Megan Sykes, MD
Megan Sykes’ research career, during which she has published >420 papers and book chapters, has focused on hematopoietic cell transplantation, organ allograft tolerance induction, xenotransplantation tolerance and Type 1 diabetes. Dr. Sykes has developed novel strategies for achieving graft-versus-tumor effects without graft-versus-host disease following hematopoietic cell transplantation (HCT). She developed an approach that has been evaluated in clinical trials of non-myeloablative haploidentical HCT whose safety and efficacy allowed trials of HCT for the induction of organ allograft tolerance, allowing intentional achievement of tolerance in humans for the first time. Dr. Sykes has dissected the tolerance mechanisms and pioneered minimal conditioning approaches for using HCT to achieve allograft and xenograft tolerance. Her work on xenogeneic thymic transplantation for tolerance induction has led, for the first time, to long-term kidney xenograft survival in non-human primates. More recently, she has extended the HCT approach to the problem of reversing autoimmunity while replacing destroyed islets of Langerhans in Type 1 diabetes. She has developed novel “humanized mouse” models that allow personalized analysis of human immune disorders and therapies. Dr. Sykes is a Past President of the International Xenotransplantation Association, served as Vice President of TTS, has repeatedly served on TTS Council and is a member of the Institute of Medicine of the National Academies and of the Association of American Physicians.
Dr. Sykes believes that a mechanistic understanding of manipulations used to achieve clinical goals is essential to the translation of these manipulations to the clinic. It is for this reason that she has consistently worked at the interface between basic science and clinical applications, and has been able to translate her research to new treatments for patients requiring bone marrow or organ transplants. In 2010, after 20 years at Massachusetts General Hospital and Harvard Medical School, Dr. Sykes moved to Columbia University to establish the Columbia Center for Translational Immunology (CCTI). The CCTI is a multidisciplinary research center whose scope includes transplantation (organ and bone marrow), autoimmune disease, tumor immunology, infectious immunity and basic immunology. Currently, the CCTI has a staff of >100 scientists and support staff, including 16 faculty members. Dr. Sykes' own laboratory program currently includes major projects in the area of xenograft tolerance induction in humanized mouse models; unique humanized mouse models for the analysis and treatment of autoimmune diseases, including Type 1 diabetes and rheumatoid arthritis (the “personalized immune” mouse); studies of lymphocyte turnover, chimerism and T cell trafficking in patients receiving intestinal and liver transplants; tracking of alloreactive T cells in human transplant recipients; and both pre-clinical and clinical studies of non-myeloablative hematopoietic cell transplantation for the induction of allograft tolerance.
Our research is in the areas of hematopoietic cell transplantation, achievement of graft-versus-leukemia effects without GVHD, organ allograft tolerance induction, autoimmune disease and xenotransplantation.
Our research has developed ways to utilize bone marrow transplantation as immunotherapy to achieve graft-versus-tumor effects while avoiding the common complication of such transplants, graft-versus-host disease. Another major area has been to utilize bone marrow transplantation for the induction of transplantation tolerance, both to organs from the same species (allografts) and from other species (xenografts). Our laboratory has worked toward the development of clinically feasible, non-toxic methods of re-educating the T cell, B cell and NK cell components of the immune system to accept allografts and xenografts without requiring long-term immunosuppressive therapy. We pioneered xenogeneic thymic transplantation as an approach to tolerance induction. We have demonstrated that non-myeloablative induction of mixed chimerism reverses the autoimmunity of Type 1 diabetes. We have recently developed novel humanized mouse models allowing "personalized" analysis of immune disease pathogenesis and immunotherapy. Additionally, we have developed novel tools for the analysis of the human alloresponse and are using these tools to better understand organ transplant immunobiology and tolerance in patients.
427. Borsotti C, Danzl NM, Nauman G, Hölzl MA, French C, Chavez E, Khosravi-Mararlooei M, Glauzy S, Delmotte FR, Meffre E, Savage DG, Campbell SR, Goland R, Greenberg E, Bi J, Satwani P, Yang S, Bathon J, Winchester R, Sykes M. HSC-extrinsic sex- and intrinsic autoimmune disease-related human B cell variation is recapitulated in humanized mice. Blood Advances. 2017. In Press.
426. Kato Y, Griesemer AD, Wu A, Sondermeijer HP, Weiner JI, Duran-Struuck R, Martinez M, Slate AR, Romanov A, Lefkowitch JH, Sykes M, Kato T. Novel H-shunt Venovenous Bypass for Liver Transplantation in Cynomolgus Macaques. Comp. Med. 2017 Oct. In Press.
425. Tan S, Li Y, Xia J, Jin CH, Hu Z, Duinkerken G, Li Y, Khosravi Maharlooei M, Chavez E, Nauman G, Danzl N, Nakayama M, Roep BO, Sykes M, Yang YG. Type 1 diabetes induction in humanized mice. Proc Natl Acad Sci. 2017 Sep 5. pii: 201710415. doi: 10.1073/pnas.1710415114. [Epub ahead of print] PMID: 28874533
424. Yamada K, Sykes M, Sachs D. Tolerance in xenotransplantation. Curr Opin Organ Tran. 2017. In Press
423. Tan, S., Xia, J., Hu, Z., Li, Y., Duinkerken, G., Jin, CH., Li, Y., Danzl, N., Nakayama, M., Roep, B., Sykes, M., Yang, YY. Human CD4 cells engineered to express a patient-derived islet autoreactive T-cell receptor cause type 1 diabetes in humanized mice. Proc Nat Acad Sci. 2017. In Press.
422. Sui L, Chen X, Leibel R, Sykes M, Egli D. Beta cell replacement in mice using human type 1 diabetes nuclear transfer embryonic stem cells. Diabetes. 2017. In Press
421. Zuber J, Sykes M. Mechanisms of Mixed Chimerism-Based Transplant Tolerance. Trends Immunol. 2017 Aug 18. pii: S1471-4906(17)30146-1. doi: 10.1016/j.it.2017.07.008. [Epub ahead of print] PMID: 28826941
420. DeWolf S, Sykes M. Alloimmune T cells in transplantation. J Clin Invest. 2017 Jun 30;127(7):2473-2481. doi: 10.1172/JCI90595. Epub 2017 Jun 19. PMCID: PMC5490749
419. Gao B, Gu Y, Rong C, Moore C, Porcheray F, Wong W, Preffer FI, Saidman SL, Fu Y, AB Cosimi B, Sachs DH, Kawai T, Sykes M, Zorn E. Dynamics of B cell recovery following kidney/bone marrow transplant recipients. Transplantation. 2017 Apr 19. doi: 10.1097/ TP.0000000000001789. [Epub ahead of print] PMID: 28422925
418. Sprangers B, DeWolf S, Savage TM, Morokata T, Obradovic A1, LoCascio SA, Shonts B1, Zuber J, Lau SP, Shah R, Morris H, Steshenko V, Zorn E, Preffer FI, Olek S, Dombkowski DM, Turka LA, Colvin R, Winchester R, Kawai T, Sykes M. Origin of enriched regulatory t cells in patients receiving combined kidney/bone marrow transplantation to induce transplantation tolerance. Am J Transplant. 2017 Mar 1. doi: 10.1111/ajt.14251. Epub 2017 Apr 10. PMID: 28251801
417. Weiner J, Zuber J, Shonts B, Yang S, Fu J, Martinez M, Farber D, Kato T, Sykes M. Long-term persistence of innate lymphoid cells in the gut after intestinal transplantation. Transplantation. 2016 Dec 8, DOI: 10.1097/TP.0000000000001593. [Epub ahead of print] PMCID: PMC4228952
416. Duran-Struuck R, Buhler L, Alonso-Guallart P, Zitsman J, Kato Y, Wu A, McMurchy A, Woodland D, Griesemer A, Martinez M, Boskovic S, Kawai T, Cosimi A, Wuu C, Slate A, Mapara M, Baker S, Tokarz R, D’Agati V, Hammer S, Pereira M, Lipkin W, Wekerle T, Levings M, Sykes M. Effect of ex vivo expanded recipient regulatory T cells on hematopoietic chimerism and kidney allograft tolerance across MHC barriers in cynomolgus macaques. Transplantation. 2017 Feb;101 (2):274-283, DOI: 10.1097/TP.0000000000001559. PMCID: PMC5263090
415. Zuber J, Shonts B, Lau S, Obradovic A, Fu J, Yang S, Lambert M, Coley S, Weiner J, Thome J, DeWolf J, Farber D, Shen Y, Caillat-Zucman S, Bhagat G, Griesemer A, Martinez M, Kato T, Sykes M. Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Science Immunology 07 Oct 2016: Vol. 1, Issue 4 eaah3732, DOI: 10.1126/sciimmunol.aah3732 PMCID: PMC5323244
414. Li HW, Vishwasrao P, Holzl MA, Chen S, Choi G, Zhao G, Sykes M. Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model. Am J Transplant. 2017 Feb;17 (2):353-364. doi: 10.1111/ajt.13957. Doi: 10.11111/ajt. Epub 2016 Aug 10.PMC5414033
413. Xia J, Hu Z, Yoshihara S, Li Y, Jin CH, Tan S, Li W, Chen Q, Sykes M, Yang YG. Modeling Human Leukemia Immunotherapy in humanized mice. EBiomedicine 2016 Jun 23 pii: S2352-3954 (16)30285-7 Doi: 10.1016/j.ebiom.2016.06.028. PMCID: PMC5006579
412. Bartlett ST, Markmann JF, Johnson P, Korgren O, Hering BJ, Scharp D, Kay TW, Bromberg J, Odorico JS, Weir GC, Bridges N, Kandaswamy R, Stock P, Friend P, Gotoh M, Cooper DK, Park CG, O;Connell P, Stabler C, Matsumoto