American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant SurgeonsFriday, December 13, 2013
Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, nonimmunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of preexisting alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC Class I-deficient and Class I/Class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC Class I-deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC Class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a T cell receptor-independent manner, of Class I-deficient donor cells.
Distribution and Compartmentalization of Human Circulating and Tissue-Resident Memory T Cell SubsetsImmunity, December 2012Thursday, December 20, 2012
Knowledge of human T cells derives chiefly from studies of peripheral blood, whereas their distribution and function in tissues remains largely unknown. Here, we present a unique analysis of human T cells in lymphoid and mucosal tissues obtained from individual organ donors, revealing tissue-intrinsic compartmentalization of naive, effector, and memory subsets conserved between diverse individuals. Effector memory CD4+ T cells producing IL-2 predominated in mucosal tissues and accumulated as central memory subsets in lymphoid tissue, whereas CD8+ T cells were maintained as naive subsets in lymphoid tissues and IFN-γ-producing effector memory CD8+ T cells in mucosal sites. The T cell activation marker CD69 was constitutively expressed by memory T cells in all tissues, distinguishing them from circulating subsets, with mucosal memory T cells exhibiting additional distinct phenotypic and functional properties. Our results provide an assessment of human T cell compartmentalization as a new baseline for understanding human adaptive immunity.
Dr. Sykes speaks to WNYC's "The Takeaway"Thursday, September 27, 2012
Tuesday, September 25, 2012
Dr Megan Sykes speaks to the New York Times about the benefits and challenges of the Humanized Mouse Model. Read the entire story here.
"If Gandhi were a stem cell, which would he be?" by Holly WobmaWednesday, July 11, 2012
Friday, March 16, 2012
"Immune Mouse that Fully Recapitulates Individual Human Immune System Developed" in Genetic Engineering & Biotechnology NewsThursday, March 15, 2012
Scientists report on the development of a mouse model that recapitulates the immune system of a single adult human. In contrast with existing humanized mouse models with immune systems derived from transplanted fetal hematopoietic stem cells (HSCs), the immune system of the model described by the Massachusetts General Hospital and Columbia University Medical Center team is derived from a relatively few adult human HSCs. These could effectively be taken from any human volunteer or patient.
Megan Sykes, M.D., and colleagues, say the the resulting "personalized immune" (PI) mice generated a robust and diverse repertoire of fully functional T cells that were self-tolerant, and exhibited immune responses that mimicked those of the adult CD34+ cell donor. The team reports on its approach and initial analyses of a diabetic PI mice in Science Translational Medicine, in a paper titled “A Model for Personalized in Vivo Analysis of Human Immune Responsiveness.”
Read the full article here.
Science Translational Medicine paper, "A Model for Personalized in Vivo Analysis of Human Immune Responsiveness"Hannes Kalscheuer, Nichole Danzl, Takashi Onoe,Ted Faust, Robert Winchester, Robin Goland, Ellen Greenberg, Thomas R. Spitzer, David G. Savage, Hiroyuki Tahara, Goda Choi, Yong-Guang Yang, Megan SykesWednesday, March 14, 2012
Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies. Immunodeficient mice receiving human fetal thymus grafts and fetal CD34+ cells intravenously produce robust human immune systems, allowing analysis of human T cell development and function. However, to use humanized mice to study human immune-mediated disorders, immune systems must be generated from adult hematopoietic cells. Here, we demonstrated robust immune reconstitution in mice with hematopoietic stem cells (HSCs) aspirated from bone marrow of adults with type 1 diabetes (T1D) and healthy control volunteers. In these humanized mice, cryopreservation of human leukocyte antigen allele–matched fetal thymic tissue prevented allogeneic adult HSC rejection. Newly generated T cells, which included regulatory T cells (Tregs), were functional and self-tolerant and had a diverse repertoire. The immune recognition of these mice mimicked that of the adult CD34+ cell donor, but the T cell phenotypes were more predominantly “naïve” than those of the adult donors. HSCs from T1D and control donors generated similar numbers of natural Tregs intrathymically; however, peripheral T cells from T1D subjects showed increased proportions of activated or memory cells compared to controls, suggesting possible HSC-intrinsic differences in T cell homeostasis that might underlie immune pathology in T1D. This “personalized immune” mouse provides a new model for individualized analysis of human immune responses that may provide new insights into not only T1D but also other forms of immune function and dysfunction as well.
Columbia University Medical Center (CUMC) scientists have developed a way to recreate an individual's immune system in a mouse.Wednesday, March 14, 2012
Columbia University Medical Center (CUMC) scientists have developed a way to recreate an individual's immune system in a mouse. The "personalized immune mouse" offers researchers an unprecedented tool for individualized analysis of abnormalities that contribute to type 1 diabetes and other autoimmune diseases, starting at the onset of disease. The findings were published today in the online edition of Science Translational Medicine.
Read more here.
Dr. Megan Sykes featured in the Spring, 2011 edition of CUMC's P&S Magazine in "Reimagining Organ Transplantation", by Susan Conova.P&S Magazine, Spring 2011Thursday, August 4, 2011
Dr. Sykes discusses the CCTI's commitment to the strategy of preventing attacks on donated organs by the creation of a chimeric immune system within the transplant patient; one that is part donor and part recipient.