Megan Sykes, M.D.
This laboratory is engaged in studies of bone marrow transplantation (BMT) directed toward two clinical applications: 1) the treatment of hematologic malignancies; and 2) the induction of specific transplantation tolerance.
Toward the first goal, we are attempting to understand the basis for our observation that, under certain circumstances, graft-vs-host (GVH) alloresponses can remain within the lymphohematopoietic system where they mediate graft-vs-leukemia (GVL) responses, without accumulating in the parenchymal target tissues where graft-versus-host disease (GVHD) occurs. We are investigating the basis of this behavior in mouse models and have recently 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. We are analyzing clinical material from a clinical bone marrow transplantation trial that is based on this approach to separating GVL from GVHD. Based on some surprising results obtained in one of these trials, we hypothesized that rejection of donor marrow in recipients prepared with less toxic, non-myeloablative regimens, might lead to anti-tumor responses. We have demonstrated in the mouse model that this is indeed the case, and that this effect is associated with the generation of tumor-specific cytotoxic responses. Studies are ongoing to understand the complex pathway, probably involving the indirect alloresponse that leads to this phenomenon, which provides a potential means of achieving anti-tumor responses without the risk of GVHD. We are beginning a clinical trial of this approach and will study the patients' anti-tumor responses in the laboratory.
Toward the second goal, we have focused on the development of non-toxic, non-myeloablative conditioning regimens using monoclonal antibodies or costimulatory blockade to eliminate host resistance to engraftment of allogeneic and xenogeneic bone marrow cells and allow creation of a mixed chimeric state, and hence the induction of specific transplantation tolerance. The clinical use of such approaches could obviate the need for risky chronic immunosuppressive therapy. We are attempting 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. We have obtained evidence that both activation-induced cell death and passive cell death lead to early deletion of these donor-reactive cells. Anergy precedes the death of peripheral donor-reactive T cells, and studies are in progress to understand these phenomena in more detail. We have begun clinical studies of the mixed chimerism approach to induce renal allograft tolerance, and our laboratory is actively investigating the mechanisms involved in tolerance in this unique cohort of patients.
Please see the Columbia Center for Translational Immunology (CCTI) website
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- 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. Epub 2011 Mar 21.
- 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.