In the previous funding cycles of this proposal, we carried out two pivotal studies of a humanized FcR non- binding anti-CD3 mAb (hOKT3?1(Ala-Ala) or teplizumab) in patients with new and recent onset Type 1 diabetes (T1D). We showed that a single course of treatment with this drug attenuates the decline in C- peptide. However, the data from these trials, as well as trials with other immune modulators have failed to induce the lasting remissions that were seen in preclinical models of T1D. This proposal addresses the basis for this long term failure and a related unresolved question in the disease pathogenesis, which is why its progression occurs over an extended period of time. We have developed a model, based on our preliminary studies with samples from the clinical trials and from the TrialNet Natural History study (TN-01) that can account for the recurrence of disease and its chronicity. We have found that there is an increase in the proportion of diabetes antigen specific CD8+ T cells from subjects at-risk for T1D vs. healthy control subjects and these cells, as well as CD8+ T cells that are reactive with conventional antigens such as EBV or unselected CD8+ T cells have a greater proportion of CD45RA+CCR7+ cells. In at-risk subjects who progress to T1D there is reduced expression of CCR7 on the diabetes-antigen specific T cells compared to the diabetes antigen specific T cells from the non-progressors. These finding s suggest that on the basis of a developmental abnormality in CD8+ T cells, there is a persisting pool of diabetes antigen specific T cells with a na?ve phenotype and our findings with other cells suggest this is genetically programmed. In individuals who progress to T1D, these cells reduce expression of CCR7 and acquire effector function. We postulate that when this occurs, possibly as a result of inflammatory or other mediators, diabetes antigen specific T cells destroy ? cells. However, the pool of precursors remains and are the source of new effectors that can cause ? cell killing with the next provocation. We plan to characterize the diabetes antigen specific CD8+CD45RA+CCR7+ T cells in at-risk subjects who do or do not progress to T1D as well as viral antigen reactive CD8+ T cells in the at-risk, diabetic, and healthy control populations using flow cytometry, functional assays, and RNA-seq. We will test the diversity of the T cell repertoire by sequencing the T cell receptors from diabetes and viral antigen specific T cells and comparing the latter in at-risk subjects or patients and healthy subjects. We will also identify genetic polymorphisms, and affected molecular pathways that are associated with the abnormality in T cell development in order to determine whether the developmental pathway affected is before or after activation by antigen. Finally we will correlate the changes in T cell phenotypes with progression of T1D detected by measurement of ? cell death and metabolic function. These studies will lead to an understanding of the chronic and recurrent nature of the disease, suggest new treatment strategies, and identify biomarkers that can identify at-risk individuals who are progressing to T1D.
CD8+ T lymphocytes are believed to be important mediators of human Type 1 diabetes. We plan to study the basis for an abnormality in CD8+ T cell development in individuals at risk and with Type 1 diabetes. These studies will suggest treatment strategies and biomarkers that can be used to follow progression of the disease.
|Tooley, James E; Vudattu, Nalini; Choi, Jinmyung et al. (2016) Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes. Eur J Immunol 46:230-41|
|Wilcox, Nicholas S; Rui, Jinxiu; Hebrok, Matthias et al. (2016) Life and death of Î² cells in Type 1 diabetes: A comprehensive review. J Autoimmun 71:51-8|
|Garyu, Justin W; Meffre, Eric; Cotsapas, Chris et al. (2016) Progress and challenges for treating Type 1 diabetes. J Autoimmun 71:1-9|
|Durning, Sean P; Preston-Hurlburt, Paula; Clark, Paul R et al. (2016) The Receptor for Advanced Glycation Endproducts Drives T Cell Survival and Inflammation in Type 1 Diabetes Mellitus. J Immunol 197:3076-3085|
|Garyu, Justin W; Uduman, Mohamed; Stewart, Alex et al. (2016) Characterization of Diabetogenic CD8+ T Cells: IMMUNE THERAPY WITH METABOLIC BLOCKADE. J Biol Chem 291:11230-40|
|Rui, Jinxiu; Deng, Songyan; Lebastchi, Jasmin et al. (2016) Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice. Diabetologia 59:1021-9|
|Herold, Kevan C; Usmani-Brown, Sahar; Ghazi, Tara et al. (2015) Î² cell death and dysfunction during type 1 diabetes development in at-risk individuals. J Clin Invest 125:1163-73|
|Hughes, Jing; Vudattu, Nalini; Sznol, Mario et al. (2015) Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 38:e55-7|
|Reed, James C; Herold, Kevan C (2015) Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol 11:308-14|
|Tooley, James E; Herold, Kevan C (2014) Biomarkers in type 1 diabetes: application to the clinical trial setting. Curr Opin Endocrinol Diabetes Obes 21:287-92|
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