Pathomechanisms of paraneoplastic neurological syndrome-neuronal damege mediated by cytotoxic T cells

点击翻译按钮获取中文摘要

A part of the paraneoplastic neurological syndrome could be diagnosed with characteristic anti-neuronal antibodies which also give the prediction for underlying cancer. Although these antibodies found in the sera and CSFs of patients is thought to be disease- specific, there is no direct evidence of a role in neuronal loss. Infiltration of CD8-positive T cells in the affected tissue was found in the patient with paraneoplastic cerebellar degeneration(PCD)and anti-Yo antibody or encepahlomyeloneuropathy with anti-Hu antibody(anti-Hu syndrome)which suggested HLA class I restricted cytotoxic T cells(CTL)may be involved in these disorders. First, we examined Vb genes of T cell receptors of infiltrated lymphocytes with RT-PCR and single strand conformational polym orphism method, that suggested the oligoclonal expansions of T cells in the tumor and the cerebellum/posterior ganglions of PCD/anti-Hu syndrome, respectively.Then we examined HLA-class I- restricted cytotoxic T lymphocyte(CTL)activity against a peptid of the Yoprotein with the HLA A24-specific peptide-binding motifs or some peptides of the Hu protein with the B7 supertype-specific peptide binding motifs. CTL activity was induced in the peripheral blood of patients with PCD/anti-Hu syndrome after stimulated with specific peptides against autologous fibroblasts expressing each peptide on their surface. To clarify that CTL might really related to the neuronal damage, CTL induced animal models should be raised.For this purpose, we immunized the mice bering common MHC motifs with these peptides and autologous dendritic cells and obtained T cell clones reactive to each peptides.