This PPG was initiated in 1998 in response to a RFA for """"""""Human Immunology Centers of Excellence"""""""" and has a well-defined, central focus on the mechanisms of antigen presentation and T cell recognition in human autoimmune diseases, in particular multiple sclerosis (MS) and type 1 diabetes (T1D). Antigen presentation is an integral component of every autoimmune disease process and thus represents an important scientific and clinical problem. The six investigators who come together in this PPG have highly complementary areas of expertise and have formed a cohesive, multidisciplinary program under the guidance of the Program Director. During the present funding period this group has been highly productive, documented by numerous joint publications that have had a significant impact on the field. The overarching hypothesis is that the development and progression of autoimmune diseases are controlled by specialized populations of antigen presenting cells that serve distinct roles in tolerance induction versus propagation of autoimmunity. There are four major themes that connect the individual projects of this PPG. A previously unrecognized population of lymph node stromal cells with functional similarities to thymic medullary epithelial cells induces peripheral tolerance by expression of a wide variety of peripheral tissue antigens, and the biology of this cell population and potential therapeutic applications will be investigated (Projects 1 &2). The role of self-reactive B cells as efficient antigen presenting cells for T cells with the same specificity will be examined in a new mouse model that resembles a severe subtype of MS. New technologies, including a nanowell technique for functional definition of B cell populations at a single cell level and fluorescent self-antigen tetramers, will be used to define the functional properties of self-reactive B cells in patients with MS and T1D (Projects 3 &4). Particular emphasis will be placed on definition of the antigen presentation mechanisms responsible for T cell differentiation into regulatory and effector T cell subsets (Projects 1-3) and on characterization of the unique recognition and signaling properties of self-reactive T cells isolated from patients with MS and T1D (Projects 1 &4). During the past two funding cycles, the program has already had an impact on the development of therapeutics, and the areas of investigation for the next funding period offer a significant number of new opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045757-14
Application #
8316147
Study Section
Special Emphasis Panel (ZAI1-SR-I (S2))
Program Officer
Esch, Thomas R
Project Start
1999-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$1,768,700
Indirect Cost
$323,573
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Lowther, Daniel E; Goods, Brittany A; Lucca, Liliana E et al. (2016) PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1:
Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6
Astarita, Jillian L; Cremasco, Viviana; Fu, Jianxin et al. (2015) The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol 16:75-84

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