Director: Richard A. Flavell, Ph.D.
Goals of Center Cores
The mission of the JDRF Center for Developing Immune Therapies for Type 1 diabetes is to accelerate clinical translation of immune therapies for type 1 diabetes by developing humanized mouse models of T1DM and to use these models and human cells to understand disease mechanisms and to develop new treatments The Center is founded on the realization that translation of discoveries in basic science to treatment of patients has been slowed by the unclear relationship between rodent models of T1DM and the human disease, the need for long, large, and costly clinical trials even for initial proof of concept for new agents, and differences in rodent and human immune responses.
The Center brings together scientists who have established their careers with studies in murine immunologic systems but who recognize that new model systems are needed to apply their studies to human disease. The Center Directors are Richard Flavell and Kevan Herold. The areas of study include mechanisms of tolerance, T/B cell interactions and the effector function of pathogenic T cells, lymphocyte homing into inflammatory lesions in the islets, and induction of antigen specific tolerance with anti-CD3 mAb.
There are 5 Projects and 3 Cores in the Center. The first project (Flavell) involves the development of a humanized mouse model of type 1 diabetes. This project involves genetic approaches to improve the existing mice for reconstitution with human cells and induction of autoimmune diabetes in this model. A goal of these studies is to test whether human cytokines and MCH molecules will improve engraftment and immune responses in mice reconstituted with human CD34+ cells. In Project 2 (Wen) the role of B cells and autoantibodies in the development of diabetes will be studied. The role of B cells is not clear but of certain importance for the disease. To study the role of autoreactive B and T cells, a transgene and knock-in mouse that expresses human TCR and BCR for GAD65 will be created. Project 3 (Sherwin) involves the study of a new diabetes autoantigen (Reg), a protein involved in beta cell proliferation and whose expression is increased in beta cells during development of diabetes. The role of this antigen in autoimmune diabetes will be studied. Projects 4 (Bothwell, Ruddle and Herold) and 5 (Herold) involve the isolation and functional testing of human diabetes antigen specific T cells. The ability of reconstituted mice to predict clinical responses to immune therapies, such as anti-CD3 monoclonal antibody, will be tested. Antigen specific T cell clones will be isolated and tested for their effects in humanized mice. The cores will supply immune deficient mice to be used as recipients of human cells and a repository of human lymphocytes and CD34+ cells that can be used for creation of the humanized mice.
This Core will manage the administrative tasks of the Center. These include providing secretarial support, maintaining a Web site, arranging regular meetings of the investigators, organizing the 2 annual meetings of the Scientific Advisory Board and the annual review, and facilitating interactions with other JDRF Centers and Regeneron. Dr. Flavell will be the PI of this Core and Dr. Herold will be the co-director.
The development of humanized animal models that allow study of disease processes and testing of therapy is of major importance in developing strategies to translate knowledge in preclinical models to the ultimate prevention and cure of diabetes in humans. This core will:
- Maintain and distribute diabetes prone humanized mice carrying HLA DR and DQ transgenes.
- Generate constructs for new humanized transgene and knockin replacement mice.
- Generate and maintain other mice as needed for the members of the Center.
All of the Projects in the Center will use human cells for study. Obtaining and processing clinical material for study is a time consuming task. This core will provide clinical material for studies in the Center Projects. The materials to be collected include peripheral blood mononuclear cells (PBMC), bone marrow aspirates, serum, and DNA from patients and normal control subjects, and human islets from organ donors. The Core functions will include fulfilling the regulatory requirements for obtaining this material, isolating and storing the cells, serum, and DNA, and arranging the procurement of human pancreata that will be used for isolation of islets at the islet isolation laboratory at Massachusetts General Hospital. In addition, the Core will prepare lines of EBV-transformed B lymphocytes that can be used in the projects as antigen presenting cells or other purposes. The donors of the cells will be HLA typed for HLA-A2 and HLA-DR3, 4, and DQ8 by real-time PCR. The cells and other materials will be stored in the Yale University Repository that will be part of the Yale Clinical and Translational Science Award.