The BB/Wor Rat and the Balance Hypothesis of Autoimmunity

Mordes, John P.; Bortell, Rita; Doukas, John; Rigby, Mark R.; Whalen, Barbara J.; Zipris, Danny; Greiner, Dale L.; Rossini, Aldo A.

doi:10.1002/(sici)1099-0895(199607)12:2<103::aid-dmr161>3.0.co;2-2

Cited by 13 publications

(2 citation statements)

References 43 publications

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“…BB rats, which spontaneously develop T1D, thyroiditis, and other endocrinopathies, bear a profound lymphopenia, in contrast with KDP rats, which suffer from similar organ‐specific autoimmunity without lymphopenia (133, see above). The genetic defect responsible for lymphopenia in BB rats is a mutation of Ian5 , a member of the genes encoding the IAN (immune‐associated nucleotide‐binding protein) family of GTP‐binding proteins (134).…”

Section: Potential Imbalance Between Tregs and Self‐reactive T Cells mentioning

confidence: 99%

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Sakaguchi

Ono

Setoguchi

et al. 2006

Immunological Reviews

1,425

1,063

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Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

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Section: Potential Imbalance Between Tregs and Self‐reactive T Cells mentioning

confidence: 99%

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Sakaguchi

Ono

Setoguchi

et al. 2006

Immunological Reviews

1,425

1,063

View full text Add to dashboard Cite

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“…We chose to study thymi from BBDR rats because we have shown previously that BBDR rat ATOC recapitulate normal thymocyte development, and generate normal ratios of functional CD4 + and CD8 + single positive TCR hi cells [27,28]. The BBDR rat is phenotypically normal and disease-free, but can be induced to develop autoimmune diabetes by environmental perturbants, including viral infection [29][30][31]. Diabetes in these animals is associated with a type 1 immune response [32].…”

Section: Introductionmentioning

confidence: 99%

Type 1 cytokines polarize thymocytes during T cell development in adult thymus organ cultures

Whalen

Marounek

Mordes

et al. 2003

Journal of Autoimmunity

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Peripheral T cells can be polarized towards type 1 or type 2 cytokine immune responses during TCR engagement. Because T cell selection by peptide plus self-MHC in the thymus requires TCR engagement, we hypothesized that type 1 cytokines may polarize developing T cells. We cultured thymi from BBDR rats in adult thymus organ cultures (ATOC) under type 1 cytokine conditions in the absence of exogenous antigen. Type 1 cytokine-conditioned ATOC generated cells that spontaneously secreted high levels of IFNgamma, but not IL-4. A second exposure to type 1 cytokines further increased IFNgamma secretion by these cells, most of which were blasts that expressed the activation markers CD25, CD71, CD86, and CD134. Studies using blocking antibodies and pharmacological inhibitors suggested that both IL-18 and cognate TCR-MHC/ligand interactions were important for activation. Blocking anti-MHC class I plus anti-MHC class II antibodies, neutralizing anti-IL-18 antibody, and the p38 MAP-kinase inhibitor SB203580 each reduced IFNgamma production by approximately 75-80%. Cyclosporin A, which prevents TCR signaling, inhibited IFNgamma production by approximately 50%. These data demonstrate that exposure to type 1 cytokines during intrathymic development can polarize differentiating T cells, and suggest a mechanism by which intrathymic exposure to type 1 cytokines may modulate T cell development.

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Targeting Memory T Cells in Type 1 Diabetes

Ehlers

Rigby

2015

Curr Diab Rep

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Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to progressive destruction of pancreatic beta cells. Compared to healthy controls, a characteristic feature of patients with T1D is the presence of self-reactive T cells with a memory phenotype. These autoreactive memory T cells in both the CD4(+) and CD8(+) compartments are likely to be long-lived, strongly responsive to antigenic stimulation with less dependence on costimulation for activation and clonal expansion, and comparatively resistant to suppression by regulatory T cells (Tregs) or downregulation by immune-modulating agents. Persistence of autoreactive memory T cells likely contributes to the difficulty in preventing disease progression in new-onset T1D and maintaining allogeneic islet transplants by regular immunosuppressive regimens. The majority of immune interventions that have demonstrated some success in preserving beta cell function in the new-onset period have been shown to deplete or modulate memory T cells. Based on these and other considerations, preservation of residual beta cells early after diagnosis or restoration of beta cell mass by use of stem cell or transplantation technology will require a successful strategy to control the autoreactive memory T cell compartment, which could include depletion, inhibition of homeostatic cytokines, induction of hyporesponsiveness, or a combination of these approaches.

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The BB/Wor Rat and the Balance Hypothesis of Autoimmunity

Cited by 13 publications

References 43 publications

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Type 1 cytokines polarize thymocytes during T cell development in adult thymus organ cultures

Targeting Memory T Cells in Type 1 Diabetes

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The BB/Wor Rat and the Balance Hypothesis of Autoimmunity

Cited by 13 publications

References 43 publications

Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Foxp3+CD25+CD4+ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Type 1 cytokines polarize thymocytes during T cell development in adult thymus organ cultures

Targeting Memory T Cells in Type 1 Diabetes

Contact Info

Product

Resources

About

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease

Foxp3⁺CD25⁺CD4⁺ natural regulatory T cells in dominant self‐tolerance and autoimmune disease