Allogeneic blood or marrow transplantation (BMT) is a highly effective and potentially curative treatment for a number of hematopoietic malignancies due to the associated Graft versus Leukemia (GVL) effect. However, this beneficial GVL effect is frequently offset by the development of Graft versus Host Disease (GVHD). Development of GVHD is critically dependent on a systemic and local inflammatory response in GVHD target organs. We hypothesize that activation of early inflammatory signaling pathways in GVHD target organs controls recruitment of donor T cells to GVHD target organs (e.g. upregulation of adhesion molecules, chemokines) and induction of tissue damage. Therefore, identification of signaling pathways and candidate molecules may lead to novel approaches for future targeted therapy and prevention of GVHD. The Janus Kinase (JAK) - Signal activator of transcription (STAT) pathway is a major signaling pathway converting cytokine signals into gene expression programs regulating pro- and anti-inflammatory responses. Using rodent models of allogeneic BMT we have identified the activation of STAT1 and STAT3 to be an early event during the induction of GVHD in GVHD target organs. We propose that STAT1 and STAT3 are required mediators of inflammation in GVHD target organs and that conversely STAT1 and STAT3 may antagonize GVL effects. It is therefore the primary goal of this proposal to test the role of STAT1 and STAT3 in GVHD and GVL.
In Aim 1 we will study the requirement of STAT1 and STAT3 as mediators for GVHD addition using constitutive STAT1 or conditional STAT3 gene deficient mice and small molecule inhibitors of STAT1 and STAT3. GVHD will be induced following lethal irradiation in different immunogenetic host-donor disparities as well as in unconditioned mice. In addition using STAT1 or STAT3 gene deficient mice we will dissect the requirement of host versus donor STAT1/3 for the development of GVHD.
In Aim 2 we will study the role of STAT1 and STAT3 in regulating lymphohematopoietic GVH reactions and GVL effects in the absence or presence of conditioning-induced inflammation and will address the question whether manipulation of STAT1 or STAT3 might augment GVL effect.
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for a number of malignant and benign diseases of the hematopoietic system. Graft versus Host Disease (GVHD) and its complications are still the leading causes of morbidity and mortality after allogeneic stem cell transplantation. 15% to 50% of patients will die due to GVHD or infectious complications and precluding the widespread application of this potential curative treatment option. Therefore, it is of high significance to develop novel approaches, which allow to maintain Graft versus Leukemia (GVL) reactions, but diminish or prevent GVHD.
|Stenger, Elizabeth O; Rosborough, Brian R; Mathews, Lisa R et al. (2014) IL-12hi rapamycin-conditioned dendritic cells mediate IFN-ýý-dependent apoptosis of alloreactive CD4+ T cells in vitro and reduce lethal graft-versus-host disease. Biol Blood Marrow Transplant 20:192-201|
|Mapara, Markus Y (2013) The quest for the optimal conditioning regimen: some answers, more questions. Biol Blood Marrow Transplant 19:1275-6|
|Li, S; Fu, J; Ma, H et al. (2013) Lenalidomide-induced upregulation of CXCR4 in CD34+ hematopoietic cells, a potential mechanism of decreased hematopoietic progenitor mobilization. Leukemia 27:1407-11|
|Stenger, Elizabeth O; Turnquist, H?th R; Mapara, Markus Y et al. (2012) Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity. Blood 119:5088-103|
|Ma, Hui-Hui; Ziegler, Judy; Li, Cuiling et al. (2011) Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3. Cell Immunol 268:37-46|
|Ma, Huihui; Lu, Caisheng; Ziegler, Judith et al. (2011) Absence of Stat1 in donor CD4ýýý T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. J Clin Invest 121:2554-69|