Jeffrey Bluestone, PhD
The research in my laboratory concerns the fundamental events that regulate T-cell activation and development during immune responses to autoantigens and transplantation antigens. Our efforts have focused on understanding the basic processes that control T cell activation and tolerance. We hope that the insights gained from these studies will help in the development of a new generation of toleragenic drugs that will "turn off" selected parts of the immune system, leaving the disease-fighting capabilities intact.
Our efforts to modulate T cell activation have centered on understanding and altering the positive signals delivered by the antigen-specific T cell receptor and secondary, so-called co-stimulatory signals, or engaging the negative regulatory events such as CTLA-4, PD-1 and Notch that control T cell signal transduction. The studies focus on the blockade of co-stimulatory molecules, such as CD28 and CD40L, which are essential for a productive T cell response. Blockade of CD28 interactions with its ligands, B7-1 and B7-2, induces long term tolerance in several different animal models. However, the precise biological basis for tolerance induction remains unclear. We have used soluble receptor antagonists, monoclonal antibodies and animals deficient in individual members of the CD28/B7 pathway to define their individual roles in transplant rejection and autoimmunity. We have shown that CD28 co-stimulation blockade alters cell growth and survival, the differentiation state of the T cells and their ability to migrate into the inflammatory site. In critical studies, we showed that administration of a CD28 antagonist induces long-term, antigen-specific unresponsiveness in vivo in pancreatic islet transplant models in both mice and monkeys and regulates the progression of autoimmune diseases in mice. We are also interested in the negative regulation of immunity focused on the role of both CTLA-4 and PD-1 to shut down immune responses through selective biochemical modifications of T cell receptor signaling, alteration of T cell differentiation and cytokine regulation.
One part of the lab is focused on regulatory T cells, so called Tregs, and their involvement in autoimmunity. Our studies have identified the critical role for CD4+CD25+ Treg cells in the regulation of autoimmune diabetes. We have demonstrated that both the CTLA-4 and CD28 pathways control CD4+CD25+ regulatory T cells thus implicating these pathways in both the pathogenic and protective immune responses. In fact, co-stimulation blockade disrupts essential regulatory pathways resulting in the exacerbation of immunity in some settings and subsequent research efforts using gene array to identify novel genes that control regulatory T cell function. Moreover, this work has led to the examination of a number of other co-stimulatory molecules (4-1BB, PD-1, ICOS and CD40L) in the development and progression of diabetes. Current efforts suggest that combination therapy may be most effective in blocking diabetes in the NOD mouse model.
Additional efforts in the lab have yielded insights into the function of the CD28 homologue, CTLA-4. Our laboratory was the first to demonstrate that T cell signaling via this molecule down-regulates T cell proliferation and cytokine production. Blockade of this molecule on activated T cells promotes immune responses including enhancing tumor remission. It is now clear that CTLA-4 engagement is essential in the development and maintenance of T cell tolerance in the autoimmune setting. We have begun to elucidate the biochemical basis of this regulatory signal through its interaction with the TCR complex.
CLINICAL RESEARCH PROGRAM
We developed a novel, genetically engineered "humanized", form of an anti-CD3 mAb for use in solid organ transplantation and autoimmunity. We have shown in animal models that this class of monoclonal antibodies can induce T cells into a state of unresponsiveness that leads to long term T cell tolerance to foreign and self antigens. In human studies, we have shown that a humanized OKT3γ1 (Ala-Ala) delays disease progression in Type 1 Diabetes and psoriatic arthritis.
We have started the JDRF Center for Islet Transplantation, a comprehensive research and clinical program aimed at producing rapid clinical advances in islet transplantation. The center combines cutting-edge programs in both immunobiology and transplant biology with established clinical expertise in islet transplantation and monitoring technology. In addition, we have developed a COLLABORATIVE CENTER FOR CELL THERAPY designed to promote basic and clinical research that will lead to successful antigen-specific regulatory T cell therapy in patients. The goals of these centers are to develop and exploit novel tolerogenic drugs for the treatment of Type 1 Diabetes.
Finally, I founded and direct the Immune Tolerance Network created in 1999 to accelerate the clinical development of immune tolerance therapies. This interdisciplinary research network develops clinical trials in organ transplantation, autoimmune diseases and allergy & asthma. Including the ITN's advisory panels, the ITN is comprised of over 80 leaders in immune tolerance, from over 40 institutions spanning 9 countries. Industry, academic and government investigators all participate and there are currently over 20 clinical trials and 12 mechanism-based studies approved and underway. The ITN is dedicated to the sharing of information in a very broad sense, where possible, making unique ITN resources and protocols available to the immunology community at large. It is a key goal of the ITN to further define the mechanisms of immune tolerance in the human clinical setting. Each clinical trial is supplemented by a comprehensive set of assay studies seeking knowledge of tolerance and biological indications of therapeutic effect. In addition, we have created the ITN Registry of Tolerant Kidney Transplant Recipients, a world-wide database of patients who have maintained kidney grafts despite the cessation of all immunosuppression. Investigators seek to establish new biological markers that indicate the presence or proclivity of tolerance.
Thus, in summary, my lab has been involved in efforts to modify transplantation and autoimmune responses and understand the underlying mechanisms of T cell recognition of foreign antigens. Using this information we hope to develop novel tolerogenic therapies that can be tested in man.
For information on the Immune Tolerance Network please click here.