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.
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.
| Chaudhri, Apoorvi; Xiao, Yanping; Klee, Alyssa N et al. (2018) PD-L1 Binds to B7-1 Only In Cis on the Same Cell Surface. Cancer Immunol Res 6:921-929 |
| Ahn, Eunseon; Araki, Koichi; Hashimoto, Masao et al. (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:4749-4754 |
| Wu, Yongxia; Schutt, Steven; Paz, Katelyn et al. (2018) MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice. Blood 131:1974-1986 |
| Gartlan, Kate H; Bommiasamy, Hemamalini; Paz, Katelyn et al. (2018) A critical role for donor-derived IL-22 in cutaneous chronic GVHD. Am J Transplant 18:810-820 |
| Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57 |
| Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848 |
| Owen, David L; Mahmud, Shawn A; Vang, Kieng B et al. (2018) Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis. J Immunol 200:3926-3933 |
| Prestipino, Alessandro; Emhardt, Alica J; Aumann, Konrad et al. (2018) Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10: |
| Du, Jing; Flynn, Ryan; Paz, Katelyn et al. (2018) Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients. Blood 131:1743-1754 |
| Zeiser, Robert; Sarantopoulos, Stefanie; Blazar, Bruce R (2018) B-cell targeting in chronic graft-versus-host disease. Blood 131:1399-1405 |
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