Medical Student Research Fellowship for Summer 2007
Mentor: Mark Siegelman, M.D., Ph.D.
Room number: NB6.412
Mail Code: 9072
Phone number: 8-4121
Project title: Activation Markers of Regulatory T cells in Autoimmune Disease
Human subjects IRB approved project numbers (where applicable):
102006-035 and 0103-061 (November 2006; modification to add Ms. Vigeland pending)
Animal subjects IRB approved project number (where applicable):
0554-06-07-1 (May 2006; will be updated to 0554-07-07-1 in June 2007; modification to add Ms. Vigeland pending)
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects)
Brief Description of Project:
We have described a form of the CD44 receptor (CD44act) that initiates the extravasation of T lymphocytes into inflamed tissues via its interaction with its endothelial ligand hyaluronan (HA). Our studies demonstrate that this ligand-binding form of CD44 serves as an in vivo marker for a discrete state of regulatory T cell activation and enhanced regulatory function and that it is unique in this regard (1). This is consistent with our parallel observation of high levels of CD44act on the well-characterized subset of "naturally-occurring" CD4CD25+ Treg from normal mice and humans after in vitro activation. Based on our results indicating that Treg have a predilection for expression of CD44act compared to T effector counterparts, and the correlation of this expression with superior regulatory function, we hypothesize that in patients with autoimmune conditions (Inflammatory Bowel Disease (IBD), and adult Rheumatoid Arthritis, currently being pursued), CD44act on endogenous entero-or-auto-antigen-specific Treg will identify the most highly efficacious Treg for therapeutic use. The student will be involved in assessing the existence and characterization of cells expressing CD44act in peripheral blood of patients with IBD (Ulcerative Colitis, Crohn's disease) and RA. We have recently demonstrated enrichment of the CD44act bearing cells in the CD4CD25+ subsets, consistent with the "naturally occurring" Treg subset, and have begun to assess regulatory function in in vitro assays. The current goals will be:
a) to further characterize the endogenous CD44act positive T cells found in autoimmune conditions, and determine their association with disease status/severity.
b) isolate this small T cell subset for functional assessment in proliferation and other assays, and
c) assist in developing protocols for expansion of these T cell subsets in vitro, for more intensive characterization, and in anticipation that these cells will be of clinical utility in the future.
She will work with Dr. Westergaard in GI clinic and Valerie Branch in Arthritis clinic to develop skills related to patient-oriented research. She will participate in patient assessment, study enrollment, and blood collection in clinic. In the laboratory, she will conduct PBMC isolations and functional characterization of PBMC, including separation techniques for various T cell subsets, among these magnetic bead separations, flow cytometry, laminar flow adhesion analyses, and in vitro assays for regulatory T cell function. The student may also participate in parallel studies using mouse models of IBD to directly validate the therapeutic utility of this select T cell population in disease modulation. Direct demonstration, in a clinical context, of the ability of these cells to down-regulate autologous T effector cells would represent a significant finding with respect to management and treatment of autoimmune disease.
1. Firan, M., Dhillon, S., Estess, P., and Siegelman, M. 2006. Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood 107:619-627.
Previous Research Activities or Publications with Medical Students:
Summer, 2006: Rajesh Shah (Motiwala), Medical Student Research Fellow
November 2006 - present: Rajesh Shah: part-time student researcher.
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