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. 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 will test mice with PTEN deficiency in GC B cells to determine whether heightened PI3K expression augments cGVHD. Conversely, we will test p110d and pan-PI3K inhibitors to determine whether targeting PI3K in GC B cells and cGVHD causing T cells can be used to prevent or treat cGVHD. We will test the hypotheses that the PD1 pathway members (aim 1A) and the novel PD-L2 receptor (RGMb) (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). This application represents a full collaboration between 4 laboratories: Dr. Blazar, Arlene Sharpe, Gordon Freeman and Larry Turka to work together to enable understanding of the roles of pathways costimulatory and coinhibitory pathways in regulating cGVHD and provide insights into how to develop novel strategies for manipulating these pathways to treat cGVHD.
Our goal is to develop clinically therapies to prevent and treat cGVHD which is a major source of morbidity and mortality post-transplant, limiting the more widespread use of this methodology for the treatment of malignant and non-malignant disorders.
|Ince, M Nedim; Blazar, Bruce R; Edmond, Michael B et al. (2016) Reply. Inflamm Bowel Dis 22:E27-8|
|Ince, M Nedim; Blazar, Bruce R; Edmond, Michael B et al. (2016) Understanding Luminal Microorganisms and Their Potential Effectiveness in Treating Intestinal Inflammation. Inflamm Bowel Dis 22:194-201|
|McDonald-Hyman, Cameron; Turka, Laurence A; Blazar, Bruce R (2015) Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation. Sci Transl Med 7:280rv2|
|Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan et al. (2015) Therapeutic activity of multiple common ?-chain cytokine inhibition in acute and chronic GVHD. Blood 125:570-80|