Dr. Megan Sykes' Research
Megan Sykes, MD
Director, Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons
Director of Research, Transplant Initiative, NewYork-Presbyterian Hospital
Dr. Sykes is engaged in studies of hematopoietic stem cell transplantation (HSCT) directed toward three clinical applications: 1) the treatment of hematologic malignancies; 2) the induction of specific transplantation tolerance; 3) curing Type 1 diabetes. Toward the first goal, she has developed a number of approaches to separating graft-vs-host disease (GVHD) and graft-vs-leukemia/lymphoma (GVL) effects.
One of these approaches involves non-myeloablative establishment of mixed chimerism, followed by delayed donor lymphocyte infusions (DLIs). She has demonstrated that DLIs given under such conditions mediate GVL without GVHD because of a lack of inflammation in the epithelial GVHD target tissues. Her lab has demonstrated that such inflammation serves as a checkpoint for the transmigration of GVH-reactive T cells from the lymphohematopoietic system to the epithelial GVHD target tissues. Dr. Sykes and her colleagues have translated this approach into novel clinical trials of non-myeloablative mixed chimerism induction across HLA barriers, followed by delayed DLI in an effort to achieve GVL without GVHD. Toward the second goal, she has focused on the development of non-toxic, non-myeloablative conditioning regimens using mAbs or costimulatory blockade, to eliminate host resistance to engraftment of allogeneic and xenogeneic hematopoietic cells and allow creation of a mixed chimeric state without the usual attendant risks of hematopoietic cell transplantation, for the purpose of inducing specific transplantation tolerance. Tolerance obviates the need for risky chronic immunosuppressive therapy and is the “holy grail” of the transplant field. She and her colleagues have developed novel animal models and translated them to pioneering studies that for the first time achieved kidney allograft tolerance in patients.
Toward the third goal, Dr. Sykes’ work in an animal model has shown that the mixed chimerism approach can be used to simultaneously reverse the autoimmune process in a Type 1 diabetes model while inducing allograft tolerance. This state permits acceptance of donor islets, curing diabetes without risk of rejection or autoimmune recurrence. Dr. Sykes has initiated a pre-clinical large animal program at CUMC, specifically organ, islet and bone marrow transplantation in cymomolgus monkeys, in order to bring these strategies for tolerance induction closer to clinical application. She is also engaged in novel studies of lymphoid cell population turnover in blood and allografts of intestinal transplant recipients. In analyzing mechanisms of tolerance in combined kidney/BMT recipients, Dr. Sykes’ team has recently developed a novel approach to tracking the fate of donor-reactive T cells in transplant recipients that is under active investigation. Dr. Sykes and colleagues have developed and studied humanized mice with robust human immune systems derived from human fetal thymus tissue and hematopoietic stem cells. They have used this model to obtain fundamental information on human lymphocyte development and homeostasis and have used it applied a method of xenograft tolerance induction that Dr. Sykes pioneered, namely xenogeneic thymic transplantation, to demonstrate the capacity of porcine thymic transplantation to support development of a centrally tolerized, normal human T cell repertoire. Ongoing studies aim to understand and correct imbalances in T cell homeostasis that may result from development in a xenogeneic thymus graft.
Recently, Dr. Sykes’ lab has succeeded in adapting the humanized mouse model to generate immune systems from adult human bone marrow stem cells in a model termed the “Personalized Immune” mouse, which is being used to understand the fundamental immunoregulatory abnormalities that underly the development of autoimmune diseases.
Anette Wu, MD, MPH
Julien Zuber MD, PhD
HaoWei Li, MD, PhD
Markus Hozl, PhD
Chiara Borsotti, PhD
David Woodland, MD
Nichole Danzl, PhD
Yojiro Kato, MD
1. Zhao Y, Swenson K, Sergio JJ, Arn JS, Sachs DH, Sykes M. Skin graft tolerance across a discordant xenogeneic barrier. Nat. Med. 1996:2(11):1211-1216.
2. Wekerle T, Kurtz J, Ito H, Ronquillo JV, Dong V, Zhao G, Shaffer JM, Sayegh MH, Sykes M. Allogeneic bone marrow transplantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat. Med. 2000;6:464-469.
3. Nikolic B, Takeuchi Y, Leykin I, Smith RN, Sykes M. Mixed hematopoietic chimerism allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 2004;53(2)376-383.
4. Sykes M, Nikolic B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature 2005;435:620-627.
5. Chakraverty R, Cote D, Buchli J, Cotter P, Hsu R, Zhao G, Sachs T, Pitsilldes C, Bronson R, Means T, Lin C, Sykes M. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J. Exp. Med. 2006;203(8):2021-2031.
6. Yang Y and Sykes M. Xenotransplantation - Current status and a perspective on the future. Nat. Rev. Immunol. 2007; 7(7):519-531.
7. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman S, Shaffer J, Preffer F, Ding R, Sharma V, Fishman J, Dey BR, Ko D, Hertl M, Goes N, Wong W, Williams W, Colvin RB, Sykes M, and Sachs DH. HLA-mismatched renal transplantation without maintenance immunosupression. New Engl. J. Med. 2008; 358(4): 353-361. PMCID: 18216355.
8. Gibbons C and Sykes M. Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed chimerism. Immunol. Rev. 2008; 223: 334-360. PMCID: 2680695.
9. Andreola G, Chittenden M, Shaffer J, Cosimi A.B, Kawai T, Cotter P, LoCascio SA, Morokata T, Dey BR, Tolkoff-Rubin NT, Preffer F, Bonnefoix T, Kattleman K, Spitzer TR, Sachs DH, Sykes M. Mechanisms of Donor-Specific Tolerance in Recipients of Haploidentical Combined Bone Marrow/Kidney Transplantation. Am J Transplant. 2011 Jun;11(6):1236-1247. doi: 10.1111/j.1600-6143.2011.03566 PMID: 21645255.
10. Lucas C, Workman CJ, Beyaz S, LoCascio S, Zhao G, Vignali DAA, Sykes M. LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L. Blood. 2011 May 19;117(20):5532-40 PMID: 21422469.