The T cell immunoglobulin mucin (TIM) family of novel receptor-ligand pairs plays important roles in T cell activation, differentiation and effector function, and in regulation of immune responses in autoimmunity and allergy/asthma, but its functions in alloimmune responses are poorly defined. Our central hypothesis, supported by extensive preliminary data, is that the TIM-1 :TIM-4 pathway, by affecting T helper cell differentiation, play important roles in alloimmune responses and tolerance in vivo. In addition, data from our group and others suggest a possible role of the TIM family of molecules in the function of regulatory T cells. The main goal of this proposal is to define the role and understand the mechanisms of action of the TIM-1:TIM-4 pathway in regulating alloimmune responses in vivo as a means of achieving durable and reproducible tolerance in murine transplant models. Unique tools, including anti-TIM agonistic and blocking antibodies and fusion proteins, and gene knockout and TCR transgenic animals will be used to dissect the functions of the TIM-1 :TIM-4 pathway in alloimmunity using vascularized transplant models of acute and chronic rejection, and stringent models of skin transplantation. More specifically, the aims of the project are: 1. To investigate the functions of the TIM-1 :TIM-4 pathway in alloimmune responses in vivo. 2. To investigate the functions of the TIM-1 :TIM-4 pathway in chronic rejection. 3. To investigate the mechanisms of action of targeting the TIM-1 :TIM-4 pathway in alloreactivity and tolerance via defining the fate of alloreactive T cells in vivo. 4. To study the role of the TIM-1 :TIM-4 pathway in generation/function of Foxp3 regulatory T cells in vivo. Overall, our specific aims describe complimentary approaches that should lead to the development of innovative strategies to permit solid organ graft acceptance without chronic rejection to translate to primates and humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070820-04
Application #
7876993
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$408,625
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Ueno, Takuya; Yeung, Melissa Y; McGrath, Martina et al. (2012) Intact B7-H3 signaling promotes allograft prolongation through preferential suppression of Th1 effector responses. Eur J Immunol 42:2343-53
Ashoor, Isa F; Najafian, Nader (2012) Rejection and regulation: a tight balance. Curr Opin Organ Transplant 17:1-7
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
Yeung, M Y; McGrath, M; Najafian, N (2011) The emerging role of the TIM molecules in transplantation. Am J Transplant 11:2012-9
Ding, Qing; Yeung, Melissa; Camirand, Geoffrey et al. (2011) Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest 121:3645-56
Rong, Song; Park, Joon-Keun; Kirsch, Torsten et al. (2011) The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury. J Am Soc Nephrol 22:484-95
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
Boenisch, Olaf; D'Addio, Francesca; Watanabe, Toshihiko et al. (2010) TIM-3: a novel regulatory molecule of alloimmune activation. J Immunol 185:5806-19

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