The complement system, traditionally considered part of the innate immune repertoire has been implicated as a modulator of cell mediated allograft injury. Our group has further shown that alternative pathway complement components C3, factor D and factor B are produced and upregulated by T cells and by APCs during cognate interactions, and that a complement regulatory molecule, decay accelerating factor (DAF), modulates the strength of induced effector T cell responses. The physiologic importance of APC-expressed DAF is highlighted by the findings that T cell immunity is enhanced in the absence of DAF, this augmentation is alternative pathway complement dependent, and it is partially inhibited by administration of an anti-C5 mAb. Detailed mechanisms underlying these observations need to be worked out and signals initiating complement component production need to be determined, particularly in the context of transplantation. Our preliminary results support the following hypothesis: Cognate interactions between alloreactive T cells and APCs accompanied by costimulatory signals provided through CD28/CD80/86 results in production and release of alternative pathway complement by both partners, and complement activation at the T cell: APC interface. The locally produced complement split products, including anaphylotoxins C3a and C5a, bind to receptors on T cells and APCs, and in part, through upregulating cytokine secretion, function as requisite signals to optimally induce activation, expansion and differentiation of effector T cells and to limit apoptosis. Using state of the art cellular immunology, complementology and transplantation techniques we will test the molecular mechanisms underlying complement's modulatory effects on induction of alloreactive effector T cell immunity, 2) test the hypothesis that bone marrow cell derived complement and DAF are essential modulators of alloreactive T cell immunity, 3) determine the requirement for C3a and/or C5a and their receptors, C3aR and C5aR as modulators of alloreactive T cell immunity, and 4) test the hypothesis that locally produced and activated alternative pathway complement is an essential downstream intermediary of CD28-induced costimulation for alloreactive T cells. The findings will provide new basic insight into the physiology of T cell alloreactivity that is known to lead to acute and chronic transplant rejection and will potentially provide novel therapeutic targets to treat these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071185-04
Application #
7787068
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$424,521
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Cravedi, Paolo; Heeger, Peter S (2014) Complement as a multifaceted modulator of kidney transplant injury. J Clin Invest 124:2348-54

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