Maximizing Immune Responses: The Effects of Covalent Peptide Linkage to Beta-2-Microglobulin
Abstract:Major histocompatability molecules (MHC) are involved in presentation of peptide antigens for recognition by the immune system. The density and stability of presented peptides is a critical parameter in determining the magnitude of the immune response. Increasing the half-life and density of an MHC class I‐peptide complex should promote a stronger cytotoxic T lymphocyte (CTL) response to clinically important peptides, including those that exhibit low or suboptimal MHC class I binding affinity. We hypothesized that the covalent linkage of a known tumor antigen peptide to beta-2-microglobulin (2m) would increase peptide immunogenicity and, therefore, in vivo effectiveness as an antitumor vaccine in BALB/c mice. The iL3 peptide fusion protein (iL3-L12-h2m) was developed based on the mutant iL3 peptide, derived from the L3 ribosomal protein, and expressed in the mutagenized murine fibroblastic tumor cell line, BCA34. The iL3-L12-2m and a negative control fusion protein utilizing the H-2Kd-restricted NP(147‐155) influenza peptide (NP-L12-h2m) were both produced in E. coli for exogenous antigen presentation by dendritic cells. In vitro, the iL3-L12-h2m protein was found to stabilize H-2Kd over time on the surface of H-2Kd-expressing target cells and sensitized them to peptide-specific CTL-mediated lysis. Furthermore, mice immunized with dendritic cells pulsed with the iL3-L12-h2m protein rejected a challenge with BCA34 cells significantly more so than mice immunized with dendritic cells pulsed with free peptide and h2m. We conclude that vaccines incorporating peptides covalently linked to 2m may have future potential in the specific targeting of human malignancy.
Document Type: Research Article
Publication date: 2008-05-01
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Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.