It is clear from the work already done in defining the natural history of T1D that it is a complex disease that develops over years influenced by genes, environment and subtle alterations in immune function. This results in a failure of immune tolerance and the acquisition of pathogenic responses directed at the pancreatic islets. In this proposal we will address one specific mechanism that may contribute to this cascade toward autoimmunity;the enhanced responsiveness of CD4 T cells to IL-6. We will then determine if enhanced phosphorylation of STAT3 in response to IL-6 or a related cytokine IL-21 contribute to the resistance of Teff to suppression that is present at onset and immediately prior to the development of T1D. Such a connection may yield a disease mechanism that could be targeted therapeutically. Further, we will perform these assays with samples from the TrialNet natural history study (TN01) for which we have already determined the level of Teff resistance and IL-2R signaling. This will allow us to integrate our understanding of these immune alterations in relationship to each other and to the timeline of disease development. In this way we will be able to determine when each of these immune features IL-6(pSTAT3), IL-21(pSTAT3), IL-2(pSTAT5) and Teff resistance is present in the progression to disease, and further if the combination these features is more predictive of disease development and progression. This integration of data will allow us to map out the immune features of diabetes development;such a map will allow us to identify the who, when and what as we consider therapeutic intervention to prevent the development of T1D. Specifically, we pose the hypothesis that enhanced responsiveness to IL-6 and or IL-21 predates the development of T1D and contributes to the development of Teff resistance. Additionally, we will examine the hypothesis that the combination of enhanced IL-6(pSTAT3) and blunted IL-2(pSTAT5) responses result in an increase in pathogenic CD4 T cells and impaired Treg development and function resulting in the progression to T1D.
T1D is one of the most common diseases of childhood and although medical progress has led to great improvement in the treatment and survival of individuals with diabetes, it continues to be an incurable chronic disease. Several challenges have hindered our ability to find a cure for T1D;the many factors that contribute to its development and the fact that the disease processed is established months to years prior to diagnosis. In this grant we propose to use samples from individuals prior to the development of diabetes in order to dissect the role of CD4 T cell response to the cytokines IL-6 and IL-21 in the development of disease. We then plan to integrate our findings with our other studies of these samples to understand their role in altered tolerance and to establish a timeline of immune alteration in the context of beta cell destruction and clinical disease.