Pavan Reddy, M.D.
Co-Director, BMT and Hematological Malignancy Program
Associate Professor of Internal Medicine
Associate Chief, Basic Research/Division of Hematology/Oncology
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.
- 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.
- 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.
- 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.
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.
Maeda Y, Tawara I, Teshima T, Hashimoto D, Matsuoka K, Tanimoto M, Reddy P. Lymphopenia Induced Proliferation of Donor T Cells Reduces Their Capacity for Causing Acute Graft-Versus-Host Disease. Experimental Hematol 2007, 35:274-286.
Sun Y, Reddy P. Histone deacetylase inhibitors: novel immuno-modulators. Current Enzyme Inhibition 2007, 3:207-215.
Sun Y, Tawara I, Toubai T, Reddy P. Pathophysiology of Acute Graft-vs-Host Disease: Recent Advances. Translational Research: Journal of laboratory and Clinical Medicine 2007, 150:197-214.
Durán-Strüück R, Tawara I, Lowler K, Clouthier SG, Weisiger E, Rogers C, Luker G, Kumanogoh A, Liu C, Ferrara JL, Reddy P. A novel role for the semaphorin Sema4D in the induction of alloresponses. Biology of Blood and Marrow Transplantation 2007, 13:1294-1303.
Reddy P, Zou W. Blocking HDACs boosts CD4+Foxp3+ regulatory T cells. Naure Medicine 2007, 13:1282–1284.
Reddy P, Arora M, Guimond M, Mackall CL. GVHD: a continuing barrier to the safety of allogeneic transplantation. Biol Blood Marrow Transplant 2008 Jan;15:162-8.
Nicolasora NP, Reddy P, Kaul DR. Biopsy-proven severe adenoviral diarrhea responding to low-dose cidofovir. Transpl Inf Dis 2008, 10:346-350.
Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ, Jones D, Khaled Y, Kitko CL, Bickley D, Krijanovski O, Reddy P, Yanik G, Ferrara JLM. Etanercept plus methylprednisolone as initial therapy for acute GVHD. Blood 2008, 111:2470-2475.
Durán-Strüück R, Reddy P. Biological Advances in Acute GVHD. Transplantation 2008, 85:303-308.
Toubai T, Sun Y, Reddy P. Pathophysiology of acute GVHD. Biology of Blood and Marrow Transplantation 2008, 2: 101-117.
Gatza E, Rogerts DE, Clouthier SG, Lowler KP, Tawara I, Liu C, Reddy P, Ferrara JLMExtracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells. Blood 2008, 112:1515-1521.
Tawara I, Maeda Y, Sun Y, Lowler K, Toubai T, Liu C, MacKenzie A, Reddy P. Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft versus host disease. Experimental Hematology. 2008, 8:988-96.
Durán-Strüück R, Hartigan A, Clouthier SG, Dyson MC, Lowler K, Gatza E, Tawara I, Toubai T, Weisiger E, Hugunin K, Reddy P, Wilkinson JE. Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies. J Transl Med. 2008, 6(1):10.
Reddy P, Sun Y, Toubai T, Durán-Strüück R, Clouthier SG, Weisiger E, Maeda Y, 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. Journal of Clinical Investigation 2008,;118:2562-2573.
Toubai T, Sun Y, Reddy P. GVHD pathophysiology: is acute different from chronic? Bailliere's Best Practice and Research: Clinical Hematology 2008, 21:101-117.
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 JL. A biomarker panel for acute graft versus host disease. Blood 2009, 113:273-278.
Toubai T, Shono Y, Nishihira J, Ibata M, Suigita J, Kato N, Ohkawara T, Tone S, Lowler KP, Ota S, Tanaka J, Asaka M, Reddy P, Imamura M. Serum macrophage migration inhibitory factor (MIF) levels after allogeneic hematopoietic stem cell transplantation. Int J Lab Hematol 2009, 31:161-168.
Khaled Y, Abidi MH, Janakiraman N, Kato K, Levine JE, Reddy P, Medina M, Peres E, Hanbali A, Mineishi S. Outcomes after auto-SCT in African Americans with multiple myeloma. Bone Marrow Transplantation 2009, 43(11):845-51.
Ferrara JL: Levine JE, Reddy P, Holler E. Graft-versus-host disease. The Lancet, 2009 May 2;373(9674):1550-61.
Khaled Y, Reddy P, Krijanovski O. Emerging drugs for acute graft-versus-host disease. Expert Opinion Emerging Drugs 2009, 14(2):219-32.
Sun Y, Chin YE, Weisiger E, Malter C, Tawara I, Toubai T, Gatza E, Mascagni P, Dinarello CA, Reddy P. Cutting edge: Negative regulation of dendritic cells through acetylation of the nonhistone protein STAT-3. Journal of Immunology, 2009 May 15;182(10):5899-903.
Khaled Y, Mellacheruvu S, Reddy P, Peres E, Mineishi S. Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect. Bone Marrow Transplantation, 2009, 44(5):325-6. Letter to the Editor.
Choi S, Reddy P. Graft-versus-host disease. British Medical Journal Point of Care. 2009. Epocrates Online.