Evaluation of molecular and cellular mechanisms of helper T cell-mediated immunity during tumor-rejection

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The purpose of this project is to evaluate the function of DC subsets and the mechanisms of Th1 /Th2 balance control, which are critical for development of tumor-specific CTL -mediated immunotherapy. We have demonstrated the following evidence. 1. Th1-dominant immunity is critical for activation of Th1 /Tc1 circuit important for tumor-specific immunotherapy. 2. BMDC1, which were induced from bone-marrow cells by culture with GM-CSF, IL-3 and Th1 cytokines, exhibited a potent stimulating activity for inducing allogeneic CTL. Moreover, combination therapy with BM DC1, inactivated tumor and tumor antigen protein caused a complete rejection of tumor tissue. 3. We established a culture method for inducing leukemia-specific CTL from PBMC of leukemia patients. 4. We established the method to prepare gene-modified tumor-specific Th1 cells using tumor-specific TCR genes or Iggene.Especially, it was demonstrated that transfer of class-I-restricted TCR genes into Th1 cells resulted in the generation of functional class-I-restricted Th1 cells. 5. CpG coencapsulated with tumor antigen protein induced tetramer-positive CTL in tumor-bearing mice and cured the mice from tumor. 6. We established a method to prepare Th1 cells, which specifically react to cancer-testis tumor antigen such as NY-ESO-1, MAGE-A4. These Th1 cells are useful to determine helper epitopes of tumor antigen.