Medical Student Research Fellowship for Summer 2007
Mentor: Mark Siegelman, M.D., Ph.D.
Department: Pathology
Room number: NB6.412
Mail Code: 9072
Phone number: 8-4121
E-mail: mark.siegelman@utsouthwestern.edu
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)
Patient-based research
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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