James L. M. Ferrara, M.D., D.Sc.
Director, Blood and Marrow Transplant Program
Ruth Heyn Professor of Pediatric Oncology
American Cancer Society Clinical Research Professor
Professor of Pediatrics and Internal Medicine

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:

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 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.

Gatza E, Rogers CE, Clouthier SG, Lowler KP, Tawara I, Liu C, Reddy P, Ferrara JLM. Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood. 112:1515-1521, 2008.

Reddy P, Sun Y, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E, Yoshinobu M, Tawara I, Krijanovski O, Gatza E, Liu C, Malter C, Mascagni P, Dinarello CA, Ferrara JLM. Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase dependent dendritic cell functions and regulates experimental graft-versus-host disease. J Clin Investigation 2008, 118: 2562-2573.

Paczesny S, Krijanovski O, Braun TM, Choi S, Clouthier SG, Kuick R, Misek DE, Cooke KR, Kitko CL, Weyand A, Bickley D, Jones D, Whitfield J, Reddy P, Levine JE, Hanash SM, Ferrara JLM. A biomarker panel for acute graft versus host disease. Blood 2009, 113:273-278.