Pavan Reddy, M.D.
Assistant Professor,
Department of Internal Medicine

reddypr@umich.edu

Allogeneic bone marrow transplantation is the most potent form of immune therapy against a number of malignant diseases by its graft-versus-leukemia/tumor effect. However, acute graft-versus-host disease (GVHD) the major complication of allogeneic BMT is tightly linked to the Graft-versus-leukemia (GVL) effect. The immunobiology of GVHD and GVL responses are complex and cytokines are critical for regulating immune responses. My laboratory focused on understanding the role of cytokines and cellular effectors in the biology of GVHD/GVL by utilizing well-characterized mouse models of allogeneic BMT. Our laboratory specifically focuses on the following three aspects of GVHD / GVL.

1. Evaluate the role of IL-18: We have previously shown that a single cytokine, interleukin-18, can modulate GVHD/GVL responses through differential mechanisms. Future studies are being planned on examining the cellular and molecular pathways that are responsible for these differential mechanisms of action by IL-18.
2. Development of novel immuno-modulators: We have recently discovered that histone deacetylase inhibitors, the anti-neoplastic drugs, are a novel suppressors of the secretion of multiple pro-inflammatory cytokines and can also regulate the function of antigen presenting cells / T cella and modulate GVHD and GVL. Some of these exciting preliminary results have been published in the journal PNAS. We are in the process of dissecting the mechanisms of immune modulation by alteration of histone acetylation and the effect of such modulation on GVHD/GVL.
3. Determine the role of direct and indirect antigen presentation in GVHD and GVL: We are investigating the role direct antigen presentation by GVHD target / tumor cells or by cross-presentation by host derived APCs or donor APCs in mediating GVH responses. We are also exploring the role of allo-antigen expression in these responses.

Representative Publications

Reddy P , Teshima T, KuKuruga M, Ordemann R, Liu C, Lowler K, Ferrara JLM. Interleukin –18 Regulates Acute Graft-versus-Host Disease by Enhancing Fas- Mediated Donor T cell Apoptosis. The Journal of Experimental Medicine. 2001. 194 (10); 1433-1440.

Teshima T, Ordemann R, Reddy P , Gagin S, Liu C, Cooke KR, Ferrara JLM. Acute Graft versus Host Disease Does Not Require Allo-antigen Expression on Host Epithelium. Nature Medicine 2002 . 8(6): 575-581.

Reddy P, Teshima T, Hildebrandt G, Duffner U, Maeda Y, Cooke K, Ferrara JLM. IL-18 preserves a perforin mediated GVL effect after experimental allogeneic BMT. Blood. 2002. 100: 3429-3431.

Reddy P, Teshima T, Hildebrandt G, Williams D, Liu C, Ferrara JLM. Pretreatment of donors with IL-18 attenuates acute GVHD via STAT6 and preserves GVL. Blood. 2003. 101(7):2877-85.

Reddy P , Ferrara JLM. Immunobiology of acute graft-versus-host disease . Blood Reviews. 2003. 17(4):187-94.

 Teshima T, Reddy P , Liu C, Williams D, Cooke K, Ferrara JLM. Impaired thymic negative selection causes autoimmune graft-versus-host disease. Blood. 2003. 102: 429-435 (Plenary Paper)

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 preserves graft-versus-leukemia effect. Proceedings of the National Academy of Sciences. 2004. Mar 16;101(11):3921-6.

Duffner U, Maeda Y, Cooke KR, Reddy P , Ordemann R, Liu C, Ferrara JLM, Teshima T. Host Dendritic Cells Alone Are Sufficient to Initiate Acute Graft-versus-Host Disease . Journal of Immunology. 2004. Jun 15;172(12):7393-8

Reddy P . Interleukin-18: Recent Advances. Current Opinion in Hematology. 2004 Nov; 11(6):405-410.

Min CK, Maeda Y, Lowler K, Liu C, Clouthier S., Lofthus D., Weisiger E, Ferrara JLM, Reddy P. Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T cell subsets after experimental allogeneic bone marrow transplantation. Blood. 2004 Nov 15;104(10):3393-9.

Reddy P et al. "A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses". Nature Medicine. 2005 Nov;11(11):1244-9.

Ferrara JL and Reddy. "Pathophysiology of graft-versus-host disease"
Semin Hematol. 2006 Jan;43(1):3-10.