title: Hydrogel-delivered GM-CSF overcomes nonresponsiveness to hepatitis B vaccine through the recruitment and activation of dendritic cells.
abstract: The standard hepatitis B surface Ag (HBsAg) vaccine fails to induce anti-hepatitis B surface Abs in 5-10% of healthy subjects, a phenomenon known as HBsAg nonresponsiveness, which is closely related to HLA class II alleles and impaired Th cell responses to HBsAg in these subjects. We hypothesized that GM-CSF, a potent adjuvant in enhancing the Ag-presentation activity of APCs, might help to generate Th cell responses in nonresponders, subsequently providing help for B cells to produce anti-hepatitis B surface Abs. We used a thermosensitive biodegradable copolymer (hydrogel) system to codeliver HBsAg and GM-CSF to achieve maximal local cytokine activity at the injection site. In responder mouse strains, hydrogel-formulated HBsAg plus GM-CSF (Gel/HBs+GM) vaccine elicited much greater anti-hepatitis B surface Ab titers and Th cell proliferative responses than a commercial aluminum-formulated HBsAg vaccine or free HBsAg. The adjuvant effect of the Gel/HBs+GM vaccine was dependent upon the local release of GM-CSF. More importantly, the Gel/HBs+GM vaccine elicited high HBsAg-specific Ab titers and Th cell responses in B10.M mice, a mouse strain that does not respond to the current HBsAg vaccine because of its H-2 haplotype. Analysis of the draining lymph nodes of Gel/HBs+GM vaccine-treated mice revealed an elevated number of CD11c(+) dendritic cells showing enhanced expression of MHC class II and a variety of costimulatory molecules. These results demonstrate that hydrogel-formulated GM-CSF might represent a simple and effective method to generate next-generation hepatitis B virus vaccines for inducing anti-hepatitis B surface Abs in nonresponders.
authors.affiliation: Graduate Institute of Microbiology, National Taiwan University, Taipei, Taiwan.
authors.forename: Ho-Yuan
authors.initials: HY
authors.lastname: Chou
authors.forename: Xi-Zhang
authors.initials: XZ
authors.lastname: Lin
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Pan
authors.forename: Ping-Yi
authors.initials: PY
authors.lastname: Wu
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Shen
authors.forename: Mi-Hua
authors.initials: MH
authors.lastname: Tao
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000276:immunology; D006514:Hepatitis B Surface Antigens / Q000008:administration & dosage* / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014611:Vaccination / Q000379:methods
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; D000949:Histocompatibility Antigens Class II; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor