Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. An ideal anti-inflammatory therapy for MS should be one that is neural antigen-specific, i.e., it suppresses only inflammatory cells that cause neural tissue injury but not those that protect against infections. Recently, major advances have been made in our understanding of a naturally occurring lymphocyte subset called regulatory T (Treg) cells that are used precisely by the immune system to perform antigen-specific immunosuppression. They play indispensable roles in maintaining health since their deficiency in mice and humans causes fatal inflammatory diseases. They may also be directly involved in the pathogenesis of MS since their functions and numbers are significantly reduced in patients studied by several groups. More importantly, a number of laboratories including ours have shown that adoptive transfer of myelin-specific Treg cells effectively prevents and ameliorates experimental autoimmune encephalomyelitis, a model for MS, in a myelin-specific manner, not affecting immunity against unrelated antigens. These new advances have led to the recognition that transfusion of myelin-specific Treg cells represents an ideal form of adoptive cell therapy for MS. However, Treg cells are still among the least understood T cell subsets, and consequently the most difficult to use for therapeutic applications. This proposal is inspired by recent discoveries from several laboratories including ours that c-Rel, the lymphoid member of the nuclear factor-?B family and a risk factor for human inflammatory diseases, is a key controller of Treg cell development and function. The objectives of this proposal are to (i) determine how c-Rel turns on Foxp3 gene to initiate Treg cell differentiation, (ii) determine how Foxp3 terminates c-Rel activity to stabilize Treg cell function and (iii) develop a new combination therapy for autoimmune encephalomyelitis by targeting the c-Rel-Foxp3 axis.

Public Health Relevance

These studies will not only help advance our understanding of the pathogenesis of autoimmune diseases such as MS, but also aid in developing a new combination therapy for the treatment of MS. Therefore, this project should advance both scientific knowledge and clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099216-02
Application #
8664789
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2013-05-25
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$400,000
Indirect Cost
$150,000
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lou, Yunwei; Sun, Honghong; Morrissey, Samantha et al. (2014) Critical roles of TIPE2 protein in murine experimental colitis. J Immunol 193:1064-70