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Maximizing Immune Responses: The Effects of Covalent Peptide Linkage to Beta-2-Microglobulin

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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-h2m) 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-h2m) were both produced in E. coli for exogenous antigen presentation by dendritic cells. In vitro, the iL3-L12-h2m 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-h2m protein rejected a challenge with BCA34 cells significantly more so than mice immunized with dendritic cells pulsed with free peptide and h2m. We conclude that vaccines incorporating peptides covalently linked to 2m may have future potential in the specific targeting of human malignancy.

Keywords: Cancer; Dendritic cells; Fusion proteins

Document Type: Research Article

DOI: https://doi.org/10.3727/096504008786111347

Publication date: 2008-05-01

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