Medical Student Research Fellowship for Summer 2006
Mentor: Mark Siegelman, MD, PhD/Henrik Westergaard, MD
Department: Pathology/Gastroenterology (Internal Medicine)
Room number: NB6.412
Mail Code: 9072
Phone number: 8-4121
Project title: Utility of a Regulatory T Cell Marker in Inflammatory Bowel Disease
Human subjects IRB approved project number (where applicable):
#102005-035 (November 2005; modification to add Mr. Motiwala pending)
Animal subjects IRB approved project number (where applicable):
0554-05-05-1 (August 2005; modification to add Mr. Motiwala 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 Inflammatory Bowel Disease (IBD), CD44act on endogenous enteroantigen-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). The goals will be:
a) to determine whether endogenous CD44act positive T cells can be found and isolated from patients with IBD on the basis of this marker
b) whether these cells can be shown to be functional and more efficacious as regulatory T cells.
The student will work with Dr. Westergaard in GI clinic to develop skills related to patient-oriented research. He will pariticipate in patient assessment, study enrollment, and blood collection in clinic. In the laboratory, he will conduct PBMC isolations and functional characterization of PBMC, including 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 treating disease. 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.
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