Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Yang, Wen; Hussain, Shabbir; Mi, Qing‐Sheng; Santamaría, Pere; Delovitch, Terry L.

doi:10.4049/jimmunol.173.7.4407

Cited by 20 publications

(20 citation statements)

References 55 publications

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“…First, direct introduction of toxic moieties through the IL-2/ IL-2 receptor complex overcomes the relative resistance of NOD lymphocytes to apoptosis (as compared with wildtype mice) [49,50], and the decreased susceptibility of diabetogenic cells to Treg-mediated inhibition [33,51,52]. Inasmuch as B cell lymphoma protein 2 (BCL-2) is associated with the survival of islet-infiltrating T cells [18], IL2-cas was found to reduce the BCL-2/apoptosis regulator BAX ratio in a model of toxic colitis [25], suggesting that the fusion protein sensitises pathogenic lymphocytes to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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Aims/hypothesis Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide. Methods IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro. Results IL2-cas induced apoptosis in T cells expressing the α chain of the IL-2 receptor (cluster of differentiation [CD] 25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25 -FOXP3 + T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival. Conclusions/interpretation Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25 + regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3 + T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.

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Section: Discussionmentioning

confidence: 99%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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“…On the other hand, NOR T-cells are more susceptible than those from NOD mice to activation-induced cell death (AICD) (34). Therefore, abortive activation followed by AICD may limit the effector function of NOR diabetogenic CD4 T-cells.…”

Section: Discussionmentioning

confidence: 99%

Idd9/11Genetic Locus Regulates Diabetogenic Activity of CD4 T-Cells in Nonobese Diabetic (NOD) Mice

et al. 2008

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OBJECTIVE-Although the H2g7 major histocompatibility complex (MHC) provides the primary pathogenic component, the development of T-cell-mediated autoimmune type 1 diabetes in NOD mice also requires contributions from other susceptibility (Idd) genes. Despite sharing the H2 g7 MHC, the closely NODrelated NOR strain remains type 1 diabetes resistant because of contributions of protective Idd5.2, Idd9/11, and Idd13 region alleles. To aid their eventual identification, we evaluated cell types in which non-MHC Idd resistance genes in NOR mice exert disease-protective effects. RESEARCH DESIGN AND METHODS-Adoptive transferand bone marrow chimerism approaches tested the diabetogenic activity of CD4 and CD8 T-cells from NOR mice and NOD stocks congenic for NOR-derived Idd resistance loci. Tetramer staining and mimotope stimulation tested the frequency and proliferative capacity of CD4 BDC2.5-like cells. Regulatory T-cells (Tregs) were identified by Foxp3 staining and functionally assessed by in vitro suppression assays.RESULTS-NOR CD4 T-cells were less diabetogenic than those from NOD mice. The failure of NOR CD4 T-cells to induce type 1 diabetes was not due to decreased proliferative capacity of BDC2.5 clonotypic-like cells. The frequency and function of Tregs in NOD and NOR mice were also equivalent. However, bone marrow chimerism experiments demonstrated that intrinsic factors inhibited the pathogenic activity of NOR CD4 T-cells. The NOR Idd9/11 resistance region on chromosome 4 was found to diminish the diabetogenic activity of CD4 but not CD8 T-cells. CONCLUSIONS-In

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“…Anti-CD3, whole Ab and fragments [F(ab )2], will induce depletion of activated T cells from pancreatic islets but the effect is transient [22,23]. Long-term effects of anti-CD3 appear to be mediated by the induction of regulatory T cells, CD4 + CD25 + , in mesenteric and pancreatic lymph nodes [24] and by depletion of cell autoreactive CD8 + T cells [17]. Therefore, we selected anti-CD3 mAb as a potential intervention that would attenuate the development of T1DM in the NOD mouse and allow pregnancy to continue for the evaluation of the potential transfer of immunotolerance in the offspring.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-CD3 monoclonal antibody (mAb) given intravenously has been used to reverse diabetes in NOD mice [14][15][16] and to prevent diabetes from occurring [17]. In addition, orally administered anti-CD3 has been shown to be biologically active in the gut and to suppress autoimmune disease [18].…”

Section: Introductionmentioning

confidence: 99%

Oral anti‐CD3 monoclonal antibody delays diabetes in non‐obese diabetic (NOD) mice: effects on pregnancy and offspring—a preliminary report

Bevier

Trujillo

Primbs

et al. 2011

Diabetes Metabolism Res

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Perturbed Homeostasis of Peripheral T Cells Elicits Decreased Susceptibility to Anti-CD3-Induced Apoptosis in Prediabetic Nonobese Diabetic Mice

Cited by 20 publications

References 55 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Idd9/11Genetic Locus Regulates Diabetogenic Activity of CD4 T-Cells in Nonobese Diabetic (NOD) Mice

Oral anti‐CD3 monoclonal antibody delays diabetes in non‐obese diabetic (NOD) mice: effects on pregnancy and offspring—a preliminary report

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