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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI056299-10
Application #
8712934
Study Section
Special Emphasis Panel (ZAI1-RJ-I (J1))
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$546,568
Indirect Cost
$89,100
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Xu, Jie; Sun, Heather H; Fletcher, Christopher D M et al. (2016) Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders. Am J Surg Pathol 40:443-53
Borges, Christopher M; Reichenbach, Dawn K; Kim, Beom Seok et al. (2016) Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival. Transpl Int 29:930-40
Chapuy, Bjoern; Roemer, Margaretha G M; Stewart, Chip et al. (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869-81
Schildberg, Frank A; Klein, Sarah R; Freeman, Gordon J et al. (2016) Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 44:955-72
Schönle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9
Flynn, Ryan; Paz, Katelyn; Du, Jing et al. (2016) Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood 127:2144-54
Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26
Hirakawa, Masahiro; Matos, Tiago; Liu, Hongye et al. (2016) Low-dose IL-2 selectively activates subsets of CD4(+) Tregs and NK cells. JCI Insight 1:e89278
Li, Wei; Liu, Liangyi; Gomez, Aurelie et al. (2016) Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 1:
Lo, Tsun-Ho; Silveira, Pablo A; Fromm, Phillip D et al. (2016) Characterization of the Expression and Function of the C-Type Lectin Receptor CD302 in Mice and Humans Reveals a Role in Dendritic Cell Migration. J Immunol 197:885-98

Showing the most recent 10 out of 257 publications