Breakdown in Peripheral Tolerance in Type 1 Diabetes in Mice and Humans

Jeker, Lukas T.; Bour-Jordan, Hélène; Bluestone, Jeffrey A.

doi:10.1101/cshperspect.a007807

Cited by 72 publications

(75 citation statements)

References 198 publications

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“…Development of spontaneous diabetes in NOD mice is critically linked to the balance and polarization of effector and regulatory T cells (17). A growing pancreatic insulitis composed of diabetogenic effector T cells occurs over time and results in the loss and destruction of insulin-producing b-cells in the islets.…”

Section: Reduction In Mda5 Induces Regulatory Rather Than Effector Immentioning

confidence: 99%

Reduced Expression of the MDA5 Gene IFIH1 Prevents Autoimmune Diabetes

2015

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Although it is widely accepted that type 1 diabetes (T1D) is the result of the autoimmune destruction of insulin-producing β-cells in the pancreas, little is known about the events leading to islet autoimmunity. Epidemiological and genetic data have associated virus infections and antiviral type I interferon (IFN-I) response genes with T1D. Genetic variants in the T1D risk locus interferon induced with helicase C domain 1 (IFIH1) have been identified by genome-wide association studies to confer resistance to T1D and result in the reduction in expression of the intracellular RNA virus sensor known as melanoma differentiation–associated protein 5 (MDA5). Here, we translate the reduction in IFIH1 gene expression that results in protection from T1D. Our functional studies demonstrate that mice heterozygous at the Ifih1 gene express less than half the level of MDA5 protein, which leads to a unique antiviral IFN-I signature and adaptive response after virus infection that protects from T1D. IFIH1 heterozygous mice have a regulatory rather than effector T-cell response at the site of autoimmunity, supporting IFIH1 expression as an essential regulator of the diabetogenic T-cell response and providing a potential mechanism for patients carrying IFIH1 protective polymorphisms.

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Section: Reduction In Mda5 Induces Regulatory Rather Than Effector Immentioning

confidence: 99%

Reduced Expression of the MDA5 Gene IFIH1 Prevents Autoimmune Diabetes

2015

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“…The NOD mouse has been used extensively in T1D studies with a specific focus on the role of T cell-mediated autoimmunity [15]. Two populations of T cells are particularly relevant to T1D pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1

et al. 2014

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The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes. Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus. However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D). We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner. Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes. These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1. Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity. Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.

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“…For example, in autoimmunity and viral immunopathology, lesions are more severe when the balance of T effectors to regulatory cells favors the former (10,21). Addition- ϩ Foxp3 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions

Reddy

Schreiber

Rajasagi

et al. 2012

J Virol

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Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4 + T cells. Hence, targeting proinflammatory CD4 + T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naïve animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4 + gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.

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Breakdown in Peripheral Tolerance in Type 1 Diabetes in Mice and Humans

Cited by 72 publications

References 198 publications

Reduced Expression of the MDA5 Gene IFIH1 Prevents Autoimmune Diabetes

Reduced Expression of the MDA5 Gene IFIH1 Prevents Autoimmune Diabetes

Autoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1

TNFRSF25 Agonistic Antibody and Galectin-9 Combination Therapy Controls Herpes Simplex Virus-Induced Immunoinflammatory Lesions

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