T cell costimulation in anti-tumor immunity and autoimmunity

Costimulatory molecules, including 4-IBB, CTLA-4, and B7, play a critical role in the activation, sustenance, and regulation of T cell immune responses. Manipulation of these pathways holds promise for the development of therapies for cancer and autoimmunity. Administration of anti-4-1BB monoclonal antibody (mAb) has been demonstrated to boost anti-tumor immunity in animal models, with varying conclusions regarding mechanism of action. Using a model of tumor-specific CD8 T cell adoptive immunotherapy, we demonstrate that anti-4-IBB mAb can mediate the rejection of large established tumors in the absence of CD4 T cell help. Anti-4-1BB mAb increases populations of tumor-specific CD8 T cells in peripheral blood by reduction of activation-induced cell death, but not increased T cell proliferation.; The use of anti-CTLA-4 mAb has also been shown to enhance anti-tumor immunity. Here we describe the use of two novel "humanized" mouse models to screen anti-human CTLA-4 mAb for translation to human cancer therapy. Using the hu-PBL-SCID model of Epstein-Barr virus (EBV)-associated lymphoproliferative disease, we show that anti-human CTLA-4 mAb promotes the in vivo expansion of human CD8 and CD4 T cells, and the generation of antigen specific CD8 T cell responses to EBV lymphoma. This correlates with reduced levels of the oncogenic EBV protein LMP-1, and increased survival and delay of lymphoproliferative disease in these mice. We also characterize the creation of a knock-in mouse model in which mouse T cells express the human CTLA-4 molecule. Preliminary testing in this mouse model supports the use of this model to screen anti-human CTLA-4 mAb for clinical use.; Immunological function of B7/CD28/CTLA-4 interaction in immune activation and tolerance is fundamental to successful immune intervention targeted at costimulatory molecules. As an integrated part of this dissertation, I have devoted considerable effort to investigating the basic immunobiology of T cell costimulation. We describe the spontaneous development of whole-body alopecia, lymphadenopathy, and skin disease in mice lacking B7 molecules. This disease is mediated by autoimmune CD4 T cells, which induce multi-organ inflammation when transferred to mice expressing B7 molecules. This disease may result from impaired development of CD4+CD25+ regulatory T cells (Treg) in B7-deficient mice. Since provision of Treg can abrogate the multi-organ inflammation despite lack of B7 molecules on the auto-pathogenic T cells, interaction between CTLA-4 on Treg and B7-1/2 on effector T cells is not essential for Treg function.