Bone marrow transplant (BMT) is a potentially curative therapy for a variety of hematological malignancies, but its application is limited by the high incidence of graft versus host disease (GVHD), and immune complication whereby donor cells attack host tissues. GVHD is even more common in aged recipients, which, in combination with their increased susceptibility to chemotherapy- and radiation-induced injury, makes treating older patients with hematologic malignancies a significant challenge. The increase in GVHD has been shown to be due to the increased stimulatory capacity of older antigen presenting cells (ARC), the cells that activate donor T cells to cause host tissue injury. Our data implicate the enzyme indoleamine 2,3-dixogyenase (IDO) as a critical mediator of GVHD suppression. In addition, our preliminary results indicate IDO may act by decreasing the stimulatory capacity of APC, leading to fewer activated donor T cells and less tissue damage. Therefore, we hypothesize that decreasing the stimulatory capacity of aged APC via the induction of IDO will significantly improve GVHD outcomes. This application proposes a series of experiments designed to determine the site, cell type, and action of IDO expression during GVHD and whether suboptimal IDO activity explains the increased stimulatory capacity of older APC and their heightened ability to cause GVHD. We will analyze IDO expression by immunohistochemical staining and test functional significance using murine GVHD models comparing wild-type recipients to recipients that are genetically deficient in IDO. We also propose to develop novel methods of GVHD inhibition using the IDO pathway, both by inducing IDO pretransplant and by administering kynurenine metabolites, the downstream products of IDO activity. We will test these treatments in young and aged mice to determine their potential efficacy in treating human disease. ? ?
Bone marrow transplant remains the best treatment for many malignant diseases, but its use is restricted because of a common and serious side effect called graft versus host disease (GVHD), which is especially severe in older patients. By studying the positive and negative signals required for the generation of GVHD, we hope to identify new targets for GVHD therapy and prevention, thus allowing wider use of potentially curative bone marrow transplants. Specifically, we will study the ability of an immunosuppressive enzyme known as IDO to suppress GVHD in aged recipients. ? ? ?
| Jasperson, Lisa K; Bucher, Christoph; Panoskaltsis-Mortari, Angela et al. (2009) Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114:5062-70 |
