Identification of B7 family members (B7-1 and B7-2) and their receptors (CD28 and CTLA4) has provided important insights into molecular mechanisms for regulation of immune responses, and perhaps more importantly, several novel approaches to tumor immunotherapy. Under the support of the previous grant, the investigator's laboratory has made significant progress in the last three and a half years in understanding the structural basis of B7-B7-CTLA4 interaction, the role of B7 at the effector phase of anti-tumor immunity, and in the function of B7-CTLA4 interaction. In the next funding period, the investigator will continue to focus on the role of B7 receptors in immune regulation and tumor immunotherapy. He will identify the receptors responsible for the effector function of B7, and explore the means by which the requirement for B7 at the effector phase can be bypassed. The investigator will also determine whether the immune regulatory function of the B7-CTLA4 interaction is exerted during the development or the activation of T cells. Moreover, they will produce mice with a humanized CTLA4 molecule, and use them to screen for immunotherapeutic mAbs, and to determine the mechanism by which anti-CTLA4 mAb induces protective immunity. In order to achieve these goals, they will need to engineer T cell lineage-specific and stage-specific targeted mutation of the CTLA4 gene. They will also need to produce mice with human CTLA4 gene knock-in mice. In combination with the WT and mutant B7-1 molecules and transgenic mice produced in the last funding period, they will be able to carry out definitive analysis of the function of B7 receptors, CD28 and CTLA4, in development activation and effector function of tumor-reactive T lymphocytes. More importantly, the proposed studies will provide animal models that can be used to screen monoclonal antibodies that are of therapeutic value for human cancer.
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