Targeting p53, hdm2, and CD19: vaccination and immunologic strategies.
Peptides presented by class I major histocompatibility complex (MHC) molecules and derived from normal self-proteins that are expressed at elevated levels by cells from a variety of human (Hu) malignancies provide, in theory, potential target antigens for a broad-spectrum, cytotoxic T lymphocyte (CTL)-based immunotherapy of cancer and hematologic malignancies. However, as such tumor- and leukemia-associated self-proteins are also expressed at low levels in some types of normal tissues, such as thymus, spleen and lymphohemopoietic cells, these self-MHC-self-peptide complexes may also represent thymic and/or peripheral tolerogens, thereby preventing immune responses. This is particularly true for class I MHC-peptide complexes expressed by bone marrow-derived cells in the thymus, as such expression would cause negative selection of immature thymic T cells with high avidity for self-MHC-self-peptide complexes. This intrathymic deletion of potentially self-reactive T cells could result in a peripheral T cell repertoire purged of CTL precursors with sufficient avidity to recognize natural tumor associated self-epitopes presented by class I MHC molecules on tumor cells. HLA-transgenic (Tg) mice provide the basis of an experimental strategy that exploits species differences between Hu and murine (Mu) protein sequences in order to circumvent self-tolerance and obtain HLA-restricted CTL specific for epitopes derived from tumor- and leukemia-associated Hu self proteins, such as p53, Her-2/neu, hdm2 and CD19.
Voss
R H
RH
Department of Hematology, III. Medizinische Klinik, Johannes Gutenberg-University, Mainz, Germany.
Lotz
C
C
Cellary
A
A
Theobald
M
M
D000818:Animals; D017951:Antigen Presentation; D018941:Antigens, CD19 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051736:Proto-Oncogene Proteins c-mdm2; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*; D014611:Vaccination
D018941:Antigens, CD19; D015395:Histocompatibility Antigens Class I; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2