INDUCTION OF IMMUNE RESPONSES TO WILMS TUMOR 1 (WT1), A SELF-ANTIGEN, IN MICE

Immunology;vaccination;self-antigen;Immunology

Saint-Fleur, AshleyLevitsky, Hyam I. ;

Johns Hopkins University

关键词: Immunology;    vaccination;    self-antigen;    Immunology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/39279/SAINT-FLEUR-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

WT1, Wilms tumor 1, protein is overexpressed in a wide variety of cancers, including hematopoietic malignancies and solid tumors. WT1 is an attractive tumor-associated antigen to target for cancer immunotherapy as it is not normally expressed in adult human tissues, except in a few restricted locations, including CD34+ cells of the bone marrow, glomerular podocytes of the kidney, Sertoli cells of the testis, and granulosa cells of the ovary. However, because of its critical role in embryonic development and its expression in hematopoietic stem cells (HSCs), WT1 is a self-antigen. High affinity T cells are deleted from the repertoire in the thymus, leaving only low avidity T cells. Activating and expanding T cells that can recognize and kill WT1-expressing cancers has been difficult because the frequencies of WT1-specific T cells are very low. Moreover, these T cells may be anergic or suppressed by regulatory T cells. To obtain WT1-specific T cells from mice, which also express WT1 in the spleen stroma, we used a spectrum of immunization strategies,including vaccination with cDNA, protein, adjuvants, Listeria vaccines, WT1-expressing BMDCs, and WT1 overexpressing tumor cell lines. One approach to eliciting functional T cells that detect self-antigens that has been successful is the use of xenogeneic DNA vaccines. This approach works because the antigen is similar enough that cross-reactive epitopes may be utilized, but different enough to circumvent tolerance barriers. We created a consensus sequence DNA vaccine, based on homologous WT1 genes from ten different species. This maintained WT1 exons conserved across species, but was different enough at various amino acid positions to circumvent tolerance. The consensus sequence is 91% identical to the wild type murine WT1 sequence. Lymphocytes from mice vaccinated with the consensus WT1 DNA vaccine respond to a wild type murine WT1 peptide library. Our findings suggest that using a consensus sequence DNA vaccine is an effective method to produce an immune response to a self-antigen.