This application seeks support for elucidating the role of the SLAMF receptors in the pathogenesis of Systemic Lupus Erythematosus (SLE) with the ultimate goal to develop SLAMF-based therapeutic strategies that can be applied to SLE patients. Because of the outcomes of our studies with cells derived from SLE patients and our exciting findings with genetically altered mice, which develop lupus-related autoimmunity, we now have the systems in place to dissect how cell interaction mechanisms and signaling initiated by the SLAMF receptors contribute to the control of tolerance to autoantigens and to the pathogenesis of human SLE. These insights and tools are the basis for a Program Project application entitled: """"""""SLAM FAMILY RECEPTOR CONTROLLED PATHWAYS TO SLE"""""""" for three interlinked projects and two supporting Cores. P#1 The Slamf3, Slamf5 and Slamf6 receptor-induced pathways to murine lupus. P#2 Functional analyses of human and mouse SLAMF4SLAMF2 receptor / ligand interactions in murine and human SLE. P#3 Function of human SLAMF receptors in SLE immune cells. PL: Core A Genetic Mouse Core. Core B Administrative Core. In this Administrative Core we specifically propose to: SA#1. Nurture scientific interactions between the investigators in the three projects in the program through frequent meetings;particularly by streamlining the transition from mouse experiments to Translational Research with materials from SLE patients. SA#2. Facilitate the exchange of reagents, technical information and patient materials. SA#3. Facilitate administrative interactions between the members of the program.

Public Health Relevance

Results of these studies should lead to 1) better diagnostic tools to complement currently used indexes, 2) reliable and specific biomarkers to monitor and hopefully predict disease activitiy and 3) novel treatment protocols for SLE patients to replace or add to immunosuppresive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI065687-08
Application #
8733827
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Comte, Denis; Karampetsou, Maria P; Yoshida, Nobuya et al. (2017) Signaling Lymphocytic Activation Molecule Family Member 7 Engagement Restores Defective Effector CD8+ T Cell Function in Systemic Lupus Erythematosus. Arthritis Rheumatol 69:1035-1044
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2017) Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2. Arthritis Rheumatol 69:808-813
Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin et al. (2016) Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. J Immunol 196:4915-24
Cuenca, Marta; Romero, Xavier; Sintes, Jordi et al. (2016) Targeting of Ly9 (CD229) Disrupts Marginal Zone and B1 B Cell Homeostasis and Antibody Responses. J Immunol 196:726-37
Kis-Toth, Katalin; Comte, Denis; Karampetsou, Maria P et al. (2016) Selective Loss of Signaling Lymphocytic Activation Molecule Family Member 4-Positive CD8+ T Cells Contributes to the Decreased Cytotoxic Cell Activity in Systemic Lupus Erythematosus. Arthritis Rheumatol 68:164-73
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6
McArdel, Shannon L; Brown, Daniel R; Sobel, Raymond A et al. (2016) Anti-CD48 Monoclonal Antibody Attenuates Experimental Autoimmune Encephalomyelitis by Limiting the Number of Pathogenic CD4+ T Cells. J Immunol 197:3038-3048
McArdel, Shannon L; Terhorst, Cox; Sharpe, Arlene H (2016) Roles of CD48 in regulating immunity and tolerance. Clin Immunol 164:10-20
Wang, Ninghai; Keszei, Marton; Halibozek, Peter et al. (2016) Slamf6 negatively regulates autoimmunity. Clin Immunol 173:19-26
Chaudhary, Anu; Leite, Mara; Kulasekara, Bridget R et al. (2016) Human Diversity in a Cell Surface Receptor that Inhibits Autophagy. Curr Biol 26:1791-801

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