Clinical Trials at BIDMC
Review our current research studies.
Immunology Research
Research on Immune Responses
BIDMC's Division of Immunology conducts leading-edge research on innate and adaptive immune responses with human cells using knockout and knock-in mice.
Under the leadership of Division Chief Cox Terhorst, PhD, immunology faculty, fellows and graduate students partner with investigators across BIDMC and Harvard. Collaborators include members of the Divisions of Gastroenterology, Allergy and Inflammation, and Rheumatology at BIDMC and with members of the Harvard Center for the Study of Inflammatory Bowel Diseases (CSIBD) and the Harvard Center for Primary Immuno Deficiencies.
Dr. Terhorst serves as Associate Director of CSIBD. He is also Course Director of Immunology 219 "The Primary Immunodeficiencies," which is attended by Graduate Students of the Harvard Immunology Program and by undergraduates from Harvard College.
At HMS the Terhorst lab has played a key role in discovering or elucidating the following immune networks leading to interfering agents.
Over the years the work in the Terhorst lab has been conducted by a group of extremely talented graduate students and post-doctoral fellows (>125). Many of them are now international leaders in their fields in Academia or Pharma. In addition, Dr. Terhorst has served as a mentor to thirty physician scientists who are now full professors at leading institutions across the globe, including four endowed professors of medicine at Harvard Medical School.
Past and Current Research
Our past and current immunology research includes:
- Function of the CD1a, b, c, d and HT genes, which encode b2m-associated non-MHC glycoproteins.
- Discovery of the CD3g,d,e,z proteins and genes.
- Elucidating assembly pathways of a/b and g/d T Cell antigen Receptors with CD3 and TCR/CD3 function in mature T cells and during thymic development.
- Discovery of a CD3g Primary Immuno Deficiency.
- Development of a novel animal models for Inflammatory Bowel diseases and their pathogenic T cell, dendritic cells and macrophage pathways.
- Discovery of SH2D1A [SAP], a gene, which is affected in patients with X-linked Lymphoproliferative Disease X(LP).
- SLAMFamily [SLAMF] cell surface receptors induce signal transduction networks in lymphocytes and macrophages that are modulated by the adapters SAP or EAT-2
- Several SLAMF receptors are also microbial sensors, which function in innate immune responses and intestinal inflammation.
- SLAMF receptors and their adapters differentially regulate adaptive immune responses in Systemic lupus erythematosus [SLE].
- Empowering regulatory T cells after AAV-based gene therapy
Publications
Our researchers have authored numerous impactful studies and papers in the field of Immunology over the years.
More About Immunology Research
Pathogenesis of Experimental Inflammatory Bowel Disease
Studies with genetically well-defined mouse models of Inflammatory Bowel Diseases, i.e. experimental colitis, led to an understanding that perturbations of the finely-tuned balance between the immune system and the vast antigenic load of the colon can result in disease. Aggressor CD4+ T helper 1 (Th1) cells accumulate in the lamina propria followed by inflammation of the intestinal mucosa. Bacterial antigens are presented to these Th1 cells by professional Antigen Presenting Cells (APC). In healthy mice the aggressor Th1 cells are prevented from expanding and thus initiating colitis by regulatory T cells (Treg). However, we do not understand the interactions of these cell types in the regulation of normal and abnormal immune responses to colonic bacteria.
Our studies examine the homeostatic balance between colitis-inducing CD4 T cells and Treg cells. The fundamental strategy is to examine the contribution of key APC and T cell surface receptor/ligand pairs in the education of the pathogenic T cells and Treg cells in IBD. The results of these studies have already suggested therapeutic strategies that can be applied to IBD patients, for we have successfully used a series of antibody reagents to ameliorate experiment colitis in the mouse.
X-linked Lymphoproliferative Disease
Childhood primary immunodeficiency disorders can be viewed as "experiments of nature" in which a discrete genetic defect affects the expression and/or the structure/function of essential lymphocyte proteins and results in immune dysfunctions. X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene with three major disease manifestations: fatal infectious mononucleosis, B cell lymphomas and dys-gammaglobulinemia. SH2D1A encodes SAP (SLAM Associated Protein), which is a single free SH2-domain protein that controls signal transduction in T lymphocytes, NK cells, a B cell subset and platelets. Physicochemical and biochemical studies emphasize the unique interactions of SAP with the cytoplasmic tails of six of the SLAM-family of receptors. Through a second set of unique interactions, SAP recruits tyrosine phosphokinases to the SLAM receptors. We thus have the systems in place to clarify how the absence of SAP causes XLP.
The SLAM Gene Family Controls Innate and Adaptive Immunity
The SLAM family of nine cell surface receptors is emerging as a crucial set of regulatory genes for both adaptive and innate immunity. SLAM (Signaling Lymphocyte Activation Molecule or SLAMF1) is a self-ligand receptor at the interface between T cells and professional antigen presenting cells. But, SLAMF1 is also the primary receptor for measles virus, which causes severe immune suppression. We find that SLAMF1-, F2-, F4-, F6- and F8- deficient mice have abnormal responses to both bacteria and parasites. This is the result of a defect in the final stage of CD4+ T cell differentiation and/or of defective killing of bacteria by SLAM-deficient macrophages, tissue dendritic cells and neutrophils. Thus, SLAM family members serve as regulators of the innate and adaptive immune response to bacterial and viral infections
Preliminary genetic studies in humans and mice indicate that variations in one or several of the genes in the SLAM locus may influence a propensity to develop SLE.
The gene for EAT-2 (SH2D1B) maps in close proximity to the SLAM genes on human and mouse chromosome 1. Three dimensional structure analyses demonstrate that the adapter EAT-2 is very similar to SAP, and it too interacts with the cytoplasmic tails of members of the SLAM family. We are currently investigating the role of EAT-2A and -B in macrophages, neutrophils, dendritic cells and platelets using our recently developed EAT-2A, EAT2-B and EAT2-(A+B) knockout mice.
Empowering Regulatory T Cells After AAV-Based Gene Therapy
This work is a collaboration with Professor Roland Herzog at Indian University. A large number of viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, and with many more in preclinical stages. Because efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive, viral vector gene therapy is now used to treat or even cure diseases for which there had been no or only suboptimal treatments.
However, innate and adaptive immune responses to both vectors and their transgene cargo constitute substantial hurdles to clinical development in several instances. Examples of ameliorating such immune responses in animal models have been discovered.
Research at BIDMC
Our culture of collaboration and innovation guides scientific discoveries that are helping to transform medical care.
Meet the Research Team
Advancing Care, Research & Education
Department of Medicine
The Department of Medicine at BIDMC is a recognized leader in patient care, medical education and biomedical research.
Education
The Department of Medicine is renowned for its teaching, with educational programs led by a team of nationally-known faculty.
Services
BIDMC's Department of Medicine provides a wide range of patient care services, from routine primary care through advanced specialty care.
