The ultimate goal of designing new immunomodulatory therapies for transplantation is the induction and maintenance of a state of donor- specific immunologic tolerance. The main goal of the project is to study the role of novel T cell costimulatory pathways in regulating alloimmune responses in vivo. T cell costimulatory blockade directed at the CD28-B7 and/or CD154-CD40 pathways, while effective in some rodent models, may not be effective in reproducibly inducing tolerance in murine transplant models, and in primates. We hypothesize that this may be due to several mechanisms including the functions of other T cell costimulatory pathways, and/or this may be due to several mechanisms including the functions of other T cell costimulatory pathways, and/or B7/CD154 costimulation blockade resistant CD8+ alloreactive T cells or memory T cells. In this project, we will focus on studying the functions of the ICOS/B7h, CD134-CD134L (OX40-OX40L) and CD27-CD70 T cell costimulatory pathways because of their established unique functions in immune responses. We have a number of unique and important tools that will enable us to dissect the functions, mechanisms, and interactions of these novel costimulatory pathways in regulating alloimmune responses in vivo. We have made available gene knockout animals (ICOS and CD134L), a transgenic animal that constitutively expresses ICOS on T cells (ICOS/c), and CD8+ and CD4+ transgenic mice that are alloreactive to specific class I and class II MHC antigens, respectively. We also have monoclonal antibodies and fusion proteins directed at the newly identified T cell co-stimulatory molecules (ICOSL/B7h, CD134L, CD70). We plan to study th functions of the three noel T cell costimulatory pathways and dissect their interactions 3ityh the CD28/CDTLA-4-B7-1/B7-2 and CD154-CD450 pathways, with the goal of achieving and defining the mechanisms of transplantation tolerance in murine vascularized cardiac and skin (as a stringent model) transplantation models. Understanding the functions of th new T cell costimulatory pathways in alloimmune responses is important development of novel strategies to induce transplantation tolerance to translate to primates and ultimately humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI051559-01
Application #
6464775
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kehn, Patricia J
Project Start
2002-04-15
Project End
2007-03-31
Budget Start
2002-04-15
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$344,081
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Riella, Leonardo V; Sayegh, Mohamed H (2013) T-cell co-stimulatory blockade in transplantation: two steps forward one step back! Expert Opin Biol Ther 13:1557-68
Zhao, X; Boenisch, O; Yeung, M et al. (2012) Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. Am J Transplant 12:90-101
Riella, L V; Paterson, A M; Sharpe, A H et al. (2012) Role of the PD-1 pathway in the immune response. Am J Transplant 12:2575-87
Riella, L V; Liu, T; Yang, J et al. (2012) Deleterious effect of CTLA4-Ig on a Treg-dependent transplant model. Am J Transplant 12:846-55
Riella, L V; Watanabe, T; Sage, P T et al. (2011) Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts. Am J Transplant 11:832-40
D'Addio, Francesca; Riella, Leonardo V; Mfarrej, Bechara G et al. (2011) The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance. J Immunol 187:4530-41
Yang, Jun; Riella, Leonardo V; Chock, Susanne et al. (2011) The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 187:1113-9
Pilat, Nina; Sayegh, Mohamed H; Wekerle, Thomas (2011) Costimulatory pathways in transplantation. Semin Immunol 23:293-303
Riella, Leonardo V; Ueno, Takuya; Batal, Ibrahim et al. (2011) Blockade of Notch ligand ?1 promotes allograft survival by inhibiting alloreactive Th1 cells and cytotoxic T cell generation. J Immunol 187:4629-38
Fiorina, Paolo; Jurewicz, Mollie; Vergani, Andrea et al. (2011) Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1. J Immunol 186:121-31

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