James L. M. Ferrara, M.D.
Professor, Departments of Internal Medicine and Pediatrics
Director, Combined Bone Marrow Transplant Program

ferrara@umich.edu

My laboratory investigates the immunobiology of bone marrow transplantation (BMT). A major therapeutic benefit of allogeneic BMT resides in the graft versus leukemia (GVL) effect which is mediated by cytotoxic pathways of cytolytic T cells and natural killer cells. The GVL effect is tightly linked to graft versus host disease (GVHD), a major toxicity of BMT. Using well defined mouse models, our research has shown that cascades of inflammatory cytokines amplify GVHD and that blockade of cascade checkpoints can prevent GVHD. Furthermore, many of these anti-inflammatory strategies preserve cytolytic T lymphocyte function, permitting a separation of GVL and GVHD in well defined animal models.

We have recently determined that epithelial targets of GVHD are damaged primarily by cytokines and that neutralization of cytokines can suppress the inflammation of GVHD but preserve beneficial graft versus tumor effects. We have also shown that histone deacetylase inhibitors can prevent inflammatory cytokine release while preserving CTL function and GVL effects. We are investigating the mechanisms of these exciting new strategies with the intent of designing innovative clinical trials.

Representative Publications

Ordemann R, Hutchinson R, Friedman J, Burakoff SJ, Reddy P, Duffner U, Braun TM, Liu C, Teshima T, Ferrara JLM. Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease. Journal of Clinical Investigation, 109:1249-1256, 2002.

Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR, Ferrara JLM. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nature Medicine, 8:575-581, 2002.

Reddy P, Maeda Y, Hotary K, Liu C, Reznikov L, Dinarello C, Ferrara JLM. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserve graft-versus-leukemia effect. Pro Natl Acad Sci 101: 3921-3926, 2004.

Reddy PR, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JLM. A critical role for antigen presenting cells and alloantigen expression in graft-versus-leukemia responses. Nature Medicine 11:1244-1249, 2005.

Weissinger EM, Schiffer E, Hertenstein B, Ferrara JLM, Holler E, Stadler M, Kolb HJ, Zander A, Zurbig P, Kellmann M, Ganser A. Proteomic patterns predict acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood, 109:1-36, 2007.