Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice

Noorchashm, Hooman; Moore, Daniel J.; Noto, Lauren E.; Noorchashm, Negin; Reed, Amy J.; Reed, Alison L.; Song, Howard K.; Mozaffari, Reza; Jevnikar, Anthony M.; Barker, Clyde F.; Naji, Ali

doi:10.4049/jimmunol.165.8.4685

Cited by 59 publications

(73 citation statements)

References 54 publications

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“…Although the exact role of B cell involvement is unclear, it is suggested that the antigenpresenting ability of B cells is critical in NOD-associated T cell activation [13][14][15] and selection of the diabetogenic T cell repertoire. CCR5 expression is not reported for B cells, but nearly all B cells from NOD mice showed elevated expression of this receptor (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

et al. 2004

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Lymphocyte infiltration to pancreatic islets is associated to chemoattraction, as are other inflammatory autoimmune processes. We examined whether development of insulitis and diabetes depends on chemoattraction of lymphocytes via the CCR5 chemokine receptor. In non-obese diabetic (NOD) mice, a substantial fraction of peripheral T cells and virtually all B cells expressed high CCR5 levels. CCR5 expression characterized the effector T cell phenotype, suggesting their potential involvement in disease development. In view of these findings and the CCL5 (RANTES, the CCR5 ligand) expression by pancreatic islets, we treated NOD mice with a neutralizing anti-CCR5 antibody. This did not influence peri-insulitis advancement, but inhibited g -cell destruction and diabetes. These data demonstrate a role of CCR5-dependent chemoattraction in insulitis progression to islet destruction, suggesting the potential value of therapeutic intervention by CCR5 targeting.

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Section: Discussionmentioning

confidence: 99%

“…1). Although T cells from NOD mice transfer disease [11,12], B cells are also reported to have an important role in diabetes development and probably in antigen presentation in this context [13][14][15]. Lymphocyte CCR5 expression was similar in 4-month-old NOD mice (not shown).…”

Section: Activated T Cells In Nod Mice Express a Functional Ccr5 Recementioning

confidence: 99%

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

et al. 2004

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“…Using CFSE labeling, they found that NOD CD4 T cells responded less well to anti-CD3 stimulation compared with B6 CD4 T cells, a phenomenon related to the non-MHC genes in the NOD genetic background and not to the expression of the MHC haplotype [71]. Both B cell and non-B cell antigen-presenting cells were tested for their ability to effectively activate CD4 T cells.…”

Section: B Cell Characteristics In Nod Micementioning

confidence: 99%

B Cells in Autoimmune Diabetes

Wong

Liu²

2005

Rev Diab Stud

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■ AbstractAutoantibodies have been used as good markers for the prediction of future development of type 1 diabetes mellitus (T1DM), but are not thought to be pathogenic in this disease. The role of B cells that produce autoantibodies in the pathogenesis of human T1DM is largely unknown. In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, it has been shown that B cells may contribute multifariously to the pathogenesis of the disease. Some aspects of deficiencies of B cell tolerance may lead to the circulation of autoreactive B cells. In addition, the antigenpresenting function of autoantigen specific B cells is likely to be particularly important, and autoantibodies are also considered to play a critical role. This review discusses the possible aspects of B cells involved in the development of autoimmune diabetes.

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“…In addition, NOD mice exhibit a large array of cellular and humoral immune abnormalities including defective macrophage and dendritic cell maturation (12,13), defects in CD4 ϩ T cell response to superantigens (14,15), low levels of NK and NKT cell activity (16 -19), and deficiencies in regulatory CD4…”

mentioning

confidence: 99%

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

Pearson¹,

Markees

Serreze

et al. 2003

The Journal of Immunology

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Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD × C57BL/6)F1 mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F1 mice shared the dendritic cell maturation defects and abnormal CD4+ T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

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Impaired CD4 T Cell Activation Due to Reliance Upon B Cell-Mediated Costimulation in Nonobese Diabetic (NOD) Mice

Cited by 59 publications

References 54 publications

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

B Cells in Autoimmune Diabetes

Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice

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