Graft Versus Host Disease and Anti-tumor Activity

Lisbeth Welniak, Ph.D. (University of Nevada, Las Vegas)

Graft versus Host Disease (GVHD) is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (HSCT). Current management of GVHD relies on global depletion or suppression of T cells, the cell type responsible for disease. However, allogeneic HSCT provides beneficial anti-tumor effects that are mediated by T cells.

Greater understanding of the mechanisms involved in GVHD is necessary to prevent or minimize the disease without losing the associated graft-versus-tumor (GVT) activity of the graft. The role of interleukin-12 (IL-12) in GVHD has been studied and both positive and negative effects have been attributed to cytokine. Recent reports have shown that strategies that depleted IL-12 would have also depleted IL-23, a cytokine that shares a common p40 subunit with IL-12. I have found, using p40 deficient mice, that the combined loss of IL-12 and IL-23 ameliorations GVHD as would be expected. In striking contrast, loss of IL-12 alone (in IL-12 p35 deficient mice) exacerbates disease. This project will define the effects of IL-12 and IL-23 in murine bone marrow transplant models of acute GVHD and determine the mechanism(s) for the immunostimulatory and immunosuppressive activities of IL-12 and IL-23. I will use mice that are disparate at both MHC major and minor antigens and available as IL-12 wild type, p40 deficient or IL-12 p35 deficient animals to characterize and quantify alloreactive T cell expansion, Th1/Th2 polarization and tissue-specific disease associated injury. I will also assess endogenous IL-12 and IL-23 for allogeneic anti-tumor effects and their association with GVHD in the murine models examined in specific aim 1. The overall goal is to determine if IL-12 and/or IL-23 are potential targets for therapeutic modulation to promote the anti-tumor activity of allogeneic hematopoietic stem cell transplants while diminishing the incidence or severity of GVHD.