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)
Type
Research Program Projects (P01)
Project #
5P01AI065687-08
Application #
8733827
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
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
Kis-Toth, Katalin; Tsokos, George C (2014) Engagement of SLAMF2/CD48 prolongs the time frame of effective T cell activation by supporting mature dendritic cell survival. J Immunol 192:4436-42
Romero, Xavier; Sintes, Jordi; Engel, Pablo (2014) Role of SLAM family receptors and specific adapter SAP in innate-like lymphocytes. Crit Rev Immunol 34:263-99
Sintes, Jordi; Cuenca, Marta; Romero, Xavier et al. (2013) Cutting edge: Ly9 (CD229), a SLAM family receptor, negatively regulates the development of thymic innate memory-like CD8+ T and invariant NKT cells. J Immunol 190:21-6
Keszei, Marton; Detre, Cynthia; Castro, Wilson et al. (2013) Expansion of an osteopontin-expressing T follicular helper cell subset correlates with autoimmunity in B6.Sle1b mice and is suppressed by the H1-isoform of the Slamf6 receptor. FASEB J 27:3123-31
Niewold, Timothy B; Kelly, Jennifer A; Kariuki, Silvia N et al. (2012) IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann Rheum Dis 71:463-8
Chatterjee, Madhumouli; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. J Immunol 188:1206-12
Rivas, Manuel A; Beaudoin, Melissa; Gardet, Agnes et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43:1066-73
Chatterjee, Madhumouli; Kis-Toth, Katalin; Thai, To-Ha et al. (2011) SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells. Autoimmunity 44:211-8
Keszei, Marton; Latchman, Yvette E; Vanguri, Vijay K et al. (2011) Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice. Int Immunol 23:149-58
Brown, Daniel R; Calpe, Silvia; Keszei, Marton et al. (2011) Cutting edge: an NK cell-independent role for Slamf4 in controlling humoral autoimmunity. J Immunol 187:21-5

Showing the most recent 10 out of 31 publications