
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Abstract During the development of type I diabetes mellitus in nonobese diabetic (NOD) mice, T cell autoimmunity gradually spreads among β cell Ags. Little is known about how autoantigen-based immunotherapies affect this spreading hierarchy. We treated newborn NOD mice with different autoantigenic β cell peptides (in adjuvant) and characterized their T cell responses at 4 wk of age, when autoimmunity is usually just beginning to arise to a few β cell Ag determinants. Surprisingly, we found that regardless of whether an early, or late target determinant was administered, autoimmunity had already arisen to all tested β cell autoantigen determinants, far in advance of when autoimmunity would have naturally arisen to these determinants. Thus, rather than limiting the loss of self-tolerance, immunotherapy caused the natural spreading hierarchy to be bypassed and autoreactivities to develop precociously. Evidently, young NOD mice have a broad array of β cell-reactive T cells whose activation/expansion can occur rapidly after treatment with a single β cell autoantigen. Notably, the precocious autoreactivities were Th2 type, with the exception that a burst of precocious Th1 responses was also induced to the injected autoantigen and there were always some Th1 responses to glutamic acid decarboxylase. Similarly treated type 1 diabetes mellitus-resistant mouse strains developed Th2 responses only to the injected Ag. Thus, autoantigen administration can induce a cascade of autoimmune responses in healthy (preautoimmune) mice that are merely genetically susceptible to spontaneous autoimmune disease. Such phenomena have not been observed in experimental autoimmune disease models and may have important clinical implications.Keywords:
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SUMMARY Previous studies have shown that a transgenic I-Eα gene, the mouse homologue of human DRα gene, prevents the development of insulitis and hence of diabetes in NOD mice. To investigate the mechanism of this prevention, we generated two strains of NOD mice expressing DRαEβ molecule: DRα-24-NOD expressing DRαEβ molecule on thymic epithelial cells (TEC) and bone marrow-derived cells (BDC), and DRα-30-NOD expressing DRαEβ molecule only on the TEC, and these mice were monitored for disease development. Because the DRαEβ molecule reconstituted I-E controlled immune regulation, it would become clear which cell type, TEC or BDC, was responsible for the I-E-mediated disease protection. To our surprise, however, DRα-24-NOD developed insulitis and diabetes comparably to non-transgenic littermates. This suggested that the difference in structure between DRα and Eα molecules contributed to the difference in preventive effect on the development of insulitis and diabetes between DRα-24-NOD and Eα-NOD. In an analysis of the T cell proliferative responses to glutamic acid decarboxylase (GAD) 65-derived peptides which were known to be diabetogenic autoantigens, it was shown that DRα-24-NOD and NOD acquired comparable level of T cell response to GAD 509–528 but 5–10-fold higher response was observed in Eα-NOD. This suggested that I-ANOD and EαEβNOD molecules could present GAD 509–528 peptide to T cells, while DRαEβNOD could not. Furthermore, T cells from DRα transgenic mice showed proliferative response to antigen-presenting cells from Eα transgenic mice in primary mixed lymphocyte reaction. This also suggested that the EαEβ molecule does differ in structure and peptide binding from the DRαEβ molecule. Present data suggested a possibility that the T cell repertoire selection, or the T cell response to GAD 65 and/or other unknown antigens specifically mediated by I-E molecule, may contribute to the prevention of disease development in Eα-NOD.
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The non-obese diabetic (NOD) mouse is a good model of insulin-dependent diabetes mellitus. Autoreactive T cells may play a fundamental role in disease initiation in this model, while disregulation of such cells may result from an abnormal thymic microenvironment. Diabetes is prevented in NOD mice by direct introduction of an E alpha d transgene (NOD-E) or a modified I-A beta chain of NOD origin (NOD-PRO or NOD-ASP). To investigate if disease pathology in NOD mice, protection from disease in transgenic NOD-E and NOD-PRO and partial protection from disease in NOD-ASP can be attributed to alterations in the thymic microenvironment, immunohistochemical and flow cytometric analysis of the thymi of these mouse strains was studied. Thymi from NOD and NOD-E mice showed a progressive increase in thymic B-cell percentage from 12 weeks of age. This was accompanied by a concomitant loss in thymic epithelial cells with the appearance of large epithelial-free areas mainly at the corticomedullary junction, which increased in size and number with age and contained the B-cell clusters. Such thymic B cells did not express CD5 and were absent in CBA, NOD-ASP and NOD-PRO mice as were the epithelial cell-free spaces, even at 5 months of age. Therefore the mechanisms of disease protection in the transgenic NOD-E and NOD-ASP/NOD-PRO mice may differ if these thymic abnormalities are related to disease.
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The non-obese diabetic (NOD) mouse spontaneously develops diabetes and is a widely used model of Type 1 Diabetes in humans. The major histocompatibility complex class II plays an important role in governing disease susceptibility in NOD mice. NOD mice express a rare I-A allele, I-Ag7, and do not express I-E molecules. Interestingly, transgenic NOD mice which express I-E (NOD-E) fail to develop diabetes although, the protective mechanism(s) are incompletely understood. Initially, we explored whether diabetes prevention was due to deletion of autoreactive T cells. Through adoptive transfer with depletion of CD25+T cells, we demonstrated that autoreactive T cells were present in the periphery of NOD-E mice. Although, BDC2.5NOD T cells proliferated less in the pancreatic lymph nodes of NOD-E mice, we found that they transferred disease with a similar kinetic in NOD.scid and NOD-E.scid recipients suggesting that there was little difference in peripheral antigen presentation in NOD-E mice. We also found that there were no proportional or functional differences between NOD and NOD-E T regs. Our studies indicate that autoreactive T cells are present within the periphery of NOD-E mice but that these cells are present in low numbers suggesting that peripheral tolerogenic mechanisms are able to prevent them from inducing diabetes.
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Neonatal studies in different mouse strains reveal that early life colonization affects the development of adaptive immunity in mice. The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes, but neonatal studies of NOD mice are lacking. We hypothesized that NOD mice deviate from another much used mouse strain, C57BL/6, with respect to postnatal microbiota and/or hematopoiesis and compared this in newborn mice of dams housed under the same conditions. A distinct bacteria profile rich in staphylococci was found at postnatal days (PND) 1–4 in NOD mice. Furthermore, a distinct splenic cell profile high in a granulocytic phenotype was evident in the neonatal NOD mice whereas neonatal C57BL/6 mice showed a profile rich in monocytes. Neonatal expression of Reg3g and Muc2 in the gut was deviating in NOD mice and coincided with fewer bacteria attaching to the Mucosal surface in NOD compared to C57BL/6 mice.
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Abstract The non‐obese diabetic (NOD) mouse is an established animal model of the autoimmune disease, insulin‐dependent diabetes mellitus (IDDM). The NOD‐E mouse is a transgenic mouse which expresses the I‐E molecule (absent in NOD mice). Expression of I‐E protects these mice from both insulitis and IDDM.We have investigated the possible mechanisms of this protection by constructing bone marrow, and combined bone marrow and thymus chimeras between NOD and NOD‐E mice. Our data suggest that thymic epithelium may play no direct role in either protection against, or promotion of, IDDM. Protection from diabetes is provided either by NOD‐E donor bone marrow or NOD‐E recipient non‐thymic radioresistant cells. The means by which protection may be achieved in this system are discussed.
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Abstract 12/15-lipoxygenase (12/15-LO) reacts with fatty acids to produce pro-inflammatory lipids, enhance IL-12 production by macrophages (MΦ), and its product 12-(S)-HETE induces pancreatic β-cell apoptosis at nM concentrations. Congenic NOD mice deficient in 12/15-LO (NOD-Alox15null) show a significant decrease in Type 1 diabetes (T1D) development (2.5 vs. >60% in ♀ by 30 wks). We tested the effects of the deficiency on the immune system in NOD-Alox15null vs. NOD mice. Adoptive transfer of diabetic (diab) or non-diabetic (non-diab) NOD, and non-diab NOD-Alox15null splenocytes (cells) determined ability of T1D disease transfer in NOD.scids. Both diab and non-diab NOD cells conferred T1D in NOD.scid hosts, but non-diab NOD-Alox15null cells did not (>8 wks post-transfer). NOD-Alox15null.scids were also injected with either NOD (diab and non-diab) or NOD-Alox15null (non-diab) cells. NOD cells still transferred disease, but NOD-Alox15null cells did not. As transferred splenocytes were mainly T and B cells, we tested for 12/15-LO mRNA expression in these subsets. 12/15-LO levels were minimally detectable, suggesting that immune effects are likely due to indirect effects on B and T cells. To study the mechanism, we looked at the role of 12/15-LO on APCs. Fewer MΦ infiltrate the pancreas of NOD-Alox15null mice at 4 wks of age compared to NOD controls. Also, MΦ from 10-wko NOD-Alox15null mice show reduced IL-12 expression compared to age-matched NODs. Therefore, 12/15-LO is a key regulator of the autoimmune response leading to T1D.
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Abstract: In addition to providing a large source of donor tissue, xenogeneic islet transplantation might avoid recurrent autoimmunity in patients with type 1 diabetes. To examine this possibility further, xenogeneic pig islets were transplanted into recipient mice in the presence or absence of autoimmunity. Spontaneously, non‐obese diabetic (NOD) recipients rejected isografts rapidly whether or not the recipients were depleted of CD4+ T‐cells. Young NOD mice made diabetic with streptozotocin accepted islet isografts without immunosuppression, indicating that destructive autoimmunity did not develop in these recipients. Pig xenografts were rejected equally quickly in the two types of NOD recipients in the absence of immunosuppression and survived for up to 9 weeks in both types of NOD recipients after CD4 depletion. BALB/c mice often accepted pig xenografts indefinitely after anti‐CD4 antibody treatment. These results suggest that pig islets are resistant to recurrent autoimmunity when CD4+ T‐cells are depleted. The difficulty in obtaining indefinite islet xenograft survival in NOD recipients occurs independently from the development of destructive autoimmunity.
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The non-obese diabetic (NOD) mouse is an excellent animal model of autoimmune diabetes associated with insulitis. The progression of insulitis causes the destruction of pancreatic beta cells, resulting in the development of hyperglycemia. Although it has been well documented that T cells are required for the development of insulitis and diabetes in NOD mice, the importance of B cells remains unclear. To clarify the role of B cells in the pathogenesis of NOD mice, we therefore generated B cell-deficient NOD (B-NOD) mice. Surprisingly, none (of 13) of the B-NOD mice developed diabetes by 40 weeks of age, while the control littermates with B cells (B+NOD) suffered from a high proportion (43 of 49) of diabetes. The insulin reactivity of B+NOD mice was significantly impaired, while the B-NOD mice showed a good insulin response, thus suggesting the pancreatic beta cell function to be well preserved in B-NOD mice. Although B-NOD mice did develop insulitis, the extent of insulitis was significantly suppressed. These data thus provide the direct evidence that B cells are essential for the progression of insulitis and the development of diabetes in NOD mice.
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The development of type I diabetes in the nonobese diabetic (NOD) mouse is under the control of multiple genes, one or more of which is linked to the major histocompatibility complex (MHC). The MHC class II region has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis and diabetes. To examine the effect of expressing an I-E+ or I-E- non-NOD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congenic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not diabetes. The remaining four congenic strains were free of insulitis and diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed with the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus expressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosphamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontaneous diabetes developed as well. These data are the first to demonstrate that I-E+ NOD mice develop diabetes, indicating that expression of I-E in NOD mice is not in itself sufficient to prevent insulitis or diabetes. In fact, I-E- F1 strains were no more protected from diabetes than I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes are important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.
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