Thymectomy and Radiation-Induced Type 1 Diabetes in Nonlymphopenic BB Rats

Ramanathan, Sheela; Paterson, Andrew D.; Marandi, Leili; Guyader, Dominique; Poussier, Philippe

doi:10.2337/diabetes.51.10.2975

Cited by 21 publications

(12 citation statements)

References 49 publications

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“…In some models of autoimmunity, diseases were obtained by the transfer of pathogenic cells in sublethally irradiated recipients (32,33). Thus, 1 mo after intraocular injection of AAV2/5-HA, mice were sublethally irradiated and injected i.v.…”

Section: Injection Of Ha-specific T Cells In Irradiated Mice Expressimentioning

confidence: 99%

Regulatory T Cells Control Uveoretinitis Induced by Pathogenic Th1 Cells Reacting to a Specific Retinal Neoantigen

Terrada

Fisson

Kozak³

et al. 2006

The Journal of Immunology

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In many clinical cases, uveitis develops secondary to an infection. This could result from peripheral activation followed by ocular penetration and reactivation of T cells specific for microbial Ags expressed in the retina. To gain insights into the pathophysiology of uveitis, we developed a new mouse model based on stable retinal expression of influenza virus hemagglutinin (HA) neoantigen by adeno-associated virus-mediated gene transfer. One month thereafter, we adoptively transferred HA-specific T cells, which were activated in vitro or in vivo. Intraocular inflammation was clinically and histologically observed in all animals within 15 days. The ocular infiltrate was composed mostly of macrophages and HA-specific T cells with a proinflammatory cytokine profile. Depletion of CD4+CD25+ regulatory T cells exacerbated the disease, whereas HA-specific CD4+CD25+ T cells given i.v. controlled the disease. This novel model should allow to better study the pathophysiology and therapeutic of uveitis.

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Section: Injection Of Ha-specific T Cells In Irradiated Mice Expressimentioning

confidence: 99%

Regulatory T Cells Control Uveoretinitis Induced by Pathogenic Th1 Cells Reacting to a Specific Retinal Neoantigen

Terrada

Fisson

Kozak³

et al. 2006

The Journal of Immunology

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“…The resulting BBnon-lyp rats are nonlymphopenic, hence, spontaneous type 1 diabetes resistant. Animals were maintained under specific pathogen-and virus antibody-free conditions, and, starting at 2 months, were screened for type 1 diabetes development as previously described (19). Nondiabetic littermates were killed at 4 months, after which the pancreas was fixed in 10% formalin and assessed histologically after hematoxylin and eosin staining.…”

Section: Methodsmentioning

confidence: 99%

“…BBnon-lyp rats are an Iddm2 congenic inbred line derived by the introgression of the wild-type Iddm2 locus from the BBDR strain into the BBDP strain. Backcross breeders were selected for a normal proportion of peripheral blood T-lymphocytes by flowcytometry for Ͼ10 generations, then intercrossed (19). The resulting BBnon-lyp rats are nonlymphopenic, hence, spontaneous type 1 diabetes resistant.…”

Section: Methodsmentioning

confidence: 99%

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A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes

et al. 2007

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OBJECTIVE—The biobreeding diabetes-prone (BBDP) rat spontaneously develops type 1 diabetes. Two of the genetic factors contributing to this syndrome are the major histocompatibility complex (Iddm1) and a Gimap5 mutation (Iddm2) responsible for a T-lymphopenia. Susceptibility to experimentally induced type 1 diabetes is widespread among nonlymphopenic (wild-type Iddm2) rat strains provided they share the BBDP Iddm1 allele. The question follows as to whether spontaneous and experimentally induced type 1 diabetes share susceptibility loci besides Iddm1. Our objectives were to map a novel, serendipitously discovered Iddm locus, confirm its effects by developing congenic sublines, and assess its differential contribution to spontaneous and experimentally induced type 1 diabetes. RESEARCH DESIGN AND METHODS—An unexpected reduction in spontaneous type 1 diabetes incidence (86 to 31%, P < 0.0001) was observed in a BBDP line congenic for a Wistar Furth–derived allotypic marker, RT7 (chromosome 13). Genome-wide analysis revealed that, besides the RT7 locus, a Wistar Furth chromosome 8 fragment had also been introduced. The contribution of these intervals to diabetes resistance was assessed through linkage analysis using 134 F2 (BBDP × double congenic line) animals and a panel of congenic sublines. One of these sublines, resistant to spontaneous type 1 diabetes, was tested for susceptibility to experimentally induced type 1 diabetes. RESULTS—Both linkage analysis and congenic sublines mapped a novel locus (Iddm24) to the telomeric 10.34 Mb of chromosome 8, influencing cumulative incidence and age of onset of spontaneous type 1 diabetes but not insulitis nor experimentally induced type 1 diabetes. CONCLUSIONS—This study has identified a type 1 diabetes susceptibility locus that appears to act after the development of insulitis and that regulates spontaneous type 1 diabetes exclusively.

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“…Consequently, recent thymic emigrants are short-lived, leading to a significant loss of peripheral CD4 + and CD8 + T cells and extensive lymphopenia (13,14). In contrast, congenic diabetes-resistant BB (DR-BB) rats carrying the wild-type form of the Gimap5 gene are normopenic and develop T1DM only after TLR engagement, thymectomy, or depletion of regulatory T (T reg ) cells (15,16). Whereas the relative contribution of Th1 and Th17 effector T (T eff ) cells to the pathogenesis of T1DM in DP-BB rats remains to be determined, a crucial role of T reg cells has been established by several groups.…”

mentioning

confidence: 99%

Type 1 Diabetes in BioBreeding Rats Is Critically Linked to an Imbalance between Th17 and Regulatory T Cells and an Altered TCR Repertoire

Brandt

Fischer

Walter

et al. 2010

The Journal of Immunology

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Diabetes-prone BioBreeding (DP-BB) rats spontaneously develop type 1 diabetes mellitus (T1DM) on grounds of their MHC haplotype RT1u and a point mutation in the Gimap5 gene. In this study, we report that DP-BB rats exhibit an increasingly severe imbalance, in particular between Th17 and regulatory T (Treg) cells, within the first months of age. This can be assigned to an excess in effector T cells because neither the percentage nor the function of the Treg cells is compromised. Flow cytometric analysis of Vβ segment usage and CDR3 spectratyping further suggest that the disturbed repertoire of peripheral T cells may also contribute to the development of T1DM in DP-BB rats. Importantly, expansion of Treg cells in vivo by means of a CD28 superagonistic Ab as well as adoptive transfer of Treg cells efficiently interferes with the development of T1DM in DP-BB rats, whereas treatment with conventional Th cells does not afford protection. Using a newly generated strain of enhanced GFP transgenic rats, we could further demonstrate that the transferred Treg cells persist in the recipient rats for several months and partially correct the imbalance between Th17 and Treg cells. Thus, our data support the hypothesis that unchecked effector T cell action and a disturbed T cell repertoire contribute to the development of T1DM in DP-BB rats, which may also have implications for a better understanding of the human disease.

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Thymectomy and Radiation-Induced Type 1 Diabetes in Nonlymphopenic BB Rats

Cited by 21 publications

References 49 publications

Regulatory T Cells Control Uveoretinitis Induced by Pathogenic Th1 Cells Reacting to a Specific Retinal Neoantigen

Regulatory T Cells Control Uveoretinitis Induced by Pathogenic Th1 Cells Reacting to a Specific Retinal Neoantigen

A Novel Susceptibility Locus on Rat Chromosome 8 Affects Spontaneous but Not Experimentally Induced Type 1 Diabetes

Type 1 Diabetes in BioBreeding Rats Is Critically Linked to an Imbalance between Th17 and Regulatory T Cells and an Altered TCR Repertoire

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