Megan Sykes, M.D., is the Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences (in Surgery) at Columbia University. She is the founding Director of the Columbia Center for Translational Immunology (CCTI) at Columbia University, Director of Research for the Transplant Initiative at Columbia University Medical Center (CUMC) and Director of Bone Marrow Transplantation Research, Division of Hematology/Oncology at CUMC. Dr. Sykes completed her MD training at the University of Toronto in 1982, after which she completed a medical residency, then moved to the National Institutes of Health, Bethesda, MD in 1985 as a Fogarty Visiting Associate. She joined the Massachusetts General Hospital and Harvard Medical School as an Assistant Professor in 1990 and was tenured as a full Professor in 1999, then named to the Harold and Ellen Danser Chair in Surgery. She moved to Columbia University in 2010 to establish the CCTI, which now includes a thriving pre-clinical transplant program and a staff of 115 people, including 19 faculty members, 16 laboratory programs in transplantation, autoimmune disease, infection and cancer immunology and 6 core facilities.
Dr. Sykes introduced the idea that graft-versus-leukemia/lymphoma effects could be separated from graft-versus-host disease (GVHD) following hematopoietic cell transplantation (HCT) by allowing GVH-reactive T cells to expand while preventing migration to the epithelial GVHD target tissues. She showed that inflammation was a critical checkpoint for such migration, which was avoided when GVH-reactive T cells were administered after conditioning-induced inflammation had subsided in mixed chimeras. These studies led to clinical trials of non-myeloablative haploidentical HCT that achieved mixed chimerism across HLA barriers without GVHD. These results paved the way for the first clinical trials of mixed chimerism that achieved renal allograft tolerance across HLA barriers. Dr. Sykes dissected the role of intrathymic and peripheral tolerance mechanisms and pioneered minimal conditioning approaches for using HCT to achieve allograft and xenograft tolerance. Her work demonstrated that (and identified mechanisms by which) mixed chimerism achieves natural antibody-producing B cell tolerance and NK cell tolerance in addition to T cell tolerance. She developed a method of tracking the alloreactive T cell repertoire in human transplant recipients and has used it along with other techniques to understand T lymphocyte dynamics in the graft and the periphery of human transplant recipients. This work led to the discovery of hematopoietic progenitors in the human intestinal mucosa and demonstration of their turnover from a circulating pool in human intestinal allograft recipients. She has pioneered the development and use of humanized mouse models for the study of Type 1 diabetes and for xenograft tolerance induction. Her work on xenogeneic thymic transplantation for tolerance induction led, for the first time, to long-term kidney xenograft survival in non-human primates.
Dr. Sykes has published more than 490 papers and chapters describing her work. She has served on the Transplantation Society (TTS) Council and has been President of the International Xenotransplantation Association (IXA) and Vice President of TTS. She has received many honors and awards, including the Wyeth-Ayerst Young Investigator Award from the American Society of Transplant Physicians (1998), the AST Basic Science Established Investigator Award (2007), the TTS Roche Award for Outstanding Achievement in Transplantation Science (Basic) (2010), the TTS Award for Outstanding Achievement in Transplantation (Basic Science) (2014), and the 2018 Medawar Prize. She is a member of the Association of American Physicians, a Distinguished Fellow of the American Association of Immunologists, a Fellow of the American Association for the Advancement of Science, and an Honorary Member of IXA. She was inducted into the Institute of Medicine of the National Academies (now the National Academy of Medicine) in 2009. Dr. Sykes is President of the Federation of Clinical Immunology Societies (FOCIS).
The first report of three-way macrochimerism and alloreactivity using single cell profiling in a patient receiving multivisceral transplantation following loss of an initial liver-intestine transplant
Nathan Suek1, Wenyu Jiao1, Grant Feuer1, Katherine D Long1, Constanza B Muntnich1, Adriana P Rey1, Kristjana Frangaj1, Rebecca Jones1, Alaka Gorur1, Peter Liou2, Prakash Satwani3, Adam Griesemer1,2, Joshua Weiner1,2, Mercedes Martinez3, Tomoaki Kato2, Megan Sykes1,2,4, Jianing Fu1.
1Columbia Center for Translational Immunology, Columbia University, New York, NY, United States; 2Department of Surgery, Columbia University, New York, NY, United States; 3Department of Pediatrics, Columbia University, New York, NY, United States; 4Department of Microbiology and Immunology, Columbia University, New York, NY, United States
Purpose: We previously showed that macrochimerism (≥4% peak level of donor T cells) in recipient blood and slower replacement of donor T cells in the intestinal allograft by the recipient are associated with less rejection. Three-way chimerism and alloreactivity following re-transplantation have not been explored.
Methods: We monitored blood and intragraft chimerism of a patient who rejected a liver-intestinal transplant (LITx) and subsequently received a multivisceral transplant (MVTx). The recipient and two donors were distinguished by HLA allele-specific antibodies using flow cytometry. T cells of Donor 2 origin were analyzed using single cell TCRαβ and RNA sequencing. Alloreactive graft 2 vs host (G2vH) or graft 2 vs graft 1 (G2vG1) clones were identified using bulk TCR sequencing on proliferated cells in mixed lymphocyte reactions.
Results: The patient received LITx at 20 months of age from a 3-month-old donor (Donor 1). Severe rejection occurred on postoperative day 19 (POD19) and graft failure was complete by POD786 with donor blood chimerism never exceeding 2.36% (on POD9). Meanwhile, recipient T cell chimerism in the graft surpassed 95% by POD19. The patient received MVTx from a 19-month-old donor (Donor 2) on POD786. Four episodes of mild rejection and one of mild-moderate rejection occurred over the next 5 years. Blood macrochimerism from Donor 2 peaked at 29.9% on POD20. Macrochimerism from Donor 1 peaked at 8.98% on POD48 after the 2nd Tx. Recipient T cell chimerism in the 2nd graft was < 25% by POD251, but increased to 94-99% by POD377, and remained > 80% through POD1004. We detected shared Donor 2 T cell clones between the baseline POD0 gut sample with POD8/20 PBMCs and/or POD126 bone marrow, consistent with migration of Donor 2 T cells from the intestinal graft into the recipient hematopoietic system. Among those samples, G2vH and G2vG1 CD8 clones had cytotoxic effector phenotypes but had mostly distinct clonotypes. In contrast, late (POD1004) intragraft G2vH and G2vG1 clones expressed primarily tissue-resident memory (TRM) phenotypes, consistent with long-term persistence of donor TRMs in quiescent grafts.
Conclusion: We provide the first report of three-way macrochimerism and alloreactivity in a patient receiving multiple intestinal transplants. These data elucidate the complex multidirectional alloresponse in intestinal transplant and form the basis for future studies to enhance tolerance.
National Institute of Allergy and Infectious Diseases (NIAID) under grant P01 AI106697. Department of Defense, under a Congressionally Directed Medical Research Program Discovery Award W81XWH-20-1-0159. Nelson Family Transplantation Innovation Award Program at the Columbia University Irving Medical Center under the Nelson Faculty Development Awards .
[1] Intestinal transplantation
[2] Immune cell profiling
[3] Chimerism
[4] Bidirectional alloresponse
