Despite tremendous strides in transplantation over the past 60 years, with great advances in short-term graft survival, long-term survival is comparatively poor. This is likely due to the fact that immunosuppressive strategies, though clearly improved over the years, are not tolerogenic. True transplantation tolerance is likely to arise not from improved immunosuppression, but from developing novel strategies based on improved understanding of the physiologic mechanisms which maintain self-tolerance, and the barriers that mediate resistance to tolerance. Moreover, approaches for transplantation tolerance are likely to be applicable for the treatment of many autoimmune disorders as well. Our approach is based on the premise that the mechanisms which mediate peripheral self-tolerance may prove most easily exploited to generate tolerance alloantigens in adults. The overall theme is that the availability of novel t cell activation/differentiation signals, the cytokine milieu, and the presence or absence of inflammation collectively determine whether T cells will be directed towards regulation or effector/memory functions, and thus these parameters determine the ultimate outcome of the alloimmune response;rejection versus tolerance.
The aims of project #1 are designed to test the central hypothesis that the TIM-1 :TIM-4 pathway, by affecting Th1/Th2 cell differentiation, generation of effector/memory T cells, and possibly regulatory T cell generation and function, plays an important role in alloimmune and autoimmune responses and tolerance in the setting of islet transplantation.
The aims of project #2 are focused on the concept that two events occurring very early during the process of engraftment, inflammation and antigen encounter, determine graft outcome and tolerance susceptibility by modulating the balance between regulatory cells and effector/memory cells. Lastly, project #3 will study how the cytokine milieu determines the balance between the development of pathogenic T cells and tolerogenic regulatory cells. Together, these investigations should provide new insights into how alloimmune T cell responses are initiated and controlled. The results should yield useful new information that can be harnessed to develop novel tolerogenic strategies to test in primates and ultimately humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PA-I (M2))
Program Officer
Kehn, Patricia J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Fan, Martin Y; Low, Jun Siong; Tanimine, Naoki et al. (2018) Differential Roles of IL-2 Signaling in Developing versus Mature Tregs. Cell Rep 25:1204-1213.e4
Priyadharshini, Bhavana; Loschi, Michael; Newton, Ryan H et al. (2018) Cutting Edge: TGF-? and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets. J Immunol 201:2215-2219
Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212
Alessandrini, Alessandro; Turka, Laurence A (2017) FOXP3-Positive Regulatory T Cells and Kidney Allograft Tolerance. Am J Kidney Dis 69:667-674
Carlson, Alicia L; Fujisaki, Joji; Wu, Juwell et al. (2013) Tracking single cells in live animals using a photoconvertible near-infrared cell membrane label. PLoS One 8:e69257
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
Koulmanda, Maria; Bhasin, Manoj; Awdeh, Zuheir et al. (2012) The role of TNF-? in mice with type 1- and 2- diabetes. PLoS One 7:e33254
Harris, John E; Harris, Tajie H; Weninger, Wolfgang et al. (2012) A mouse model of vitiligo with focused epidermal depigmentation requires IFN-ýý for autoreactive CD8ýýý T-cell accumulation in the skin. J Invest Dermatol 132:1869-76
Lieberman, Scott M; Kim, Jiyeon S; Corbo-Rodgers, Evann et al. (2012) Site-specific accumulation of recently activated CD4+ Foxp3+ regulatory T cells following adoptive transfer. Eur J Immunol 42:1429-35
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

Showing the most recent 10 out of 123 publications