James L. M. Ferrara,
Ruth Heyn Professor of Pediatric Oncology
American Cancer Society Clinical Research Professor
Professor of Pediatrics and Communicable Diseases
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.
Current projects in the laboratory are:
Modulation of the bioenergetics of activated effector cells to prevent and test GVHD. Inhibition of ATP synthesis cause selective mitochondria stress in GVHD effector cells and we are investigating the metabolic pathways involved.
Discovery and validation of GVHD biomarkers. We have used the BMT biorepository that contains over 20,000 samples from more than 2,000 BMT patients to be the first in the world to identify and validate plasma biomarkers of GVHD with both diagnostic and prognostic value. We are now designing clinical trials using these biomarkers.
Gastrointestinal (GI) GVHD biology. We have discovered that Paneth cells, guardians of the intestinal stem cells that are the targets of GI GVHD are also damaged during disease progression. We have now developed a new clinical GI GVHD scoring system to enable clinical trial development and we are investigating the manipulation of Paneth cells in reducing GVHD.
Harris AC, Ferrara JLM, Braun TM, Holler E, Teshima T, Levine JE, Choi SW, Landfried K, Akashi K, Vander Lugt M, Couriel DR, Reddy P, and Paczesny S. Plasma Biomarkers of Lower Gastrointestinal and Liver Acute Graft-Versus-Host Disease. Blood: blood-2011-10-387357;EPub: January 27, 2012, doi:10.1182/blood-2011-10-387357. PMCID:PMC3327467.
Gatza E, Wahl DR, Opipari AW, Sundberg TB, Reddy PR, Liu C, Glick GD, Ferrara JLM. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Science Translational Medicine. 2011. 3(64-67):113-120. PMID: 21270339 Abstract Reprint Full Text (http://www.ncbi.nlm.nih.gov/pubmed/21270339)
Paczesny S, Braun TM, Levine JE, Hogan J, Crawford J, Coffing B, Olsen S, Choi SW, Wang H, Faca V, Pitteri S, Zhang O, Chin A, Kitko CL, Mineishi S, Yanik G, Peres P, Hanauer D, Wang Y, Reddy P, Hanash S, Ferrara JLM. Elafin is a biomarker of graft versus host disease of the skin. Science Translational Medicine 2010. (2)13:13ra2, 50-57. Abstract Reprint Full Text
Ferrara JLM, Levine J, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009, 373:1550-1561. NIHMSID: NIHMS115970. PMCID: PMC2735047 Abstract Reprint Full Text (http://www.ncbi.nlm.nih.gov/pubmed?term=PMC2735047)
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.
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 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.