The Mapara Lab's research is primarily focused on developing new approaches to improve the outcome of patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation.
Role of STAT1 in GVHD
STAT1 is the major downstream signal transducer for type I and II interferons. Our lab is focusing on the question how STAT1 regulates GVHD. Regulatory CD4+CD25+Foxp3+ T cells (Treg) have been shown to be critical regulators of immune tolerance, inflammation, and autoimmunity. Given their potent suppressive effects in various preclinical models, freshly isolated or ex vivoexpanded Treg cells constitute a very attractive strategy for the treatment of various inflammatory conditions including Graft versus Host Disease (GVHD) following allogeneic blood or marrow transplantation (BMT). We have recently shown that 1) STAT1 inhibits expansion of natural Treg (nTreg) and inducible Treg (iTreg) ex vivo and in vivo; 2) ex vivo expanded STAT1-deficient Treg cells are more resistant to apoptosis and have a higher proliferative capacity than wildtype Treg leading to enhanced ex vivo expansion; 3) ex vivoexpanded STAT1-deficient Treg cells are superior in suppressing GVHD in vivo. We are now further evaluating how STAT1 regulates homing of Treg cells to GVHD target organs and whether STAT1-silencing can be used to promote expansion of Treg cells in vivo. In addition to the role of STAT1 in Treg cells we are working on how STAT1 affects GVL responses and host APC function following allogeneic BMT and its role in regulating tissue infiltration and destruction during the effector phase of GVHD.
Inhibition of inflammatory signaling pathways for prevention and treatment of GVHD: Identification of novel molecular targets
The major goal of this project is to identify promising molecular targets to inhibit the development of GVHD following allogeneic HSCT. We have shown that Histone Deacetylase (HDAC) Inhibitors can modulate the inflammatory response and attenuate development of GVHD following fully MHC-mismatched BMT. Using small molecule inhibitors we are planning to identify druggable targets which could help prevent or treat GVHD. Another aspect we are pursuing in the lab is the role of anti-inflammatory endogenous lipids (e.g. Resolvins) as modulators of GVHD in murine BMT models.
Regulation of Donor-Lymphocyte Infusion (DLI)-mediated GVL effects
Donor lymphocyte infusion (DLI) following allogeneic bone marrow transplantation (BMT) is a very potent form of immunotherapy and can lead to Graft versus Leukemia (GVL) effects in the absence of Graft versus Host Disease (GVHD). However, DLI-mediated GVL effects can be transient and relapse of the underlying malignancy is an important clinical problem. We have demonstrated in rodent BMT models that loss of GVL reactivity following DLI administration coincides with extinction of the alloreactive population. We are interested in determining the molecular mechanisms underlying the extinction of this alloreactive population with the goal of identifying molecular targets to achieve sustained GVL-effects.
Hui-Hui Ma, MD, PhD