We, and others, have shown that the negative T cell costimulatory pathways play a critical role in regulating alloimmune responses and tolerance. Our overall hypothesis is that the integration of positive and negative signals delivered by allogeneic hematopoietic and/or parenchymal cells under inflammatory conditions dictates tolerance vs tissue destruction. Our main goal is to define the relationship between these signals at the tissue level and outcome of alloantigen exposure during graft-vs-host disease (GVHD) and organ grafting models. Lessons learned from these distinct but interrelated and complementary models will further our understanding of the mechanisms of GVHD and organ allograft rejection and tolerance. These studies will lead to development of novel therapeutic strategies by harnessing the physiologic mechanisms that regulate immune responses. We propose to address three questions: 1) What is the role of hematopoietic vs parenchyma cell expression of negative costimulatory molecules in alloimmunity and tolerance? 2) What are the important and unique interactions between positive and negative costimulatory pathways that determine the fate of alloimmune response in an inflammatory environment? 3) What are the effects and mechanisms of targeting of these pathways in preclinical models of alloimmune responses? Our specific aims are:
AIM 1 : To investigate the functions of the PD-1:PD-L1,-L2 negative costimulatory pathway in GVHD and solid organ transplants. 1A. Study the role of the PD-1 pathway in GVHD focusing on the parenchymal vs hematopoietic cell expression of PD-1 ligands in regulating alloimmunity. 1B. Study the role of PD-1 pathway interactions with the CD28/B7 positive T cell costimulatory pathway that augments and donor Tregs that suppress GVHD. 1C: To investigate the functions and mechanisms of PD-1:PD-L1 and B7-1/PD-L1 interactions in alloimmune responses in models of solid organ transplantation.
AIM 2 : To investigate the functions of B7-H3 expression on hematopoietic vs parenchymal cells during GVHD (2A). In order to define the exact functions of this novel pathway in alloimmunity we plan to characterize the B7-H3 receptor, TLT2, and clone a putative second and inhibitory B7-H3 receptor (2B). We have a number of unique tools that will enable us to dissect the functions, mechanisms, and interactions of negative and positive costimulatory pathways and the microenvironment that will permit the optimal targeting of costimulatory pathways to inhibit detrimental T cell alloresponses that limit hematopoietic and solid organ allograft acceptance.

Public Health Relevance

The results of our studies should have major implications for the understanding of the physiologic pathways that regulate alloimmune responses and provide the rationale to develop novel therapeutic strategies to prevent and treat GHVD, and induce tolerance in solid organ and cell transplantation.

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-RJ-I (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
Flynn, Ryan; Du, Jing; Veenstra, Rachelle G et al. (2014) Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 123:3988-98
Penaloza-MacMaster, Pablo; Kamphorst, Alice O; Wieland, Andreas et al. (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211:1905-18
Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian et al. (2014) Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant 20:173-82
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Xiao, Yanping; Yu, Sanhong; Zhu, Baogong et al. (2014) RGMb is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance. J Exp Med 211:943-59
Porichis, Filippos; Hart, Meghan G; Zupkosky, Jennifer et al. (2014) Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol 88:2508-18
Mott, Kevin R; Allen, Sariah J; Zandian, Mandana et al. (2014) Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. PLoS One 9:e87617
Joller, Nicole; Lozano, Ester; Burkett, Patrick R et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40:569-81
Alexander, Kylie A; Flynn, Ryan; Lineburg, Katie E et al. (2014) CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest 124:4266-80
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53

Showing the most recent 10 out of 152 publications