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1.
Zoonoses Public Health ; 56(6-7): 391-406, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19486321

RESUMO

The αGal HyperAcute(®) Technology exploits a robust zoonotic blockade to enhance potency of antiviral vaccines. Naturally acquired immunity against the common αGal epitope [galactose-alpha(1,3)-galactose-beta(1,4)N-acetylglucosamine-R (Gal-α(1,3)-Gal-ß(1,4)-GlcNAc-R)] is facilitated by the loss of a key enzyme in the epitope's biosynthetic pathway. As human cells are devoid of this epitope, chronic stimulus from gut flora leads to high levels of circulating anti-αGal antibodies and the development of a robust immune pathway. As the αGal epitope is immediately recognized as foreign, the naturally acquired αGal immune pathway in humans serves as a strong barrier to zoonotic infection. The αGal HyperAcute(®) Technology takes advantage of this natural process to facilitate the rapid presentation of modified antigens to antigen-presenting cells, leading to a strong immune response. The evolutionary immunity to αGal ensures that the presence of αGal epitopes on antigens will lead to a robust immune response involving cross-activation of T(H)1 immunity, characterized by cytokine secretion and increased phagocytic activity, and T(H)2 immunity characterized by high antibody titres. αGal epitopes can be applied to antiviral vaccines by biological, enzymatic or chemical means. Several detection methods that directly and indirectly verify αGal addition are discussed. Enhanced immunogenicity (humoral and cellular) of αGal-modified vaccines is shown for several antiviral vaccine candidates. αGal modification of antiviral vaccine components leads to enhanced immunogenicity. The existing body of literature describing the utility of αGal epitopes as a safe and robust immunostimulatory and -modulatory agent in humans supports the basis for applying the αGal HyperAcute(®) Technology to the improvement of antiviral vaccines, both new and currently approved.


Assuntos
Galactosiltransferases/imunologia , Galactosiltransferases/metabolismo , Vacinas Virais/imunologia , Adjuvantes Imunológicos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Células Cultivadas , Epitopos/metabolismo , Humanos , Vacinação , Zoonoses
2.
Gene Ther ; 6(1): 57-62, 1999 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10341876

RESUMO

A major obstacle to the success of gene therapy strategies that directly target cancer cells is the poor vector distribution within solid tumors. To address this problem, we developed an E1b 55 kDa attenuated, replication-competent adenovirus (Ad.TKRC) which expresses the herpes simplex-1 thymidine kinase (HSVtk) gene to sensitize tumors to ganciclovir (GCV). Efficacy of this combined strategy was tested in nude mice with subcutaneous human A375 melanoma and ME180 cervical carcinomas. Intratumoral injection of a replication-defective adenoviral vector expressing HSVtk (Ad.TK) followed by GCV treatment resulted in doubling of the survival time of mice bearing A375 tumors and 20% long-term survival of mice with ME180 tumors. Treatment of tumors with Ad.TKRC without GCV resulted in a similar antitumor effect, confirming that the replicating vector has an oncolytic effect. When GCV was initiated 3 days after Ad.TKRC injection, survival of mice with each tumor type was greatly prolonged, with 60% of animals with ME180 tumors surviving for over 160 days. These results confirm that both the oncolysis caused by a replicating virus and suicide/prodrug gene therapy with HSVtk/GCV have potent antitumor effects. When combined, these two approaches are complementary resulting in a significantly improved treatment outcome.


Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Neoplasias Experimentais/terapia , Simplexvirus/enzimologia , Timidina Quinase/genética , Adenoviridae/fisiologia , Animais , Antimetabólitos/uso terapêutico , Feminino , Ganciclovir/uso terapêutico , Melanoma/terapia , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Neoplasias do Colo do Útero/terapia , Replicação Viral
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