Chemokine-idiotype fusion DNA vaccines are potentiated by bivalency and xenogeneic sequences.
V regions of monoclonal Ig express an exquisite B-cell tumor-specific antigen called idiotype (Id). Id is a weak antigen and it is important to improve immunogenicity of Id vaccines. Chemokine receptors are expressed on antigen-presenting cells (APCs) and are promising targets for Id vaccines. Here we compare monomeric and dimeric forms of MIP-1alpha and RANTES that target Id to APCs in a mouse B lymphoma (A20) and a multiple myeloma model (MOPC315). MIP-1alpha was more potent than RANTES. The dimeric proteins were more potent than monomeric equivalents in short-term assays. When delivered in vivo by intramuscular injection of plasmids followed by electroporation, dimeric proteins efficiently primed APCs in draining lymph nodes for activation and proliferation of Id-specific CD4(+) T cells. Good anti-Id antibody responses were obtained, and mice immunized only once were 60% to 80% protected in both tumor models. CD8(+) T cells contributed to the protection. Antibody responses and tumor protection were reduced when the human Ig hinge = C(H)3 dimerization motif was replaced with syngeneic mouse counterparts, indicating that tumor-protective responses were dependent on xenogeneic sequences. The results suggest that bivalency and foreign sequences combine to increase the efficiency of chemokine-Id DNA vaccines.
Fredriksen
Agnete Brunsvik
AB
Institute of Immunology, University of Oslo, Oslo, Norway. a.b.fredriksen@medisin.uio.no
Bogen
Bjarne
B
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000276:immunology*; D019281:Dimerization; D018274:Electroporation; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000235:genetics / Q000276:immunology*; D007273:Injections, Intramuscular; D016393:Lymphoma, B-Cell / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D018448:Models, Immunological; D009101:Multiple Myeloma / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013997:Time Factors; D014611:Vaccination; D019444:Vaccines, DNA / Q000737:chemistry / Q000276:immunology*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D000949:Histocompatibility Antigens Class II; D007130:Immunoglobulin Idiotypes; D019402:Macrophage Inflammatory Proteins; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA