Assistant Professor of Pediatrics and Communicable Diseases
Blood and Marrow Transplant Program
Hematopoietic stem cell transplantation, T cell biology, Graft-versus-Host-Disease, cytokines and cellular pathway networks, human immunology, translational medicine
Allogeneic hematopoietic stem cell transplantation (HSCT) is a major therapy for malignant diseases of the blood and bone marrow and the most potent form of immune therapy against these diseases through its graft-versus-leukemia/tumor (GVL/GVT) effect. However, the efficacy of allogeneic HSCT has been impeded by frequent and severe graft-versus-host-disease (GVHD) that is tightly linked to the GVL/GVT effect. Both acute and chronic forms of GVHD exist. The immunobiology of GVHD and GVL responses are complex and cytokines and cellular effectors are critical. My laboratory focused on understanding the role of cytokines and cellular effectors in the biology of GVHD/GVL by discovering and investigating biomarkers in the blood and tissues of patients following allogeneic HSCT. Currently no laboratory tests exist to predict the risk of developing GVHD, responsiveness to treatment, or patient survival. The goal of our laboratory is to develop such tests integrating both proteomic and cellular biomarkers for the diagnosis and prognosis of GVHD. For proteomics, we will utilize a three-step approach: (i) discovery of proteins in an unbiased manner with a quantitative mass-spectrometry based technology, (ii) selection of the most promising candidate proteins, and (iii) validation of these candidates in a large number of allogeneic HSCT recipients using high-throughput techniques such as ELISA assays. For the study of blood cellular biomarkers, we will analyze subsets of blood cellular components that are potential GVHD biomarkers. For example, we will analyze CCR5+ regulatory T cells that migrate into chronically inflamed intestines as are found in gastrointestinal (GI) GVHD or CAMP activated plasmacytoid dendritic cells in skin GVHD. Similarly, we will analyze other subsets of cellular effectors of GVHD such as effector memory T lymphocytes expressing CD146, which may be more discernible in the circulating cells of patients with GI GVHD than in skin GVHD. We are interested in both acute and chronic GVHD, which has overlapping features of immunodeficiency and symptoms of naturally occurring autoimmune disorders. Indeed, a prominent clinical feature of chronic GVHD is a debilitating fibrosing skin disease whose gross and histologic features resemble scleroderma (SSc) and, less commonly, morphea. Because of these potential biological similarities between chronic GVHD and autoimmune diseases, our work is also relevant for those.
Paczesny S, Levine JE, Braun TM and Ferrara JL. Plasma biomarkers in GVHD: A new era? Biol Blood Marrow Transplant, 2009 Jan; 15(1 Suppl):33-38.
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 (plenary paper), 2009 Jan; 113:273-278.
Li YP, Paczesny S, Lauret E, Poirault S, Bordigoni P, Mekhloufi F, Hequet O, Bertrand Y, Ou-Yang JP, Stoltz JF, Miossec P, Eljaafari A. Human Mesenchymal Stem Cells License Adult CD34+ Hemopoietic Progenitor Cells to Differentiate into Regulatory Dendritic Cells through Activation of the Notch Pathway. Journal of Immunology, 2008 Feb 1; 180 (3): 1598-608.
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 Feb; 15;111(4):2470-75.
Paczesny S, Li YP, Li N. Latger-Cannard V., Marchal L, Ou-Yang JP, Bordigoni P, Stolz JF, Eljaafari A. Efficient generation of CD34+ progenitor-derived dendritic cells from G-CSF-mobilized peripheral mononuclear cells does not require hematopoietic stem cell enrichment. J Leukoc Biol. 2007 Apr;81(4):957-67.
Paczesny S, Shi H, Saito H, Mannoni P, Fay J, Banchereau J, Palucka AK. Measuring melanoma-specific cytotoxic T lymphocytes elicited by dendritic cell vaccines with a tumour inhibition assay in vitro. J Immunother. 2005 Mar-Apr;28(2):148-57.
Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK. Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells. J Exp Med. 2004 Jun 7;199(11):1503-11.
Paczesny S, Ueno H, Fay J, Banchereau J, Palucka AK. Dendritic cells as vectors for immunotherapy of cancer. Semin Cancer Biol. 2003 Dec;13(6):439-47.