Colin Rutner

Introduction. Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of beta-islet cells in the pancreas with resultant hyperglycemia and insulin deficiency.[1] The prevalence for T1D in the United States is 1.7/1000 in residents under the age of 20, with onset usually below the age of 30.² There is a growing body of evidence showing that T1D pathological autoimmunity is caused by failure of immune regulation characterized by the defective function of suppressive Treg cells.³ Currently, therapeutics are being developed to immunize against T1D by either mobilizing Treg cells in NOD mice models or the adoptive transfer of Treg cells in children.^4-6 Methods. Genetic susceptibility to T1D was correlated to IL-2 signaling and Treg suppressive activity in multiple studies.^7-10 IL2RA and HLA haplotypes were statistically correlated with relative levels of suppressive activity, assessed by measuring naïve T cell proliferation in the presence of Treg cells.^8,9 Treg apoptosis was assessed through apoptosis PCR arrays to determine the gene expression of pro- and anti-apoptotic genes.⁹ The frequency of Treg sub-populations was determined using flow cytometric analyses.¹⁰ Treg cells were administered in newly diagnosed T1D children; C-peptide, DDI, HbA1c, and fasting glucose were measured as well as peripheral blood levels of Tregs.⁶ In NOD mice, naïve T cells were converted to Treg cells when exposed to highly antagonistic antigens in subimmunogenic conditions.⁵ Results. Susceptible haplotypes of IL2RA and high risk HLA haplotypes were correlated with reduced Treg suppressive activity, decreased IL-2 responsiveness and increased apoptosis even in the absence of disease.^8,9 In T1D the frequency of a-Tregs was higher, but functionally impaired.¹⁰ No cytotoxicity was noted from the administration of Treg cells in newly diagnosed Type 1 diabetes patients.⁶ Two of ten patients did not require exogenous insulin half a year post-administration.⁶ Insulin mimetopes injected into NOD mice converted naïve Tcells into Treg cells, effectively preventing T1D.⁵ Conclusions. Studies show a clear genetic association of impaired IL-2 signaling and increased Treg apoptosis with disease progression.^8-10 The degree of expression of various apoptotic genes may determine T1D onset and could be critical for immunomodulatory treatments.⁹ Autoimmune reaction to destroy beta cells may be stronger in patients with residual insulin secreting capacity, and may have increased frequency of a-Tregs in order to protect the remaining beta cells.¹⁰ The administration of Tregs is safe and tolerable in newly diagnosed T1D patients.⁶ Treg mobilization may be a putative method to vaccinate against T1D.⁵

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