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 S, Ludwig B, Choudhary P, Kovatchev B, Rickels MR, Sykes M, Wood K, Kraemer K, Hwa A, Stanley E, Ricordi C, Zimmerman M, Greenstein J, Montanya E, Otokoski T. Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement. Transplantation. 2016Jul 100(7):e25-31. Doi: 10.1097 PMCID: PMC4741413
410. Hirata Y, Li HW, Takahashi K, Ishii H, Sykes M, Fujisaki J. MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice. PLoS One. 2015 Nov 6; 10(11):e0141785. Doi: 10.1371/journal.pone.014785, eCollection 2015. PMCID: PMC4636372
409. Newell KA, Asare A, Sanz I, Wei C, Rosenberg A, Gao Z, Kanaparthi S, Asare S, Lim N, Stahly M, Howell M, Knechtle S, Kirk A, Marks WH, Kawai T, Spitzer T, Tolkoff-Rubin N, Sykes M, Sachs DH, Cosimi AB, Burlingham WJ, Phippard D, Turka LA. Longitudinal studies of a B cell-derived signature of tolerance in renal transplant recipients. American Journal of Transplantation. 2015 Nov; 15(11):2908-20. Doi: 10.1111/ajt.13480. Epub 2015 Oct 13. PMCID: PMC4725587
408. DeWolf S, Morris H, Shen Y, Sykes M. Author response to comment on "Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients". Science Translational Medicine. 2015 Jul 22; 7(297):297Ir1. Doi: 10.1126/scietranslmed.aac9461. PMCID: Not Applicable.
407. Li HW, Andreola G, Carlson AL, Shao S, Lin CP, Zhao G, Sykes M. Rapid Functional Decline of Activated and Memory Graft-versus-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation. Journal of Immunology. 2015 Aug 1; 195(3): 1282-92. Doi: 10.4049/jimmunol.1401511. Epub 2015 Jun 17. PMCID: PMC4506852.
406. Sykes M. Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. Bone Marrow Transplantation. 2015 Jun; 50 Supple 2:S82-6. Doi: 10.1038/bmt.2015.102. PMCID: PMC4968035
405. Weiner J, Duran-Struuck R, Zitsman J, Buhler L, Sondermeijer H, McMurchy A, Levings M, Sykes M, Griesemer A. Restimulation After Cryopreservation and Thawing Preserves the Phenotype and Function of Expanded Baboon Regulatory T Cells. Transplantation Direct. February 2015, Volume 1 - Issue 1, p. 1-7. doi: 10.1097/TXD.0000000000000511
404. Zuber J, Rosen S, Shonts B, Sprangers B, Savage T, Richman S, Yang S, Lau S, DeWolf S, Vlad G, Zorn E, Wong W, Emond J, Martinez M, Kato T, Sykes, M. Macrochimerism in intestinal transplantation: association with lower rejection rates and multivisceral transplants, without GVHD. American Journal of Transplantation. 2015 Oct 15(10):2691-703 doi: 10.1111/ajt. 13325. Epub 2015 May 18. PMCID: PMC4575629.
403. Buchan S, Manzo T, Flutter B, Rogel A, Edwards N, Zhang L, Sivakumaran S, Ghorashian S, Carpenter B, Bennett C, Freeman G, Sykes M, Croft M, Al-Shamkhani A, Chakraverty R. OX40- and CD27-mediated co-stimulation synergize with anti-PD-L1 blockade by forcing exhausted CD8+ T cells to exit quiescence. Journal of Immunology. 2015 Jan 1: 194(1):125-33. Doi:10.4049/jimmunol. 1401644. PMCID: PMC4272895.
402. Sykes, M. Introduction of David H. Sachs, MD, Recipient of the 2014 Medawar Prize. Transplantation. 2015 Feb; 99(2): 253-4. Doi: 10.1097/TP.0000000000000594.
401. Morris H, De Wolf S, Robins H, Sprangers B, Locascio S, Shonts B, Kawai T, Wong W, Yang S, Zuber J, Shen Y, Sykes M. Tracking donor-reactive T cells: evidence for clonal deletion in tolerant kidney transplant patients. (Note: accompanied by FOCUS Article “I spy alloreactive T Cells” by Maria-Luisa Alegre.) Science Translational Medicine 7, 272ra10 (2015). PMCID: PMC4360892
400. Kawai T, Sachs DH, Sprangers B, Spitzer T, Saidman S, Zorn E, Tolkoff-Rubin N, Preffer F, Crisalli K, Gao B, Wong W, Morris H, LoCascio S, Sayre P, Shonts B, Williams W, Smith R, Colvin R, Sykes M, Cosimi A. Long-Term Results in Recipients of Combined HLA-Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression. American Journal of Transplantation. 2014 July; 14(7); 1599-611. doi: 10.1111/ajt.12731. PMID: 24903438 PMCID: PMC4228952
399. Li H, Yang YG, Sykes M. Thymic education of human T cells and regulatory T cell development in humanized mice. In: Humanized Mice for HIV Research; Poluektova LY, Garcia-Martinez JV, Koyanagi Y, Manz MG, Tager AM (Ed.), New York, NY, Springer Science+Business Media; 2014; 10: 127-140
398. Kalscheuer H, Onoe T, Dahmani A, Holzl M, Yamada K, Sykes M. Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts. Journal of Immunology, 2014 Apr 1;192(7):3442-50. doi: 10.4049/jimmunol.1302886. PMID: 24591363. PMCID: PMC3983999
397. Sykes M. Transplantation Immunology. In: The Cecil Text Book of Medicine, 25th Edition. (Eds), Goldman L, Ausiello, D. Philadelphia, PA; Saunders Elsevier; 2016. Vol. 1. Pp. 236-240
396. Sykes M. Transplantation: Moving to the Next Level. Immunological Reviews; 2014. 2014 Mar;258(1):5-11. doi: 10.1111/imr.12161. PMID: 24517422. PMCID: PMC4038030.
395. Griesemer A, Yamada K, Sykes M. Xenotransplantation: Immunological hurdles and progress toward tolerance. Immunological Reviews; 2014 Mar;258(1):241-58. doi: 10.1111/imr.12152. PMID: 24517437. PMCID: PMC4023346
394. Haspot F, Li HW, Lucas CL, Fehr T, Beyaz S, Sykes M. Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. American Journal of Transplantation, 2014 Jan 14(1): 49-58. doi: 10.1111/ajt.12525. PMID: 24304495. PMCID: PMC4045013
393. Sachs DH, Kawai T, Sykes M. Induction of Tolerance Through Mixed Chimerism. In: Turka L, Wood K, editors. Cold Spring Harbor Perspe