The CCTI occupies more than 12,000 square feet of space of newly renovated rooms in both the Black and Physicians and Surgeons Buildings at Columbia University Medical Center. The space is currently fully-equipped for cellular and molecular immunology and in vivo studies.
Core facilities within the CCTI include flow cytometry, a clinical studies core, and a transplantation tissue bank. Additionally, the advanced microscopy facilities of the Departments of Microbiology/Immunology and Dermatology as well as the imaging core in the Herbert Irving cancer center are all available to CCTI investigators. The histology core of the Berrie Diabetes Center is also available for the proposed studies.
- Xiaojuan Chen, MD, PhD
Dr. Chen’s laboratory utilizes islet transplantation models to explore areas of islet cellular and molecular biology that are pertinent to the development of diabetes as well as to the improvement of islet transplantation for the treatment of type 1 diabetes. In addition, Dr. Chen will direct a nonhuman primate research program in tolerance induction to islet allografts. Using both animal models and human islets, she will play a key role in translating tolerance therapies from animal models to the clinic.
- Remi Creusot, PhD
Dr. Creusot’s research interests revolve around the pathogenesis and prevention of Type 1 Diabetes. He and his group study how several processes that contribute to the maintenance of immune tolerance are impaired, allowing the progression of the disease. The lab is working on several new therapeutic strategies aimed at restoring immune tolerance and blocking autoimmunity. This research allies basic research, preclinical studies using mouse models and translational studies using patient samples.
- Charles Drake, MD, PhD
- Donna Farber, PhD
Research in Dr. Farber’s laboratory is focused on immunological memory and specifically on memory T cells as essential mediators of protective immunity. While it was previously thought that memory T cells mediate their protective responses through rapid migration and surveillance through tissues, it has now become clear that localization and establishment of non-circulating memory T cells resident in tissue sites is integral to immune protection. The lab is incorporating fundamental studies on mouse models with novel translational approaches on human samples to investigate tissue immune responses. They’ve identified a new subset of non-circulating tissue-resident memory T cells (TRM) in the lung that mediate optimal protective immunity in a mouse model of influenza infection and have conducted studies into mechanisms for how memory T cells become targeted to and maintained in the lung use total transcriptome profiling and bioinformatics approaches. They have also identified novel roles for specific integrins and inflammatory mediators in this process, and are studying the signaling pathways involved in resident memory T cell generation and functional recall. For their translational studies, they have established a unique collaboration and research protocol with the organ procurement organization for the New York Metropolitan area (LiveOnNY ; http://www.donatelifeny.org/) and transplant surgeons at New York Presbyterian (NYP) where they obtain multiple lymphoid and mucosal tissues from research-consented human organ donors.
- Joji Fujisaki, MD, PhD
Dr. Fujisaki’s lab’s long-term goal is to test if stem cell niches are IP sites. Their recent study (published in Nature 2011) has demonstrated evidence indicating that one of the best-characterized stem cell niches, the hematopoietic stem and progenitor cell (HSPC) niche in the bone marrow, is an IP site. They’ve demonstrated that the HSPC niche meets the experimental criterion of an IP site, a tissue where transplanted allogeneic (allo-) grafts can survive without immune suppression. Additionally, they’ve demonstrated surprisingly prolonged persistence of allo-HSPCs in immune competent mice without immune suppression. Moreover, using novel high-resolution in vivo microscopy that enables to visualize the location and the dynamic movement of individual cells in live mice, they demonstrated that FoxP3+ regulatory T cells (Tregs), a T cell subset with immune suppressive potential, preferentially form clusters with HSPCs. Treg depletion results in the loss of allo-HSPCs. The data indicate that Tregs play a critical role in maintaining IP of the HSPC niche that protects HSPCs from immunity.
The lab’s current focus is to unveil the clinical significance of IP of the HSPC niche, especially to malignancies. More specifically, they will test whether the niche shields malignant stem cells that share properties with stem cells. They’ll further elucidate mechanisms allowing the niche to provide immune protection, using in vivo multiphoton/confocal microscopy to visualize the dynamic movement and interaction of immune cells in the niche in live mice.
- Adam Griesemer, MD
Dr. Griesemer’s laboratory is investigating the ability of ex-vivo expanded Tregs to enhance bone marrow engraftment and extend the duration of mixed chimerism. The induction of durable mixed chimerism without graft-versus-host disease should in turn lead to life-long donor-specific tolerance to any co-transplanted cells (islets) or solid organs (heart, liver, lung) from the donor. They’re also collaborating with other investigators at the CCTI to study the ability of amnion-derived multipotent progenitor cells to enhance bone marrow engraftment in translational models as an alternate, and potentially synergistic, strategy to induce durable mixed chimerism.
- Arnold Han, MD, PhD
Our research investigates the function of T cells as they pertain to human diseases, including cancer and autoimmunity. We have recently developed technology than enables determination of T-cell antigen receptor (TCR) sequence and high-dimensional (> 30 parameters) functional phenotype with high accuracy and efficiency from single T cells. Pairing TCR sequence information with high-dimensional phenotypic analysis is particularly powerful in the analysis of T cells, which are exceptionally diverse. In addition to the theoretical TCR repertoire diversity of 1015, T cells can assume diverse pro-inflammatory and regulatory functions. Our approach enables the extensive study of T cell function and also the ability to recapitulate TCRs for functional studies and therapeutic application.
We now understand that T cells are fundamentally capable of recognizing and rejecting tumors as foreign tissue, and tumors grow because they have devised mechanisms of escaping T cell immunity. Recently, therapies specifically designed to incite anti-tumor T cell activity have shown enormous promise in cancer treatment. Our research investigates the function of T cells in human cancer and in mouse models with ultimate aim of identifying novel avenues of therapy. We are addressing the following questions:
- Of the diverse types of T cells present in tumors, which T cells have potential in controlling cancer and which T cells might actually be promoting cancer growth?
- How does the TCR repertoire of tumor infiltrating T cells compare with peripheral blood and normal tissue?
- How do tumor-infiltrating T cells evolve over time?
- What are the antigens driving T cells in cancer?
- How does immunotherapy affect the landscape and function of T cells, and what are T cell determinants of responsiveness to immunotherapy?
- Can we apply our technology to design effective strategies for adoptive T cell immunotherapy?
Like cancer, autoimmune diseases are also diseases of T cell tolerance. Our laboratory studies autoimmunity through the study of celiac disease, a highly prevalent autoimmune disease that shares similar genetic and immunologic features with other autoimmune diseases. Aside from its clinical impact, celiac disease is unique among autoimmune diseases in that the triggering antigen, dietary gluten, is known and its exposure can be controlled through diet. Thus, celiac disease provides a unique opportunity to study and understand human autoimmunity. We are investigating T cell responses within celiac disease through the study of blood and tissue from human volunteers. We have previously shown that CD8+ T cells in celiac disease, which mediate tissue damage, are likely responding to gluten ingestion in an antigen-specific manner, even though CD8+ T cells are not believed to directly recognize gluten peptides. Our research on celiac disease is focused on understanding how a CD4+ T cell response directed against an external antigen (dietary gluten) can enable self-tissue damage by CD8+ T cells
- Robert Hawley, PhD
- Markus Mapara, MD, PhD
The research in this laboratory is primarily focused on developing new approaches to improve the outcome of patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation.
- Ran Reshef, MD
Dr. Reshef’s lab investigates lymphocyte trafficking mechanisms that affect anti-tumor and anti-host responses in allogeneic stem-cell transplantation and in cancer immunotherapy. In addition, the lab investigates novel biomarkers that predict the outcomes of immunotherapies such as graft-versus-host disease, cancer recurrence and treatment-related toxicity.
- David H Sachs, MD
Dr. Sachs' research is directed toward the following goals in the field of transplantation:
- Induction of transplantation tolerance through mixed hematopoietic chimerism: This work was begun in mice, then extended to large animals (swine and non-human primates) and most recently to a successful clinical tolerance protocol for renal transplantation;
- Development of inbred miniature swine as a model for large animal transplantation studies and as donors of organs for xenotransplantation, through classical genetics and through genetic engineering and nuclear transfer;
- Studies of the mechanism of tolerance of vascularized allografts in miniature swine: These studies are directed toward understanding the nature of cell populations responsible for adoptive transfer of tolerance, determining the role of the thymus in tolerance and examining the mechanism by which B cell immunity to MHC antigens is controlled; and
- Development of a tolerance approach toward xenotransplantation: These studies comprise a broad program of projects directed toward tolerizing both the innate and the adaptive immune responses to xenografts and genetically engineering inbred miniature swine to minimize the primate anti-pig immune response. The overall goal of this project is to develop a clinically applicable technology for xenotransplantation of porcine organs into primates.
- Hans-Willem Snoeck, MD, PhD
The research program of the Snoeck lab primarily focuses on hematopoiesis with the aim to improve bone marrow transplantation and gene therapy targeted at hematopoietic stem cells (HSCs), and gain insight in leukemogenesis. To achieve a deeper understanding of the mechanisms involved in self-renewal of HSCs, genes underlying quantitative genetic variation in the behavior of HSCs among inbred mouse strains were mapped. After identification of allelic variation in the Prdm16 gene as one of the underlying mechanisms, the lab now focuses on the mechanism of action of Prdm16 in the renewal of HSCs. Expansion of this program into directed differentiation of human embryonic stem cells (ESCs) and induced pluripotent state cells (iPSCs) (collectively called human pluripotent cells (hPSCs)) arose from the desire to attempt to alleviate post-bone marrow transplantation immune deficiency, caused, among others, by defective T cell reconstitution. Furthermore, the capacity to generate thymic epithelial cells from human pluripotent stem cells will allow the generation of the next generation of ‘personal immune’ mice. As the thymus develops from the anterior foregut endoderm, the approaches we developed also led to strategies to generate virtually every type of cell of the respiratory system from hPSCs.
- Megan Sykes, MD
Dr. Sykes' own laboratory program currently includes major projects in the area of xenograft tolerance induction in humanized mouse models; unique humanized mouse models for the analysis and treatment of autoimmune diseases, including Type 1 diabetes and rheumatoid arthritis (the “personalized immune” mouse); studies of lymphocyte turnover, chimerism and T cell trafficking in patients receiving intestinal and liver transplants; tracking of alloreactive T cells in human transplant recipients; and both pre-clinical and clinical studies of non-myeloablative hematopoietic cell transplantation for the induction of allograft tolerance.
- Kazuhiko Yamada, MD, PhD
Dr. Yamada's research focuses principally on finding new means to induce tolerance to allogeneic and xenogeneic organ transplants (interspecies transplantation) in preclinical large animal models, concentrating mainly on the thymus as an agent for tolerance induction. His overarching aim is to elucidate the mechanisms of immunologic tolerance and to develop strategies to resolve two of the major obstacles to clinical transplantation: the shortage of donor organs and the requirement for continuous post-transplant immunosuppression. Specifically, he has focused on two pre-clinical models, the MHC inbred miniature swine and the nonhuman primate (NHP) which are supported by several NIH grants. He has performed over 1,000 cases of organ transplantation, including kidneys, thymus, heart, lung, and islets, in preclinical models. Notably, he has developed innovative procedures for the induction of tolerance by transplanting thymus or islets as a vascularized graft, so called the vascularized thymic lobe (VTL), thymokidney (TK), islet-kidney (IK) and thymo-islet-kidney (TIK) grafts in preclinical models of MHC inbred swine and non-human primate.
- Yong-Guang Yang, MD, PhD
The research in this laboratory is primarily focused on allogeneic and xenogeneic transplantation immunology, stem cell transplantation, and humanized mouse models
- Emmanuel Zorn, PhD
The primary focus of Dr. Zorn’s lab is on B cells and antibodies in mechanisms of rejection of kidney and heart transplants. More specifically, members of his lab investigate the functional implication of pre-existing graft-reactive antibodies in the blood of transplant recipients as well as de-novo antibodies developing post-transplant. Another study in Dr. Zorn’s lab examines the role of B cells infiltrating allografts, especially cardiac transplants, during chronic rejection.