title: Potent control of acute graft-versus-host disease lethality after immunization with a novel DNA vaccine targeted to B7-1/CD28 costimulatory signaling pathway.
abstract: A major challenge associated with allogeneic hematopoietic stem cell transplantation is effective prevention and/or attenuation of symptoms associated with acute graft-versus-host disease (aGVHD) that can result from a failure of either host and/or donor CD4(+)CD25(+) regulatory T (Tr) and CD8(+)CD28 suppressor T (Ts) cells to dampen immunopathogenic responses mediated by alloreactive donor CD4(+)CD28(+) Th1 (Th1) and CD8(+)CD28(-) Tc1 (Tc1) cell-mediated inflammatory processes. Considering the crucial role of CD28/B7-1 costimulatory signal pathway in development, activation, differentiation, and function of these T subsets, we developed a targeted DNA vaccine encoding the Pseudomonas exotoxin-A and the B7-1 molecule that could act as both an antagonist to Th1-mediated and Tc1-mediated responses while concomitantly acting as an agonist stimulating Tr-mediated and Ts-mediated responses as a strategy for reducing aGVHD-associated lethality. A single intramuscular injection with this vaccine significantly increased Tr and Ts levels in a murine aGVHD model. In addition, immunized mice presented with significantly diminished Th1-cytokines interferon-γ and interleukin-2 response and a moderately upregulated Th2-cytokine interleukin-10 and Th3-cytokine transforming growth factor-β response. More importantly, vaccination significantly reduced aGVHD, measured by significantly extended mean survival times, decreased mean weight loss, recovery of peripheral leukocyte numbers, disease presentation associated with mild-moderate histopathologic changes, a balanced Th1-Th2-Th3-cytokine responses and functional Tr-mediated and Ts-mediated regulatory/suppressor mechanisms at levels more potent than observed in animals treated with cyclosporine A+methotrexate. Our data first provide the proof-of-principal that B7-1-PE40KDEL targeted DNA vaccine represents a prophylactic approach for reducing alloreactive Th1-mediated and Tc-mediated aGVHD lethality by CD28/B7-1 axis.
authors: Department of Immunology and National Center for Biomedicine Analysis, Beijing 307 Hospital Affiliated to Academy of Medical Sciences, Beijing, P.R. China.
authors: Yuan
authors: Y
authors: Luo
authors: Fei
authors: F
authors: Liang
authors: Nan
authors: N
authors: Liu
authors: Hong
authors: H
authors: Xue
authors: Xinqiang
authors: X
authors: Song
authors: Fang
authors: F
authors: Yuan
authors: Juan
authors: J
authors: Long
authors: Xiao
authors: X
authors: Zhao
authors: Yuying
authors: Y
authors: Sun
authors: Yongzhi
authors: Y
authors: Xi
mesh_terms: D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000276:immunology*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology*; D018106:CD28 Antigens / Q000008:administration & dosage / Q000276:immunology*; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005098:Exotoxins / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014611:Vaccination; D019444:Vaccines, DNA / Q000008:administration & dosage*; D037521:Virulence Factors / Q000008:administration & dosage / Q000276:immunology*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D018122:B7-1 Antigen; D001427:Bacterial Toxins; D018106:CD28 Antigens; D005098:Exotoxins; D007371:Interferon-gamma; D016753:Interleukin-10; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D019444:Vaccines, DNA; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A