Previous studies demonstrated that the elevated expression and receptor binding of gastrinreleasing peptide (GRP) in various types of cancer suggest that GRP might be a putative target for immunotherapy in neoplastic diseases. DNA vaccine for hormone/growth factor immune deprivation represents a feasible and attractive approach for cancer treatment; nevertheless, there is still a need to increase the potency of the DNA vaccine. Here, based on six copies of the B cell epitope GRP 18-27 in a linear alignment as an immunogen, we designed several anti-GRP DNA vaccines containing different combinations of immunoadjuvants, such as HSP65, tetanus toxoid 830-844 (T), pan HLA-DR-binding epitope (PADRE) (P), and mycobacterial HSP70 [407][408][409][410][411][412][413][414][415][416][417][418][419][420][421][422][423][424][425][426] (M), on a backbone of pCR3.1 plasmid vector with eight 5 0 -GACGTT-3 0 CpG motifs and the VEGF183 signal peptide (VS). The effects of these immunoadjuvants in enhancing GRP-specific humoral immune response were then evaluated by comparing the respective immunogenicity and antitumor effects. Immunization of mice with pCR3.1-VS-HSP65-TP-GRP6-M2 elicited much higher levels of specific anti-GRP antibodies and more effectively inhibited the growth of a GRP-dependent tumor RM-1 in vivo. Interestingly, plasmids encoding for 2HSP70 [407][408][409][410][411][412][413][414][415][416][417][418][419][420][421][422][423][424][425][426] , but not the one with 1 or 3HSP70 [407][408][409][410][411][412][413][414][415][416][417][418][419][420][421][422][423][424][425][426] showed stronger immune stimulatory potential as well as impressive antitumor activity, suggesting that 2HSP70 407-426 is an efficient molecular adjuvant for developing self-epitope vaccines. The highly immunogenic, potent anti-tumorigenic and antiangiogenesis activities of the anti-GRP DNA vaccine offered a novel immunotherapeutic approach in the treatment of GRP-dependent tumors and their complications.
Accumulating evidence established a positive association of anti-heat shock protein 60 (HSP60) autoantibodies and the presence of atherosclerosis. However, whether anti-P277 (HSP60 437-460) autoantibodies may lead to the pathological increase in vascular permeability, a vascular leak syndrome (VLS), is unknown. In the present study, anti-P277 immunity was effectively induced in C57BL/6 mice, causing a marked increase in VLS in both normal mice and those bearing melanoma as well. Further analysis of the pathological role of anti-P277 immunity revealed that the B-cell epitopes located in P277 played a causal role in the development of VLS. Moreover, studies on endothelial cells (ECs) showed that the anti-P277 antibodies could cross-react with HSP60, highly expressed in both normal and stressed ECs, and mediate damage to cells in the presence of complement. These data suggested that humoral immune response induced by anti-P277 immunity mediates EC damage and induces VLS. These negative effects may cast shadows on P277, used as a peptide vaccine.
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