TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes

Belghith, Mériam; Bluestone, Jeffrey A.; Barriot, Samia; Mégret, Jérôme; Bach, Jean‐François; Chatenoud, Lucienne

doi:10.1038/nm924

Cited by 559 publications

(550 citation statements)

References 45 publications

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“…These data provide a basis for the understanding of the role of Treg cells and the CXCR4/SDF-1 axis in diabetogenesis, amelioration of autoimmunity and regeneration of the autologous b cells in the antea-diabetic model. In light of the accumulating evidence that Treg cells can suppress the transfer and onset of T1D, 16,17,[43][44][45][46] our findings reported here imply that an immunomodulatory regimen that improves the function of the CXCR4/SDF-1 axis and subsequent retention of Treg cells in the PLNs might become an alternative therapeutic approach for T1D.…”

Section: Treg Cells In Plns In T1dsupporting

confidence: 52%

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

et al. 2012

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Previously, we established a model in which physiologically adequate function of the autologous b cells was recovered in non-obese diabetic (NOD) mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory (Treg) cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes (PLNs). The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and b cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the b cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes (T1D).

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Section: Treg Cells In Plns In T1dsupporting

confidence: 52%

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

et al. 2012

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“…These studies indicate that anti-CD3 mAb can induce tolerance toward the pancreatic β-cell and thereby to type 1 diabetes in the NOD mouse. More recent studies suggest that the prolonged duration of the therapeutic effect may involve the induction of regulatory T-cells that can control autoimmune responses through a transforming growth factor-β–dependent mechanism (13). …”

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confidence: 99%

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

et al. 2005

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Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3γ1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 ± 9.6% of response at study entry in drug-treated patients vs. 53 ± 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA1c and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8+ T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.

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“…Another explanation for the protective effect observed is the generation of regulatory Treg cells, shown to confer tolerance in T1D animal models [14,18]. However, the similar proportion of cells expressing a Treg-related phenotype (CD4 + CD25 + , CD4 + CD62L high , CD45RB low , CD4 + CD152 + ) in mice treated with either mAb I-10 or the control mAb, the lack of detection of Th2 cells following mAb I-10 treatment and the observation that the transfer of cells from mAb I-10-treated recipients did not protect naive recipients from diabetes development, strongly suggests that the mode of action of mAb I-10 is not related to an increase of Treg or Th2 cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular lysosome‐associated membrane protein‐1 (LAMP‐1) mediates autoimmune disease progression in the NOD model of type 1 diabetes

Bittencourt¹,

Herren²,

Graber³

et al. 2005

Eur J Immunol

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Treatment (from 5 to 25 weeks of age) with a novel blocking monoclonal antibody, mAb I-10, directed against the plasma membrane (pm) form of LAMP-1, protected against development of autoimmune diabetes in the NOD mouse. A shorter course of treatment, i.e. from 5 to 12 weeks of age, significantly reduced the occurrence of insulitis as well as disease onset. Interfering with pm-LAMP-1 required continuous treatment as tolerance was not observed when treatment was stopped, and no higher proportion of cells with a T regulatory phenotype (e.g. CD4 + CD25 + ) were induced. The mechanism appears to involve modulating a proinflammatory cytokine, as the proportion of pancreaticinfiltrating IFN-c-positive cells was significantly reduced in the mAb I-10-treated group. These results demonstrate an unexpected role for pm-LAMP-1 in autoimmune disease progression, and suggest that further investigation should be performed to understand how this molecule modulates IFN-c-driven responses.

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TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes

Cited by 559 publications

References 45 publications

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

A Single Course of Anti-CD3 Monoclonal Antibody hOKT3γ1(Ala-Ala) Results in Improvement in C-Peptide Responses and Clinical Parameters for at Least 2 Years after Onset of Type 1 Diabetes

Extracellular lysosome‐associated membrane protein‐1 (LAMP‐1) mediates autoimmune disease progression in the NOD model of type 1 diabetes

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