The Fragility of Inducible Immune Tolerance in Type 1 Diabetes

Abstract

Type 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of the pancreatic beta cells by autoreactive lymphocytes. While autoreactive CD8+ T cells, CD4+ T cells, and B cells collaborate to destroy beta cells, regulatory T cells (Tregs) fail to appropriately suppress autoreactivity. This dissertation examines the mechanisms by which immune tolerance may be induced in transplant or pregnancy in the setting of basal autoimmunity in T1D. I first uncovered an age-related barrier to transplant tolerance in the mouse model of T1D, NOD mice. Young NOD mice, before the onset of pathognomonic autoimmune features, were able to be tolerized to foreign antigens in an ex-vivo model of transplantation tolerance and did not display lymphocytic infiltration in response to allogeneic islet transplant. Next, I examined an additional mode of inducible tolerance to foreign antigen, by studying pregnancy in NOD mice. I demonstrated that pre-diabetic NOD mice have poor pregnancy outcomes, with increased reabsorbed and abnormal fetuses compared to non-autoimmune B6 mice. These poor pregnancy outcomes are partially driven by increased IL-6 secreted by endothelial cells; when excess IL-6 is neutralized, NOD mice enjoy pregnancy success rates similar to B6 mice. Finally, I validated findings from the mouse using patient samples and patient data from Electronic Health Records. Using paraffin-embedded placentas, I found that pregnant patients with T1D have alterations in placental lymphocytes compared to pregnant patients without T1D. Notably, just as endothelial cells drove an abnormal phenotype in NOD mice, pregnant patients with T1D exhibit vascular complications across all A1cs, indicating a role beyond glycemia in creating adverse pregnancy outcomes. Together, these data indicate a possibility for induction of immune tolerance in T1D and illustrate interference of underlying autoimmunity. While further research is needed to uncover the precise timing and method by which autoimmunity should be interrupted, this work presents a possibility for healthier pregnancies and successful islet transplants in T1D.