Professor Megan Sykes Director, Columbia Center for Translational ImmunologyPhone: 212-304-5696 Fax: 646-426-0019 Lab Phone: 212-305-9459 Email: ms3976@columbia.edu Website: www.cumc.columbia.edu/ccti/

Professor Megan Sykes
Director, Columbia Center for Translational Immunology

Phone: 212-304-5696
Fax: 646-426-0019
Lab Phone: 212-305-9459
Email: ms3976@columbia.edu
Website: www.cumc.columbia.edu/ccti/

Megan Sykes, M.D.

Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences (in Surgery) and Director, Columbia Center for Translational Immunology
Member, National Academy of Medicine
Fellow, American Association for the Advancement of Science
M.D., University of Toronto

Transplantation immunology and Type 1 diabetes

Research
Major areas of focus in the Sykes lab include 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 (LGVHR)” 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 developed a novel high throughput sequencing-based approach to identify and track the 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.  We extended this approach to be able to identify the donor-specific Treg repertoire and demonstrated the expansion of donor-specific Tregs in patients achieving renal allograft tolerance via non-myeloablative mixed chimerism induction.

We recently used the above TCR tracking approach to understand the interplay of GVH and host-vs-graft alloresponses in human intestinal transplantation.  We used this approach in conjunction with phenotypic analyses to understand lymphocyte turnover, chimerism and T cell trafficking in patients receiving intestinal and liver transplants. We obtained 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 discovered that a LGVHR occurs spontaneously in these patients, resulting in engraftment in recipient bone marrow of donor hematopoietic progenitors and stem cells that we found to be carried in the intestinal allograft. This finding has led us to a pilot clinical trial infusing additional donor CD34+ cells at the time of intestinal LGVHR.

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 selection, homeostasis and function and enhancing T cell development through the addition of transgenic HLA molecules in the porcine thymus donor and through construction of a “hybrid” thymus that incorporates human thymic epithelial cells. 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.

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. Using these models, we have discovered genetically-controlled abnormalities in T and B cell homeostasis and selection in T1D patient-derived immune systems and are currently correlating those findings with disease-associated genetic risk variants.  We are modeling autoimmune destruction using human stem cell-derived beta cells in these PI mouse systems.

Please see the Columbia Center for Translational Immunology (CCTI) website for more information.

 

Selected Publications

  1. Sykes. M. (2022) Developing pig-to-human organ transplants. Science 378: 135-136. doi: 10.1126/science.abo7935. Epub 2022 Oct 13. PMID: 36227981 PMCID: PMC9671127

  2. Sykes, M. and Sachs, D.H. (2022) Progress in xenotransplantation: overcoming immune barriers. Nature Rev. Nephrol. 18: 745-761. doi: 10.1038/s41581-022-00624-6. Epub 2022 Oct 5

  3. Vecchione, A., Madley, R., Danzl, N.M., Borsotti, C., Khosravi-Maharlooei, M., Li, H.W., Nauman, G., Ding, X., Ho, S.H., Fousteri, G. and Sykes, M. (2022) T1D patient-derived hematopoietic stem cells are programmed to generate Tph, Tfh, and autoimmunity-associated B cell subsets in human immune system mice. Clin. Immunol. 240: 109048. doi: 10.1016/j.clim.2022.109048. Epub 2022 May 26. PMID: 35644520 PMCID: PMC9564152 (available on 2023-07-01)

  4. Nauman, G., Danzl, N.M., Lee, J., Borsotti, C., Madley, R., Fu, J., Hölzl, M.A., Dahmani, A., Gonzalez, A.D., Chavez, E., Campbell, S.R., Yang, S., Satwani, P., Liu, K. and Sykes, M. (2022) Defects in long-term APC repopulation ability of adult human bone marrow HSCs compared to fetal liver HSCs. J. Immunol. 208: 1652-1663. doi: 10.4049/jimmunol.2100966. Epub 2022 Mar 21 PMID: 35315788 PMCID: PMC8976823

  5. Podesta, M. and Sykes, M. (2022) Chimerism-based tolerance to kidney allografts in humans: novel insights and future perspectives. Front. Immunol. 12: 791725. doi: 10.3389/fimmu.2021.791725. eCollection 2021. PMID: 35069574 PMCID: PMC8767096, pp 70-76

  6. Gras-Pena, R., Danzl, N.M., Khosravi-Maharlooei, M., Campbell, S.R., Ruiz, A.E., Parks, C.A., Savage, W.M.S., Hozl, M.A., Chatterjee, D. and Sykes, M. (2022) Human stem cell-derived thymic epithelial cells  enhance human T cell development in a xenogeneic thymus. J. Allergy Clin. Immunol. 149: 1755-1771. doi: 10.1016/j.jaci.2021.09.038. Epub 2021 Oct 22. PMID: 34695489 PMCID: PMC9023620 (available on 2023-05-01)

  7. Fu, J. and Sykes, M. (2022) Emerging concepts of tissue-resident memory T cells in transplantation. Transplantation 106: 1132-1142. doi: 10.1097/TP.0000000000004000. Epub 2022 Nov 24. PMID: 34873129 PMCID: PMC9127003 (available on 2023-11-24)

  8. Fu, J., Khosravi-Maharlooei, M. and Sykes, M. (2021) High throughput human T cell receptor sequencing: a new window into repertoire establishment and alloreactivity. Front. Immunol. 12: 777756. doi: 10.3389/fimmu.2021.777756. PMID: 34804070 PMCID: PMC8604183

  9. Obradovic, A., Shen, Y., Sykes, M. and Fu, J. (2021) Integrated analysis toolset for defining and tracking alloreactive T-cell clones after human solid organ and hematopoietic stem cell transplantation. Softw. Impacts 10: 100142. doi: 10.1016/j.simpa.2021.100142. Epub 2021 Sep 23. PMID: 35291378 PMCID: PMC8920412

  10. Waffarn, E.E., Khosravi-Maharlooei, M., Vecchione, A., Shao, A., Vishwasrao, P., Hölzl, M.A., Frangaj, K., Sykes, M. and Wei Li, H.W. (2021) Mixed xenogeneic porcine chimerism tolerizes human anti-pig natural antibody-producing cells in a humanized mouse model. Xenotransplantation 28: e12691. doi: 10.1111/xen.12691. Epub 2021 Apr 26. PMID: 33904221 PMCID: PMC8376778

  11. Fu, J., Zuber, J., Shonts, B., Obradovic, A., Wang, Z., Frangaj, K., Meng, W., Rosenfeld, A.M., Waffarn, E.E., Liou, P., Lau, S.P., Savage, T.M., Yang, S., Rogers, K., Danzl, N.M., Ravella, S., Satwani, P., Luga, A., Ho, S.H., Griesemer, A.D., Shen, Y., Luning Prak, E.T., Martinez, M., Kato, T. and Sykes, M. (2021) Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation. J. Clin. Invest. 131: e141698. doi: 10.1172/JCI141698. PMID: 33630757 PMCID: PMC8062082

  12. Khosravi-Maharlooei, M., Li, H.W., Hoelzl, M., Zhao, G., Ruiz, A., Misra, A., Li, Y., Teteloshvili, N., Nauman, G., Danzl, N., Ding, X., Obradovic, A., Yang, Y.G., Luga, A., Creusot, R.J., Winchester, R. and Sykes, M. (2021) Role of the thymus in spontaneous development of a multi-organ autoimmune disease in human immune system mice. J. Autoimmun. 119: 102612. doi: 10.1016/j.jaut.2021.102612. Epub 2021 Feb 19. PMID: 33611150 PMCID: PMC8044037

  13. Madley, R., Nauman, G., Danzl, N., Borsotti, C., Khosravi-Maharlooei, M., Li, H.W., Chavez, E., Creusot, R.J., Nakayama, M., Roep, B. and Sykes, M. (2020) Negative selection of human T cells recognizing a naturally-expressed tissue-restricted antigen in the human thymus. J. Transl. Autoimmun. 3: 100061. doi: 10.1016/j.jtauto.2020.100061. eCollection 2020. PMID: 32875283 PMCID: PMC7451786

  14. Nauman, G., Borsotti, C., Danzl, N., Khosravi-Maharlooei, M., Li, H.W., Chavez, E., Stone, S. and Sykes, M. (2022) Reduced positive selection of a human TCR in a swine thymus using a humanized mouse model for xenotolerance induction. Xenotransplantation 27: e12558. doi: 10.1111/xen.12558. Epub 2019 Sep 29. PMID: 31565822 PMCID: PMC7007369

  15. Watanabe, H., Ariyoshi, Y., Pomposelli, T., Takeuchi, K., Ekanayake-Alper, D.K., Boyd, L.K., Arn, S.J., Sahara, H., Shimizu, A., Ayares, D., Lorber, M.I., Sykes, M., Sachs, D.H. and Yamada, K. (2020) Intra-bone bone marrow transplantation from hCD47 transgenic pigs to baboons prolongs chimerism to >60 days and promotes increased porcine lung transplant survival. Xenotransplantation 27: e12552. doi: 10.1111/xen.12552. Epub 2019 Sep 23. PMID: 31544995 PMCID: PMC7007336 

  16. Khosravi-Maharlooei, M., Hoelzl, M., Li, H., Madley, R., Waffarn, E., Danzl, N. and Sykes, M. (2020) Rapid thymectomy of NSG mice to analyze the role of native and grafted thymi in humanized mice. Eur. J. Immunol. 50: 138-141. doi: 10.1002/eji.201948205. Epub 2019 Nov 28.  PMID: 31583677 PMCID: PMC6940512 

  17. Savage, T.M., Shonts, B.A., Lau, S., Obradovic, A., Robbins, H., Shaked, A., Shen, Y. and Sykes, M. (2020) Deletion of donor-reactive T cell clones after human liver transplant. Am. J. Transplant. 20: 538-545. doi: 10.1111/ajt.15592. Epub 2019 Oct 3. PMID: 31509321 PMCID: PMC6984984

  18. Podestà, M.A., Binder, C., Sellberg, F., DeWolf, S., Shonts, B., Ho, S.H., Obradovic, A., Waffarn, E., Danzl, N., Berglund, D. and Sykes, M. (2020) Siplizumab selectively depletes effector memory T-cells and promotes a relative expansion of alloreactive regulatory T-cells in vitro. Am. J. Transplant. 20: 88-100. doi: 10.1111/ajt.15533. PMID: 31319439 PMCID: PMC6940533. Epub 2019 Aug 13  

  19. Sykes, M. and Sachs, D.H. Transplanting organs from pigs to humans. (2019) Science Immunol. 4: eaau6298. doi: 10.1126/sciimmunol.aau6298. PMID: 31676497 PMCID: PMC7293579

  20. Sykes, M. and Griesemer, A.D. (2019) Transplantation tolerance in nonhuman primates and humans. Bone Marrow Transplant. 54: 815-821. doi: 10.1038/s41409-019-0620-3. PMID: 31431694 PMCID: PMC7323053 

  21. Khosravi-Maharlooei, M., Obradovic, A., Misra, A., Motwani, K., Holzl, M., Seay, H.R., DeWolf, S., Nauman, G., Danzl, N., Li, H., Ho, S.H., Winchester, R., Shen, Y., Brusko, T.M. and Sykes, M. (2019) Crossreactive public TCR sequences undergo positive selection in the human thymic repertoire. J. Clin. Invest. 129: 2446-2462. doi: 10.1172/JCI124358. PMCID: PMC6546456 (Commentary provided by Antonio La Cava, M.D., Ph.D.: La Cava, A. (2019) Human T cell repertoire: what happens in thymus does not stay in thymus. J. Clin. Invest. 129: 2195-2197 https://doi.org/10.1172/JCI128371. PMCID: PMC654647)

  22. Fu, J., Zuber, J., Martinez, M., Shonts, B., Obradovic, A., Wang, H., Lau, S.P., Xia, A., Waffarn, E.E., Frangaj, K., Savage, T.M., Simpson, M.T., Yang, S., Guo, X.V., Miron, M., Senda, T., Rogers, K., Rahman, A., Ho, S.H., Shen, Y., Farber, D., Griesemer, A., Kato, T. and Sykes, M. (2019) Human intestinal allografts contain functional hematopoietic stem and progenitor cells that are maintained by a circulating pool. Cell Stem Cell 24: 227-239.e8. doi: 10.1016/j.stem.2018.11.007. Epub 2018 Nov 29. PMCID: PMC6398344 (Commentary provided by Norma Sue Kenyon, Ph.D.: Kenyon N.S. (2019) We could use more tolerance: role of intestinal-allograft-derived human stem cells. Cell Stem Cell 24: 197-198. doi: 10.1016/j.stem.2019.01.009)

  23. Savage, T.M., Shonts, B.A., Obradovic, A., Dewolf, S., Lau, S., Zuber, J., Simpson, M.T., Berglund, E., Fu, J., Yang, S., Ho, S.H., Tang, Q., Turka, L.A., Shen, Y. and Sykes, M. (2018) Early expansion of donor-specific Tregs in tolerant kidney transplant recipients. JCI Insight 3: 124086.

  24. Sui, L., Danzl, N., Campbell, S.R., Viola, R., Williams, D., Xing, Y., Wang, Y., Phillips, N., Poffenberger, G., Johannesson, B., Oberholzer, J., Powers, A.C., Leibel, R.L., Chen, X., Sykes, M. and Egli, D. (2018) beta-cell replacement in mice using human type 1 diabetes nuclear transfer embryonic stem cells. Diabetes 67: 26-35.

  25. Zuber, J. and Sykes, M. (2017) Mechanisms of mixed chimerism-based transplant tolerance. Trends Immunol. 38: 829-843.

  26. DeWolf, S. and Sykes, M. (2017) Alloimmune T cells in transplantation. J. Clin. Invest. 127: 2473-2481.

  27. Sprangers, B., DeWolf, S., Savage, T.M., Morokata, T., Obradovic, A., LoCascio, S.A., Shonts, B., Zuber, J., Lau, S.P., Shah, R., Morris, H., Steshenko, V., Zorn, E., Preffer, F.I., Olek, S., Dombkowski, D.M., Turka, L.A., Colvin, R., Winchester, R., Kawai, T. and Sykes, M. (2017) Origin of enriched regulatory T cells in patients receiving combined kidney-bone marrow transplantation to induce transplantation tolerance. Am. J. Transplant. 17: 2020-2032.

  28. Li, H.W., Vishwasrao, P., Holzl, M.A., Chen, S., Choi, G., Zhao, G. and Sykes, M. (2017) Impact of mixed xenogeneic porcine hematopoietic chimerism on human NK cell recognition in a humanized mouse model. Am. J. Transplant. 17: 353-364.

  29. Tan, S., Li, Y., Xia, J., Jin, C.H., Hu, Z., Duinkerken, G., Li, Y., Khosravi Maharlooei, M., Chavez, E., Nauman, G., Danzl, N., Nakayama, M., Roep, B.O., Sykes, M. and Yang, Y.G. (2017) Type 1 diabetes induction in humanized mice. Proc. Natl. Acad. Sci. U.S.A. 114: 10954-10959.

  30. Weiner, J., Zuber, J., Shonts, B., Yang, S., Fu, J., Martinez, M., Farber, D.L., Kato, T. and Sykes, M. (2017) Long-term persistence of innate lymphoid cells in the gut after intestinal transplantation. Transplantation 101: 2449-2454.

  31. Zuber, J., Shonts, B., Lau, S.P., Obradovic, A., Fu, J., Yang, S., Lambert, M., Coley, S., Weiner, J., Thome, J., DeWolf, S., Farber, D.L., Shen, Y., Caillat-Zucman, S., Bhagat, G., Griesemer, A., Martinez, M., Kato, T. and Sykes, M. (2016) Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Science Immunol. 1: eaah3732.

  32. DeWolf, S., Shen, Y. and Sykes, M. (2016) A new window into the human alloresponse. Transplantation 100: 1639-1649.

  33. Hirata, Y., Li, H.W., Takahashi, K., Ishii, H., Sykes, M. and Fujisaki, J. (2015) 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 10: e0141785.

  34. Li, H.W., Andreola, G., Carlson, A.L., Shao, S., Lin, C.P., Zhao, G. and Sykes, M. (2015) rapid functional decline of activated and memory graft-versus-host-reactive T cells encountering host antigens in the absence of inflammation. J. Immunol. 195: 1282-1292.

  35. Zuber, J., Rosen, S., Shonts, B., Sprangers, B., Savage, T.M., Richman, S., Yang, S., Lau, S.P., DeWolf, S., Farber, D., Vlad, G., Zorn, E., Wong, W., Emond, J., Levin, B., Martinez, M., Kato, T. and Sykes, M. (2015) Macrochimerism in intestinal transplantation: association with lower rejection rates and multivisceral transplants, without GVHD. Am. J. Transplant. 15: 2691-2703.

  36. 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.

  37. 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.

  38. Griesemer, A., Yamada, K. amd Sykes, M. (2014). Xenotransplantation: Immunological hurdles and progress toward tolerance. Immunol. Rev. 258: 241-258.

  39. 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.

  40. 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.

  41. 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.

  42. Li, H.W. and Sykes, M. (2012) Emerging concepts in haematopoietic cell transplantation. Nature Rev. Immunol. 12: 403-416. Review.

  43. 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.

  44. 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.

  45. 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.

  46. 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.

  47. 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.

  48. 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.

  49. 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.

  50. 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.

  51. 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.

  52. 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.

  53. 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.

  54. 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.

  55. 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.

  56. 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.

  57. 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.

  58. 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.

  59. 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.

  60. Zhao, Y., Ohdan, H., Manilay, J.O. and Sykes, M. (2003) NK cell tolerance in mixed allogeneic chimeras. J. Immunol. 170: 5398-5405.

  61. 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.

  62. 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.

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