The mer/axl/tyro3 subfamily of tyrosine kinases (TAM kinases) plays a powerful role in regulating activation of macrophages, dendritic cells, and NK cells by diverting cytokine production from inflammatory to noninflammatory cytokines. These receptor kinases bind to phospholipid-binding proteins which in turn bind to phospholipids, notably phosphatidylserine on apoptotic cells. These signaling molecules can thus down regulate innate immunity when they bind to dying cells or other phospholipid-containing debris. We propose to perform the first studies of these important molecules in humans and in human disease. The central hypothesis of this proposal is that these key regulatory molecules can be harnessed as potential targets for immunotherapy of lupus and other inflammatory and autoimmine disorders. The first Specific Aim is to define which human immune cells - and subsets of cells - express these molecules. In the second Aim, we will ask how expression is regulated during immune activation and cell maturation. We are especially interested in the possibility that the immunomodulatory role of immune complexes might be mediated through mer, and that the composition of immune complexes, notably their phospholipid content, may be of importance in mer cross linking. In the third Specific Aim, we will test whether cross linking of mer/axl/tyro3 (individually and together) leads to down regulation of macrophage, dendritic cell, NK cell, and lymphocyte activation in vitro. These studies will lead the way to developing an important potential therapeutic target for treatment of autoimmune and inflammatory disorders. In the fourth Specific Aim, we will examine expression of these molecules in human SLE peripheral blood, hypothesizing that this autoimmune condition may be characterized by increased expression of these kinases. We will ask whether the overexpression of type I interferon-related genes (the lupus "signature") can be diminished by cross linking of these immunoregulatory kinases. Such experiments may give support to the notion that therapeutic ligation of these receptor kinases could be used to control autoimmunity and inflammation.

Public Health Relevance

These studies are relevant to the overall mission of the ACE as they will contribute to understanding of a specific autoimmune disorder but will very likely have applications to other disases and to immunoregulation in humans in general. They are related to the T-cell cytokine polarization studies in that macrophage and DC activation is key to this process;and to the proposed stem cell transfer experiments looking at SLE immunoregulatiory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082726-05
Application #
8468110
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$198,164
Indirect Cost
$50,687
Name
Thomas Jefferson University
Department
Type
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Shao, Wen-Hai; Zhen, Yuxuan; Finkelman, Fred D et al. (2014) The Mertk receptor tyrosine kinase promotes T-B interaction stimulated by IgD B-cell receptor cross-linking. J Autoimmun 53:78-84
Zizzo, Gaetano; Cohen, Philip L (2013) IL-17 stimulates differentiation of human anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 and glucocorticoids. J Immunol 190:5237-46
Fitzgerald, Denise C; Fonseca-Kelly, Zoƫ; Cullimore, Melissa L et al. (2013) Independent and interdependent immunoregulatory effects of IL-27, IFN-?, and IL-10 in the suppression of human Th17 cells and murine experimental autoimmune encephalomyelitis. J Immunol 190:3225-34
Vuyyuru, Raja; Liu, Hongqi; Manser, Tim et al. (2011) Characteristics of Borrelia hermsii infection in human hematopoietic stem cell-engrafted mice mirror those of human relapsing fever. Proc Natl Acad Sci U S A 108:20707-12
Shao, Wen-Hai; Zhen, Yuxuan; Rosenbaum, Joshua et al. (2010) A protective role of Mer receptor tyrosine kinase in nephrotoxic serum-induced nephritis. Clin Immunol 136:236-44
Shao, Wen-Hai; Kuan, Anita P; Wang, Charlie et al. (2010) Disrupted Mer receptor tyrosine kinase expression leads to enhanced MZ B-cell responses. J Autoimmun 35:368-74
Gran, B; Yu, S; Zhang, G X et al. (2010) Accelerated thymocyte maturation in IL-12R?2-deficient mice contributes to increased susceptibility to autoimmune inflammatory demyelination. Exp Mol Pathol 89:126-34
Suh, Chang-Hee; Hilliard, Brendan; Li, Sophia et al. (2010) TAM receptor ligands in lupus: protein S but not Gas6 levels reflect disease activity in systemic lupus erythematosus. Arthritis Res Ther 12:R146
Ciric, Bogoljub; El-behi, Mohamed; Cabrera, Rosalyn et al. (2009) IL-23 drives pathogenic IL-17-producing CD8+ T cells. J Immunol 182:5296-305