Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Kevan C. Herold

Subject Area(s)

Immunology

Abstract

The mechanisms whereby immune therapies affect the progression of Type 1 diabetes (T1D) are still not well understood. Teplizumab, an FcR non-binding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8+ central memory (CD8CM) T cells in clinical responders in a clinical trial, but the generalizability of this finding and effects of teplizumab on these and other T cell subsets have not been identified. We analyzed data from 2 randomized clinical studies of teplizumab in patients with new and recent onset T1D. At the conclusion of therapy clinical responders showed a significant reduction in circulating CD4+ effector memory (CD4EM) T cells. Afterwards, an increase in the frequency and absolute number of CD8CM T cells characterized clinical responders. In vitro, teplizumab induced relative expansion of CD8CM T cells, similar to the effects in vivo. We studied gene expression by nanostring of CD8CM T cells from responders vs placebo-treated control subjects and found that genes associated with T cell signaling were decreased and genes that repress T cell activation were increased. We conclude that teplizumab may act as a partial agonist to CD8CM T cells and render the cells anergic in patients with T1D who are clinical responders to teplizumab.

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