Date of Award
Medical Doctor (MD)
Kevan C. Herold
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.
Tooley, James, "Fcr Non-Binding Anti-Cd3 Mab (teplizumab) Inactivates Cd8+ Central Memory Cells In Patients With Type 1 Diabetes And Identifies Responders To Treatment" (2015). Yale Medicine Thesis Digital Library. 2018.