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.
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.
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|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|
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|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|
|Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih et al. (2016) A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells. Oncotarget 7:26346-60|
|Sage, Peter T; Ron-Harel, Noga; Juneja, Vikram R et al. (2016) Suppression by TFRcells leads to durable and selective inhibition of B cell effector function. Nat Immunol 17:1436-1446|
|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|
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