Megan Sykes, M.D.
Major areas of focus in the Sykes lab include hematopoietic cell transplantation, organ allograft tolerance induction, xenotransplantation tolerance and Type 1 diabetes.
Dr. Sykes and her team have developed novel strategies for achieving graft-versus-tumor effects without graft-versus-host disease following hematopoietic cell transplantation (HCT). One strategy involved their observation that graft-vs-host (GVH) alloresponses can remain within the lymphohematopoietic system, where they mediate graft-vs-leukemia (GVL) responses, without accumulating in the epithelial target tissues where graft-versus-host disease (GVHD) occurs. We demonstrated a critical role of GVHD target tissue inflammation, such as that induced by toll-like receptor stimuli, in converting a beneficial "lymphohematopoietic GVH response" to GVHD. This control by inflammation is elicited at the level of access of activated GVH-reactive T cells to the GVHD target tissues. Clinical non-myeloablative HCT trials have been carried out on the basis of this approach to separating GVL from GVHD.
The Sykes lab has pioneered minimal conditioning approaches for using HCT to achieve allograft tolerance. These include monoclonal antibodies or costimulatory blockade to eliminate host resistance to engraftment of allogeneic and xenogeneic bone marrow cells, allowing creation of a mixed chimeric state, and with it the induction of specific transplantation tolerance. Studies to understand the mechanisms of peripheral tolerance of CD4 and CD8 T cells that encounter donor antigens on bone marrow cells in the presence of costimulatory blockade provided evidence that anergy precedes specific deletion of peripheral donor-reactive T cells, and this is followed by central deletional tolerance of donor-reactive T cells that develop after chimerism is established. Insights into the roles of PD-1, LAG-3, indirect presentation and various cell-cell interactions in the peripheral tolerance processes have been published by our group.
The safety and efficacy of the above clinical approach to separating GVHD and GVL, which also involved non-myeloablative induction of mixed chimerism across HLA barriers, allowed trials of HCT for the induction of organ allograft tolerance, intentionally achieving allograft tolerance in humans for the first time. The lab has analyzed the mechanism of this tolerance, which was achieved without GVHD, but with only transient chimerism. Our studies suggested that regulatory T cells (Tregs) were involved in the initial achievement of tolerance, but that either deletion or anergy is involved in the longer term. To distinguish between the latter two mechanisms, we recently developed a novel new generation sequencing-based approach to identify and track the entire TCR repertoire of donor-specific alloreactive T cells in human transplant recipients. These studies provided evidence for eventual clonal deletion of donor-specific T cell clones in tolerant patients, provided a new window into the fate of alloreactive T cells after transplant, and may provide a new, specific biomarker that is being explored in other transplant populations. Additionally, we are now able to probe and understand the human alloresponse at a new level. Major efforts in the lab include both pre-clinical and clinical studies of non-myeloablative hematopoietic cell transplantation to improve the induction of allograft tolerance and extend it to other graft types besides the kidney.
A recent new direction for the lab is the analysis of lymphocyte turnover, chimerism and T cell trafficking in patients receiving intestinal and liver transplants. We are obtaining surprising and novel insights into the exchange and origin of human lymphoid populations in the intestinal graft and the recipient and into the fate of alloreactive lymphocytes during rejection. We are using our new TCR tracking approach to understand the interplay of GVH and host-vs-graft alloresponses in these phenomena.
Because of the inadequate supply of human organs for transplantation and the strong immune response to xenografts, another major focus of work in the Sykes lab has been the induction of xenograft tolerance. Two approaches have been pioneered in the lab, namely the induction of mixed xenogeneic chimerism and xenogeneic thymic transplantation. The latter approach has led, for the first time, to long-term kidney xenograft survival in non-human primates. The lab is now focused on using humanized mice to study the impact of differentiation in a xenogeneic (porcine) thymus on T cell homeostasis and function. We have also demonstrated that mixed xenogeneic chimerism achieves natural killer cell and natural antibody-producing B cell tolerance, in addition to T cell tolerance, and we are focused on the mechanisms by which tolerance is achieved for these innate immune components.
More recently, the Sykes lab has extended the HCT approach to the problem of reversing autoimmunity while replacing destroyed islets of Langerhans in Type 1 diabetes. We have developed novel "humanized mouse" models that allow personalized analysis of human immune disorders and therapies. These models are currently being used in studies of Type 1 diabetes and rheumatoid arthritis pathogenesis using the "Personalized Immune" mouse.
Please see the Columbia Center for Translational Immunology (CCTI) website
for more information.
- Morris, H., DeWolf, S., Robins, H., Sprangers, B., Locascio, S.A., Shonts, B., Kawai, T., Wong, W., Yang, S., Zuber, J., Shen, Y. and Sykes, M. (2015) Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients. Science Transl. Med. 7: 272ra10.
- Kalscheuer, H., Onoe, T., Dahmani, A., Holzl, M., Yamada, K. and Sykes, M. (2014). Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts. J. Immunol. 192: 3442-3450.
- Griesemer, A., Yamada, K. amd Sykes, M. (2014). Xenotransplantation: Immunological hurdles and progress toward tolerance. Immunol. Rev. 258: 241-258.
- Haspot, F., Li, H.W., Lucas, C.L., Fehr, T., Beyaz, S. and Sykes, M. (2014) Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. Am. J. Transplant. 14: 49-58.
- Kawai, T., Sachs, D.H., Sykes, M. and Cosimi, A.B. for the Immune Tolerance Network (2013). HLA mismatched renal transplantation without maintenance immunosuppression-an update. Letter to the Editor. N. Engl. J. Med. 368: 1850-1852.
- Kalscheuer, H., Danzl, N., Onoe, T., Faust, T., Winchester, R., Goland, R., Greenberg, E., Spitzer, T.R., Savage, D.G., Tahara, H., Choi, G., Yang, Y.-G. and Sykes, M. (2012) A model for personalized in vivo analysis of human immune responsiveness. Science Transl. Med. 4: 125ra30.
- Li, H.W. and Sykes, M. (2012) Emerging concepts in haematopoietic cell transplantation. Nature Rev. Immunol. 12: 403-416. Review.
- Li, H.W., Sachs, J., Pichardo, C., Bronson, R., Zhao, G. and Sykes, M. (2012) Nonalloreactive T cells prevent donor lymphocyte infusion-induced graft-versus-host disease by controlling microbial stimuli. J. Immunol. 189: 5572-5581.
- Lucas, C.L., Workman, C.J., Beyaz, S., LoCascio, S., Zhao, G., Vignali, D.A. and Sykes, M. (2011) LAG-3, TGF-beta, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L. Blood 117: 5532-5540.
- Flutter, B., Edwards, N., Fallah-Arani, F., Henderson, S., Chai, J.G., Sivakumaran, S., Ghorashian, S., Bennett, C.L., Freeman, G.J., Sykes, M. and Chakraverty, R. (2010) Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J. Clin. Invest. 120: 3855-3868.
- Fehr, T., Lucas, C.L., Kurtz, J., Onoe, T., Zhao, G., Hogan, T., Vallot, C., Rao, A. and Sykes, M. (2010) A CD8 T cell-intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo. Blood 115: 1280-1287.
- Kurtz, J., Raval, F., Vallot, C., Der, J. and Sykes, M. (2009) CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance. Blood 113: 3475-3484.
- Fudaba, Y., Onoe, T., Chittenden, M., Shimizu, A., Shaffer, J.M., Bronson, R. and Sykes, M. (2008) Abnormal regulatory and effector T cell function predispose to autoimmunity following xenogeneic thymic transplantation. J. Immunol. 181: 7649-7659.
- Fehr, T., Wang, S., Haspot, F., Kurtz, J., Blaha, P., Hogan, T., Chittenden, M., Wekerle, T. and Sykes, M. (2008) Rapid deletional peripheral CD8 T cell tolerance induced by allogeneic bone marrow: role of donor class II MHC and B cells. J. Immunol. 181: 4371-4380.
- Haspot, F., Bardwell, P.D., Zhao, G. and Sykes, M. (2008) High antigen levels do not preclude B-cell tolerance induction to alpha1,3-Gal via mixed chimerism. Xenotransplantation 15: 313-320.
- Fehr, T., Haspot, F., Mollov, J., Chittenden, M., Hogan, T. and Sykes, M. (2008) Alloreactive CD8 T cell tolerance requires recipient B cells, dendritic cells, and MHC class II. J. Immunol. 181: 165-173.
- Haspot, F., Fehr, T., Gibbons, C., Zhao, G., Hogan, T., Honjo, T., Freeman, G.J. and Sykes, M. (2008) Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway. Blood 112: 2149-2155.
- Kawai, T., Cosimi, A.B., Spitzer, T.R., Tolkoff-Rubin, N., Suthanthiran, M., Saidman, S.L., Shaffer, J., Preffer, F.I., Ding, R., Sharma, V., Fishman, J.A., Dey, B., Ko, D.S., Hertl, M., Goes, N.B., Wong, W., Williams, W.W. Jr, Colvin, R.B., Sykes, M. and Sachs, D.H. (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358: 353-361.
- Hongo, D., Hadidi, S., Damrauer, S., Garrigue, V., Kraft, D., Sachs, D.H., Nikolic, B. and Sykes, M. (2007) Porcine thymic grafts protect human thymocytes from HIV-1-induced destruction. J. Infect. Dis. 196: 900-910.
- Shimizu, I., Kawahara, T., Haspot, F., Bardwell, P.D., Carroll, M.C. and Sykes, M. (2007) B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-alphaGAL-producing B-1 cells. Blood 109: 1773-1781.
- Chakraverty, R., Cote, D., Buchli, J., Cotter, P., Hsu, R., Zhao, G., Sachs, T., Pitsillides, C.M., Bronson, R., Means, T., Lin, C. and Sykes, M. (2006) An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J. Exp. Med. 203: 2021-2031.
- Chakraverty, R., Eom, H.S., Sachs, J., Buchli, J., Cotter, P., Hsu, R., Zhao, G. and Sykes, M. (2006). Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 108: 2106-2113.
- Kim, Y.M., Mapara, M.Y., Down, J.D., Johnson, K.W., Boisgerault, F., Akiyama, Y., Benichou, G., Pelot, M., Zhao, G. and Sykes, M.(2004) Graft-versus-host-reactive donor CD4 cells can induce T cell-mediated rejection of the donor marrow in mixed allogeneic chimeras prepared with nonmyeloablative conditioning. Blood 103: 732-739.
- Rubio, M.T., Kim, Y.M., Sachs, T., Mapara, M., Zhao, G. and Sykes, M. (2003) Antitumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-gamma. Blood 102: 2300-2307.
- Zhao, Y., Ohdan, H., Manilay, J.O. and Sykes, M. (2003) NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 170: 5398-5405.
- Kim, Y.M., Sachs, T., Asavaroengchai, W., Bronson, R. and Sykes, M (2003) Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J. Clin. Invest. 111: 659-669.
- Rodriguez-Barbosa, J.I., Zhao, Y., Zhao, G., Ezquerra, A. and Sykes, M. (2002) Murine CD4 T cells selected in a highly disparate xenogeneic porcine thymus graft do not show rapid decay in the absence of selecting MHC in the periphery. J. Immunol. 169: 6697-6710.
- Nikolic, B., Lee, S., Bronson, R.T., Grusby, M.J. and Sykes, M. (2000) Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J. Clin. Invest. 105: 1289-1298.
- Wekerle, T., Kurtz, J., Ito, H., Ronquillo, J.V., Dong, V., Zhao, G., Shaffer, J., Sayegh, M.H. and Sykes, M. (2000) Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nature Medicine 6: 464-469.
- Nikolic, B., Gardner, J.P., Scadden, D.T., Arn, J.S., Sachs, D.H. and Sykes, M. (1999) Normal development in porcine thymus grafts and specific tolerance of human T cells to porcine donor MHC. J. Immunol. 162: 3402-3407.
- Ohdan, H., Yang, Y.G., Shimizu, A., Swenson, K.G. and Sykes, M. (1999) Mixed chimerism induced without lethal conditioning prevents T cell- and anti-Gal alpha 1,3Gal-mediated graft rejection. J. Clin. Invest. 104: 281-290.
- Yang, Y.G., deGoma, E., Ohdan, H., Bracy, J.L., Xu, Y., Iacomini, J., Thall, A.D. and Sykes, M. (1998) Tolerization of anti-Galalpha1-3Gal natural antibody-forming B cells by induction of mixed chimerism. J. Exp. Med. 187: 1335-1342.
- Zhao, Y., Swenson, K., Sergio, J.J., Arn, J.S., Sachs, D.H. and Sykes, M. (1996) Skin graft tolerance across a discordant xenogeneic barrier. Nature Medicine 2: 1211-1216.
- Lee, L.A., Gritsch, H.A., Sergio, J.J., Arn, J.S., Glaser, R.M., Sablinski, T., Sachs, D.H., Sykes, M. (1994) Specific tolerance across a discordant xenogeneic transplantation barrier. Proc. Natl. Acad. Sci. U.S.A. 91: 10864-10867.
- Gibbons, C. and Sykes, M. (2008) Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed hematopoietic chimerism. Immunol. Rev. 223: 334-360.
- Yang, Y.G. and Sykes, M. (2007) Xenotransplantation: current status and a perspective on the future. Nature Reviews Immunology 7: 519-531.
- Chakraverty, R. and Sykes, M. (2007) The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood 110: 9-17.
- Sykes, M. and Nikolic, B. (2005) Treatment of severe autoimmune disease by stem-cell transplantation. Nature 435: 620-627.