Analysis of antigen specific T cells in response to immune therapies in MS and T1D
Kevan Herold, MD
Professor
Yale School of Medicine
Immunobiology and Medicine
General Audience Summary
In identical twins, one of whom has type 1 diabetes and the other who doesn’t, for example, both may have immune cells that are activated for beta cell molecules, but the immune cells in the unaffected sibling do not cause disease. Why? Dr. Herold will study the immune cells that have been activated for target-organ molecules, in type 1 diabetes and multiple sclerosis, to identify features that account for their ability to cause autoimmunity. In addition, anti-CD20 antibodies—against specific types of immune cells called B cells—have been used to treat both diseases, but the ways in which they change immune cells called T cells is not known. Dr. Herold will study how successful immune therapy changes these cells. He anticipates that it will lead to the identification of markers that can be used to track the diseases’ development, as well as suggesting combination therapies that may be used to extend the effectiveness of immune therapy.
Scientific Abstract
It has been known for some time that Type 1 diabetes (T1D) and Multiple sclerosis (MS) are due to immune cell destruction of target organs but there is relatively little understood about the effector cells that are responsible for the pathologies. Moreover, the ways in which successful immune therapies modulate these cells have not been identified. A curious observation concerns the efficacy of anti-CD20 antibodies since they deplete B lymphocytes but the important effector cells are thought to be T lymphocytes. In this proposal we plan to analyze, in parallel, the transcriptome of antigen specific T cells from patients with T1D and MS using single cell platforms. Our selection of patients for study offer a unique opportunity to compare responses to disease relevant (e.g. beta cell autoantigens in T1D patients) and irrelevant (e.g. myelin autoantigens in T1D patients and vice versa) Class I MHC peptides as well as to common (viral) antigens to which robust responses are known to occur. We will also have the opportunity to compare responses in the CSF to the peripheral blood in patients with MS. This will provide insight into potential differences between tissue and peripheral antigen specific T cells which will be valuable for analysis of cells for both diseases. Finally, we will test the effects of anti-CD20 mAb on the antigen specific CD8+ T cells in both diseases comparing the responses of the antigen specific CD8+ T cells. These studies and comparisons that can be made between the autoimmune diseases will provide valuable information for evaluating the unique and common mechanisms that account for autoimmunity, the host and tissue specific factors that lead to autoimmune diseases, and the effects of immune therapy on autoreactive T cells. We anticipate that they will lead to the identification of biomarkers that can be used to track progression of disease and determine appropriate times for treatment as well as suggesting combination therapies that may be used to extend the efficacy of immune therapy.