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 #
5R01AI071185-02
Application #
7390675
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
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$409,986
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
Fribourg, M; Ni, J; Nina Papavasiliou, F et al. (2018) Allospecific Memory B Cell Responses Are Dependent on Autophagy. Am J Transplant 18:102-112
A Verghese, Divya; Demir, Markus; Chun, Nicholas et al. (2018) T Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell (TREG) Generation and TREG-Dependent Cardiac Allograft Survival. J Immunol 200:2186-2198
Llaudo, Ines; Fribourg, Miguel; Medof, M Edward et al. (2018) C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival. Am J Transplant :
Chun, N; Fairchild, R L; Li, Y et al. (2017) Complement Dependence of Murine Costimulatory Blockade-Resistant Cellular Cardiac Allograft Rejection. Am J Transplant 17:2810-2819
Sheen, Joong-Hyuk; Strainic, Michael G; Liu, Jinbo et al. (2017) TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement. J Immunol 199:278-291
Purroy, Carolina; Fairchild, Robert L; Tanaka, Toshiaki et al. (2017) Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival. J Am Soc Nephrol 28:2377-2392
Stamatiades, Efstathios G; Tremblay, Marie-Eve; Bohm, Mathieu et al. (2016) Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages. Cell 166:991-1003
Chun, Nicholas; Heeger, Peter S (2016) Blurring the Lines Between Innate and Adaptive Immunity. Transplantation 100:1789-1790
Mathern, Douglas R; Heeger, Peter S (2015) Molecules Great and Small: The Complement System. Clin J Am Soc Nephrol 10:1636-50
Sheen, Joong Hyuk; Heeger, Peter S (2015) Effects of complement activation on allograft injury. Curr Opin Organ Transplant 20:468-75

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