Transplantation is the best therapy for end stage failure of many organs including kidney, heart and lungs. While short term outcomes of transplants are excellent, graft half-lives are suboptimal in large part because of chronic immune mediated injury. Our long term goal is to identify novel mechanisms of transplant injury so as to be able to apply them to develop therapuetic strategies to prolong transplant survival. Increasing evidence indicates that regulatory T cells (Tregs) could be harnessed to inhibit pathogenic anti-transplant immunity (in the absence of immune suppression) but mechanisms to accomplish this goal are hampered by inadequate understanding. Extending our previous work, our combined published and preliminary data demonstrate that complement components C3a and C5a (initially thought to be important only for innate immunity) signal via their receptors on both mouse and human Treg inhibiting induction, activation, and function whereas blockade markedly augments Treg induction, activation, function. To decipher the mechanistic connections between complement and Treg in transplantation we propose a series of studies using mouse and human cells and multiple in vivo transplant models in mice. We will use knockout and transgenic mice along with pharmacological inhibitors, blocking antibodies and knockdown technologies to a) determine the in vivo effects of C3aR/C5aR signaling on Treg in transplantation and b) To determine mechanisms linking C3aR/C5aR signaling with Treg induction and function. The expected outcomes are that we will delineate the effects of immune cell C3aR/C5aR signaling on the function of mouse Tregs in transplantation, define the molecular signaling pathways and mechanisms that explain the observed effects, and test how the murine findings translate to human Tregs. Together, the results are likely to identify novel and unanticipated immune mechanisms (innovation), and have a positive impact because they will provide new, mechanistic insight into Treg function and stability, and identify new therapeutic targets that have the potential to prolong transplant survival in humans.

Public Health Relevance

Immune mediated diseases including transplant rejection cause significant morbidity. Our studies will provide new information on how to control such immune responses in transplantation but the findings could be used to design therapies to treat T cell mediated autoimmune disease as well as to enhance protective immune responses, for example to infectious agents and or cancer (all relevant to the NIH mission)

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI071185-07
Application #
8715678
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kehn, Patricia J
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Cravedi, Paolo; van der Touw, William; Heeger, Peter S (2013) Complement regulation of T-cell alloimmunity. Semin Nephrol 33:565-74
van der Touw, William; Cravedi, Paolo; Kwan, Wing-hong et al. (2013) Cutting edge: Receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190:5921-5
Cravedi, P; Leventhal, J; Lakhani, P et al. (2013) Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant 13:2530-9
Kwan, Wing-hong; van der Touw, William; Paz-Artal, Estela et al. (2013) Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med 210:257-68
Heeger, Peter S; Kemper, Claudia (2012) Novel roles of complement in T effector cell regulation. Immunobiology 217:216-24
Vieyra, Mark; Leisman, Staci; Raedler, Hugo et al. (2011) Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection. Am J Pathol 179:766-74
Hashimoto, Daigo; Chow, Andrew; Greter, Melanie et al. (2011) Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J Exp Med 208:1069-82
Raedler, H; Vieyra, M B; Leisman, S et al. (2011) Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice. Am J Transplant 11:1397-406
Vieyra, Mark B; Heeger, Peter S (2010) Novel aspects of complement in kidney injury. Kidney Int 77:495-9
Bromberg, J S; Heeger, P S; Li, X C (2010) Evolving paradigms that determine the fate of an allograft. Am J Transplant 10:1143-8

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