Kurzfassung

We will evaluate the functional and therapeutic potential of altered p53-specific TCR expressed in human CD8+CTL and CD4+ Th ex vivo and in vivo by taking advantage of a humanized mutp53 tumour mouse model. We will also test whether target cells harbouring defined human p53 mutants are differentially susceptible to killing by p53-specific TCR-transduced human CTL. We wish to define CTL-sensitive and resistant p53 mutants and understand the molecular basis of their susceptibility/resistance to...We will evaluate the functional and therapeutic potential of altered p53-specific TCR expressed in human CD8+CTL and CD4+ Th ex vivo and in vivo by taking advantage of a humanized mutp53 tumour mouse model. We will also test whether target cells harbouring defined human p53 mutants are differentially susceptible to killing by p53-specific TCR-transduced human CTL. We wish to define CTL-sensitive and resistant p53 mutants and understand the molecular basis of their susceptibility/resistance to CTL-mediated cytolysis. The particular p53-specific TCR to be employed is of CD8-independent high affinity and allows the HLA-A*0201-restricted functional redirection of human CD4+ Th. We will therefore study both the molecular basis and kinetics of immunologic synapse formation in the absence of CD8 contribution by visualizing the interaction of p53 TCR transduced human CD4 Th with professional antigen presenting and mutp53-overexpressing tumour cells. Molecular alterations induced by hyperresponsive p53-specific TCR mutants will be identified using Affymetrix expression microarrays and proteomics in order to identify gene products responsible for hyperproliferative and antiapoptotic T cell functions. All this should serve as the basis do develop a clinical Phase I protocol.» weiterlesen» einklappen