. Our goal is to develop new therapies for chronic GVHD (cGVHD). We developed a new cGVHD model of multi-organ system injury and advanced the field by making the important observation that IgG deposition in tissues causes cGVHD. Germinal centers (GCs) are sites where B cells produce plasma cells (PCs) that secrete immunoglobulin (Ig). GC formation is supported by Tfollicular helper (TFH) and TH17 cells, and suppressed by Tfollicular regulatory (TFR) cells. Our central hypothesis is that cGVHD is modulated by the balance between GC facilitating and suppressing cells, which may be regulated by PD-1 and CD28 signals. Dr. Freeman discovered the PD-1 ligand, PD-L1, binds to B7-1 while PD-L2 binds to repulsion guidance molecule b (RGMb). PD-L2 is expressed on Th2,Th0 and bronchial epithelial cells, a cGVHD target. RGMb is expressed on lung interstitial APCs and bronchial epithelial cells. Blocking the RGMb/PD-L2 pathway precludes respiratory tolerance;its role in cGVHD is unknown. While the PD-1 blockade worsens acute GVHD, strikingly, it is highly effective in treating cGVHD, perhaps because PD-1 blockade releases the restraint on TFR suppressor function (Pr1). cGVHD results in high TFHs and low TFRs. T cells can upregulate PD-L1, which inhibits TH17 facilitated cGVHD. Dr. Kuchroo discovered that TH17 cells express endothelial protein receptor C (PROCR), which limits TH17 effector function. We hypothesize PROCR upregulation in cGVHD is designed to control immune responses. Activated protein C (aPC), a PROCR ligand, has potent anti- inflammatory effects. PD-1 blockade can alter CD28 signaling, stability and function, modulating regulatory T cells (Tregs), B cells and PCs. Conditionally targeting CD28 affected TFHs, TH17s, TFRs and GCs. The role of CD28 on this balance and is unknown but important to discern prior to cGVHD trials. TCR/CD28 and IL-2R signaling via the phosphatidylinositol 3-kinase (PI3K) pathway are essential for T cell activation, and their transcriptional programming, affecting T cell metabolism. Resting and activated Tnaive, Teffectors (Teffs), Tmemory and Tregs use distinct energy pathways. PD-1 ligation, which prevents PI3K activation, blocks CD28-mediated upregulation of glucose metabolism. After determining metabolism pathways in cGVHD, we will pursue perturbations favoring TFRs vs TFHs and GC B cells. The lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10) is the primary PI3K inhibitor. We created mice with a Treg-specific PTEN deletion to test the hypothesis that such Tregs will destabilize TFR, while small molecule PI3K inhibitors will improve TFR stability, function and PD-1 blockade efficacy. We will test the hypotheses that the PD1 pathway members (aim 1A) and the novel PD-L2 receptor (RGMb) and a regulator of TH17 pathogenicity (PROCR) (1B) uniquely alter GC formation and cGVHD pathogenesis. We will test the hypotheses that signals from CD28 and receptors that activate PI3K modulate cGVHD via TFH/TFR balance (2A). We will test the hypothesis that favoring lipid oxidation (vs glycolysis) in cGVHD mice will restore TFH/TFR balance (2B).

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard Medical School
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