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Immunological Mechanisms of Extracorporeal Photopheresis in Cutaneous T Cell Lymphoma and Graft Versus Host Disease

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Immunological Mechanisms of Extracorporeal Photopheresis in Cutaneous T Cell Lymphoma and Graft Versus Host Disease The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2012 IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE Lisa Shiue Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Immunopathology Commons, Immunoprophylaxis and Therapy Commons, Medicine and Health Sciences Commons, and the Other Immunology and Infectious Disease Commons Recommended Citation Shiue, Lisa, "IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE" (2012). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 327. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/327 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE by Lisa Harn-Ging Shiue, B.S. APPROVED: ________________________________________ Madeleine Duvic, M.D., Supervisory Professor _______________________________ Amin Alousi, M.D. ________________________________ Wei Cao, Ph.D. _________________________________ Dorothy Lewis, Ph.D. ______________________________ Greg Lizee, Ph.D. ______________________________ Xiao Ni, M.D., Ph.D. ______________________________ Stephen E. Ullrich, Ph.D. APPROVED: ________________________________________________________________ Dean, The University of Texas Graduate School of Biomedical Sciences at Houston IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE A DISSERTATION Presented to the Faculty of The University of Texas Health Science Center at Houston and The University of Texas M.D. Anderson Cancer Center Graduate School of Biomedical Sciences Program in Immunology In Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY by Lisa Harn-Ging Shiue, B.S. Houston, TX December, 2012 DEDICATIONS To my family. To the patients suffering from L-CTCL and GVHD. iii ACKNOWLEDGMENTS With gratitude, I would like to thank my mentors Dr. Madeleine Duvic and Dr. Xiao Ni for their undivided support and guidance throughout my Ph.D. study. Additionally, I am grateful for my advisory committee members, examining committee members, and supervisory committee members. I am indebted to my candidacy examining committee members, Dr. Stephen Ullrich, Dr. Greg Lizee, Dr. Elizabeth Grimm, and Dr. Wei Cao, who gave me interesting questions that made the candidacy exam enjoyable to prepare for. My supervisory committee members Dr. Stephen Ullrich, Dr. Greg Lizee, Dr. Wei Cao, Dr. Amin Alousi, and Dr. Dorothy Lewis have been instrumental in supervising my project and I thank them. As for the execution of this project, there are numerous people to thank for their help. The nurse team, Charlie, Tran, Josh, Marylou, Art, Joe, and Gladys, from the Apheresis unit at UT MD Anderson, Department of Stem Cell Transplantation, have been exceptional to work with obtaining samples. I am indebted to all the patients who participated in this study and the clinical residents/fellows who took care of them. Wendy Schober in the flow cytometry/cell sorting core facility helped me with her excellent technical support. I would also like to thank both past and present lab mates: Meg Goswami, Xiang Zhang, Drew Deniger, Chad Tremont, Joyce Osei, Chunlei Zhang, Linda Cook, Betty Yang, Wenhong Zhou, and Xiao Ni who have made the Duvic Laboratory a great place to be. iv This work was supported by the Center for Clinical and Translational Sciences, which is funded by National Institutes of Health Clinical and Translational Award UL1TR000371/TL1 RR024147/TL1TR000369 from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. v IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE Publication No.___________ Lisa Harn-Ging Shiue, B.S. Supervisory Professor: Madeleine Duvic, M.D. Extracorporeal photopheresis (ECP) is an effective, low-risk immunomodulating therapy for leukemic cutaneous T cell lymphoma (L-CTCL) and graft versus host disease (GVHD), but whether the mechanism(s) of action in these two diseases is (are) identical or different is unclear. To determine the effects of ECP in vivo, we studied regulatory T cells (T-regs), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) by immunofluorescence flow cytometry in 18 L-CTCL and 11 GVHD patients before and after ECP at Day 2, 1 month, 3 months, and 6 months. In this study, ECP was effective in 12/18 L- CTCL patients with a 66.7% overall response rate (ORR) and 6/11 GVHD patients with a 54.5% ORR. Prior to ECP, the percentages of CD4+Foxp3+ T cells in 9 L-CTCL patients were either lower (L-CTCL-Low, n=2) or higher (L- CTCL-High, n=7) than normal. Five of the 7 GVHD patients had high percentages of CD4+Foxp3+ T cells (GVHD-High). Six of 7 L-CTCL-High patients had >80% CD4+Foxp3+ T cells which were correlated with tumor cells, and were responders. Both L-CTCL-High and GVHD-High patients had decreased percentages of CD4+Foxp3+ and CD4+Foxp3+CD25- T cells after 3 months of treatment. CD4+Foxp3+CD25+ T cells increased in GVHD-High patients but decreased in L-CTCL-High patients after 3 months of ECP. In addition, numbers of CTLs were abnormal. We confirmed that numbers of CTLs were low in L- CTCL patients, but high in GVHD patients prior to ECP. After ECP, CTLs increased after 1 month in 4/6 L-CTCL patients whereas CTLs decreased after 6 vi months in 3/3 GVHD patients. Myeloid (mDCs) and plasmacytoid DCs (pDCs) were also low at baseline in L-CTCL and GVHD patients confirming the DC defect. After 6 months of ECP, numbers and percentages of mDCs and pDCs increased in L-CTCL and GVHD. MDCs were favorably increased in 8/12 L- CTCL responders whereas pDCs were favorably increased in GVHD patients. These data suggest that ECP is favorably modulating the DC subsets. In L- CTCL patients, the mDCs may orchestrate Th1 cell responses to overcome immune suppression and facilitate disease regression. However, in GVHD patients, ECP is favorably down-regulating the immune system and may be facilitating immune tolerance to auto-or allo-antigens. In both L-CTCL and GVHD patients, DCs are modulated, but the T cell responses orchestrated by the DCs are different, suggesting that ECP modulates depending on the immune milieu. _______________ vii TABLE OF CONTENTS PAGE Approval Sheet…………………………………………..…………………………...….i Title Page…………………………………………….…………………………………..ii Dedications……………………………………….…………………………………......iii Acknowledgements……………….…………………………………………….…....iv-v Abstract……………………………………………………………………….………vi-vii Table of Contents…………………………………………………………………...viii-x List of Figures……………………………………………………………………….xi-xii . List of Tables………………………………………………………………………xiii-xiv List of Abbreviations…………………………………………………………………...xv CHAPTER 1: GENERAL BACKGROUND ..................................................... 1-38 1.1 Elements of the Immune system ................................................................. 1 1.2 Innate and Adaptive Immunity .................................................................... 3 1.3 Dendritic Cells ............................................................................................ 7 1.4 T cells ....................................................................................................... 11 1.5 DC subsets and T cell immunity ............................................................... 14 1.6 Regulatory T cells ..................................................................................... 17 1.7 Cytotoxic T lymphocytes ........................................................................... 18 1.8 Cutaneous T cell Lymphoma (CTCL): Immunopathogenesis .................. 20 1.9 Sézary Syndrome (SS): History and Clinical Presentation ...................... 20 1.10 CTCL skin and clinical pathology ............................................................ 21 1.11 CTCL tumor T cell abnormalities (Immunophenotype) ........................... 22 1.12 Impaired immunity in CTCL .................................................................... 23 1.13 SS and current treatments ...................................................................... 25 1.14 Graft versus Host Disease: Immunopathogenesis ................................. 26 viii 1.15 Extracoporeal Photopheresis (ECP): History and Procedure ................ 30 1.16 ECP: Apoptosis ....................................................................................... 32 1.17 Immunomodulation by ECP: Vaccination
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