Transplantation is a life-saving procedure for patients with end-stage organ failure. Current immuno- suppression is associated with significant morbidity and a high incidence of chronic transplant dysfunction, rendering the induction of antigen-specific tolerance a desirable alternative. Therapeutic manipulation of the TIM molecules is thought to have great tolerogenic potential. In contrast to the other TIM family members, TIM- 4 is primarily expressed on APCs, including CD11c+ DCs and macrophages. Although in vitro studies utilizing TIM-4 Ig fusion proteins demonstrate that it binds costimulator ligands on T cells, the results are conflicting and the nature of costimulatory signals not well defined. Furthermore, as these co-cultures lacked APCs, the physiological role of TIM-4 on DCs was not examined. TIM-4 has also recently been identified as a phosphatidylserine receptor, capable of modulating the immune system by directing engulfment of apoptotic bodies. The relative contribution of these roles in directing immune responses remains unclear. The primary objective of this application is to address the role of TIM-4 in alloimmunity. We show that antibody-mediated blockade of TIM-4 induces long-term islet allograft survival, suggesting that TIM-4 plays a major role in regulating alloimmunity in vivo. We have also discovered that TIM-4 defines functionally distinct DC subsets involved in the determination of T helper cell fate. Furthermore, TIM-4 blockade inhibits both TIM-4 signaling initiated by TIM-4+ DCs and phagocytosis mediated by macrophages, resulting in the splenic accumulation of apoptotic bodies and a shift of phagocytic duty from macrophages to DCs. The relative contribution of these functions to the marked effect of anti-TIM-4 on graft survival is unknown and is the central focus of this proposal. We hypothesize that the graft prolongation achieved by anti-TIM-4 is due to inhibition of TIM-4 signaling to DCs and/or inhibition of T cell costimulation. Alternatively, TM-4 blockade may alter the activation status of DCs/macrophages and, consequently, allograft survival, by shifting the responsibility of apoptotic cell phagocytosis from macrophages to DCs. Thus, the specific aims are: 1. What is the role of TIM-4 in the regulation of DC phenotype and function? 2. What is the role of TIM-4 on DCs versus macrophages in allograft survival? 3. What are the mechanisms whereby TIM-4 regulates the fate of alloreactive T cells in vivo? These studies will not only provide brand new basic insight into the immunobiology of DCs and Th differentiation, but will allow us to optimize strategies for promoting allograft survival, by selectively inhibiting TIM-4 function on DCs and/or macrophages. Moreover, the insights gained from the proposed studies will have broad therapeutic potential, including the development of tolerogenic strategies in autoimmunity and allergy, while manipulation of this molecule could also be used to enhance the immune response, which would be useful in states of relative immunodeficiency (cancer and chronic infection) and in vaccine development.

Public Health Relevance

TIM-4, a molecule expressed on a subset of immune cells, plays a crucial role in determining how the immune system responds to a transplant. We now seek to investigate the mechanisms, by which this is achieved, a key step towards being able to harness its therapeutic potential to improve patient and transplant survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI101150-01A1
Application #
8707632
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Kehn, Patricia J
Project Start
2013-08-20
Project End
2014-07-31
Budget Start
2013-08-20
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$312,374
Indirect Cost
$125,832
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Yeung, Melissa Y; Najafian, Nader; Sayegh, Mohamed H (2014) Targeting CD28 to prevent transplant rejection. Expert Opin Ther Targets 18:225-42
Yeung, Melissa Y; McGrath, Martina M; Nakayama, Masafumi et al. (2013) Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival. J Immunol 191:4447-55