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Viewed Research Articles STUDIES OF HUMAN NATURAL KILLER CELL DEVELOPMENT DISSERTATION Presented in Partial Fulfillment of the Requirements for The Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Aharon G. Freud, B.S. ***** The Ohio State University 2006 Dissertation Committee: Michael A. Caligiuri, M.D., Adviser Yang Liu, Ph.D. Approved by Clay Marsh, M.D. _____________________________ Caroline Whitacre, Ph.D. Adviser The Integrated Biomedical Sciences Graduate Program ABSTRACT In recent years there has been increased emphasis placed on studying the immune system with the hope that its selective modulation, in combination with other forms of therapy, could one day eradicate infectious disease and cancer. Natural killer (NK) cells are specialized immune cells that have the ability to recognize and destroy virally infected and malignantly transformed cells without prior stimulation and to produce and release soluble factors, such as interleukins, cytokines, and chemokines, that can stimulate and recruit other cells of the immune system. Because of their unique roles in immunity, there is rationale to study NK cell development so that we might modulate NK cell numbers and or functions in patients with immune deficiency or cancer. Although much is known about how mature NK cells function and recognize their targets, the development of these cells in humans is less well characterized. Specifically, whereas it is well documented that T lymphocytes develop in the thymus and that B cell development occurs in the bone marrow (BM), the anatomical site(s) and cellular intermediates that give rise to human NK cells in vivo have remained elusive. For the past four years, my research goal has been to address these two unknowns. Through the course of many studies, we (myself along with my collaborators) have discovered that human lymph nodes (LNs) and tonsils are naturally enriched with the full complement of cellular intermediates spanning the developmental continuum from an immature hematopoietic progenitor cell (HPC) to a functionally mature NK cell. For the first time, ii these data implicate secondary lymphoid tissues (SLT) as the primary sites of human NK cell differentiation. Moreover, our data provide a new and comprehensive model for the development of human NK cells in vivo. Herein, I present these findings and provide an extended discussion relating our new data to current concepts in the field of NK cell developmental biology. iii To Ha-shem, Batyah, and Noah. iv ACKNOWLEDGMENTS I thank G-d for blessing me with life, family, health, love, and the innumerable opportunities to learn. I thank my wife, Bethany, for her undying support, love, and Noah. I thank my parents and sisters for their unconditional love and support. I thank my adviser, Michael Caligiuri, for his exceptional mentorship and guidance. I cannot thank him enough for the care he has taken in my training, professional development and personal growth. Nor can I adequately express my gratitude for the wonderful opportunity to be a part of his laboratory and to know him on both professional and personal levels. I wish to thank all current and former members of the Caligiuri Laboratory including Robert Baiocchi, Brian Becknell, Bradley Blaser, Megan Cooper, Adrienne Dorrance, Chiara Giovenzana, Todd Fehniger, Martin Guimond, Tiffany Hughes, Melissa Lee, Tom Liu, Charlene Mao, Trent Marburger, Sameek Roychowdhury, Matthew Strout, Rossana Trotta, Jeff VanDeusen, and Susan Whitman. I thank each person for his/her friendship, advice, support, and contribution to my personal and professional growth. I wish to thank Donna Bucci and Tamra Brooks for their administrative support. I thank my collaborators, Amy Ferketich, Megan Jukich, Beth Mattarese Mary McNulty, Gerard Nuovo, and Erin Smith for their assistance and expertise. I thank Richard Fertel and William Carson for their outstanding mentorship. - v - I thank my dissertation committee, Yang Liu, Clay Marsh, and Caroline Whitacre for their repeated commitments of time and effort on my behalf. I thank Alan Yates and the faculty of the Integrated Biomedical Science Graduate Program for their unwavering guidance and commitment to my education. Finally I wish to acknowledge the generous support of my education through the University Fellowship, the Medical Scientist Program Fellowship, and the multiple funding organizations that provide for the Caligiuri Laboratory. - vi - VITA May 25, 1977 ……………………………………………Born, Bloomington, Indiana 1996-2000.……………………………………………….B.S. Genetics, University of Wisconsin-Madison 2000-present.…………………………………………….Medical Scientist Program Fellow, The Ohio State University PUBLICATIONS Peer-Reviewed Research Articles 1. Freud AG, Yokohama A, Becknell B, Lee MT, Mao HC, Ferketich AK, Caligiuri MA. Evidence for discrete stages of human natural killer cell differentiation in vivo. J Exp Med. 2006 Apr 17;203(4):1033-1043.Epub 2006 Apr 10. 2. Roychowdhury S, Blaser BW, Freud AG, Katz K, Bhatt D, Ferketich AK, Bergdall V, Kusewitt D, Baiocchi RA, Caligiuri MA. IL-15 but not IL-2 rapidly induces lethal xenogeneic graft-versus-host disease. Blood. 2005 Oct 1;106(7):2433-5. Epub 2005 Jun 23. 3. Freud AG, Becknell B, Roychowdhury S, Mao HC, Ferketich AK, Nuovo GJ, Hughes TL, Marburger TB, Sung J, Baiocchi RA, Guimond M, Caligiuri MA. A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity. 2005 Mar;22(3):295-304. 4. Roychowdhury S, May KF Jr, Tzou KS, Lin T, Bhatt D, Freud AG, Guimond M, Ferketich AK, Liu Y, Caligiuri MA. Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. Cancer Res. 2004 Nov 1;64(21):8062-7. 5. Roychowdhury S, Baiocchi RA, Vourganti S, Bhatt D, Blaser BW, Freud AG, Chou J, Chen CS, Xiao JJ, Parthun M, Chan KK, Eisenbeis CF, Ferketich AK, Grever MR, - vii - Chen CS, Caligiuri MA. Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder. J Natl Cancer Inst. 2004 Oct 6;96(19):1447-57. 6. Imboden M, Shi F, Pugh TD, Freud AG, Thom NJ, Hank JA, Hao Z, Staelin ST, Sondel PM, Mahvi DM. Safety of interleukin-12 gene therapy against cancer: a murine biodistribution and toxicity study. Hum Gene Ther. 2003 Jul 20;14(11):1037-48. 7. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med. 2001 Jan 15;193(2):219-31. 8. Whitman SP, Strout MP, Marcucci G, Freud AG, Culley LL, Zeleznik-Le NJ, Mrozek K, Theil KS, Kees UR, Bloomfield CD, Caligiuri MA. The partial nontandem duplication of the MLL (ALL1) gene is a novel rearrangement that generates three distinct fusion transcripts in B-cell acute lymphoblastic leukemia. Cancer Res. 2001 Jan 1;61(1):59-63. Invited Review Articles 9. Fehniger TA, Suzuki K, VanDeusen JB, Cooper MA, Freud AG, Caligiuri MA. Fatal leukemia in interleukin-15 transgenic mice. Blood Cells Mol Dis. 2001 Jan- Feb;27(1):223-30. FIELDS OF STUDY Major Field: Integrated Biomedical Sciences with an emphasis in Immunology - viii - TABLE OF CONTENTS Page Abstract........................................................................................................................... ii Dedication....................................................................................................................... iv Acknowledgments........................................................................................................... v Vita.................................................................................................................................. vii List of Figures................................................................................................................. xi List of Tables.................................................................................................................. xiii Chapters 1. Background................................................................................................................ 1 1.1. Natural killer cells: innate immune effector cells............................ 1 1.2. General concepts of human NK cell development.......................... 2 2. Discovery of the human pre-NK cell and its natural enrichment in lymph nodes…. 6 2.1. Introduction..................................................................................... 6 2.2. Results………................................................................................. 8 2.3. Discussion........................................................................................ 15 2.4. Experimental Procedures................................................................. 20 3. Elucidation of the in vivo stages of human NK cell development............................ 44 3.1. Introduction and Review................................................................. 44 3.2. Results............................................................................................. 46 3.3. Discussion........................................................................................ 56 3.4. Experimental Procedures................................................................. 61 4. Unpublished Data and Extended Discussion.……………………………………….86 4.1. Terminal stages of human NK cell differentiation: CD56bright vs. CD56dim....................................................................
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