RESUMO
A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunoterapia , Modelos Animais , Proteínas Oncogênicas Virais/imunologia , Neoplasias do Colo do Útero/terapia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/uso terapêutico , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Chaperonina 60 , Chaperoninas/genética , Chaperoninas/imunologia , Chaperoninas/uso terapêutico , Feminino , Haplótipos/genética , Homozigoto , Humanos , Imunização , Complexo Principal de Histocompatibilidade/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Mycobacterium bovis/genética , Proteínas Oncogênicas Virais/genética , Ovário/imunologia , Ovário/metabolismo , Ovário/patologia , Papillomaviridae/genética , Papillomaviridae/imunologia , Proteínas E7 de Papillomavirus , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Células Tumorais Cultivadas/transplante , Células Tumorais Cultivadas/virologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/metabolismo , Vacinas Virais/uso terapêutico , Displasia do Colo do Útero/imunologia , Displasia do Colo do Útero/metabolismo , Displasia do Colo do Útero/terapiaRESUMO
There is a high prevalence of diseases caused by human papillomavirus (HPV) infection. Unfortunately, current treatments are inadequate. However, because there is evidence to support a role for the immune system in host defence against this virus, an immunotherapeutic approach is warranted. The existing immunotherapies are not completely effective, nor are they durable. In addition, natural history studies associated with spontaneous regression have provided little guidance to the design of successful interventions. This state of knowledge has encouraged efforts towards the development of novel immunotherapeutic strategies. Successful preclinical studies of therapeutic vaccine candidates have led to clinical studies for a variety of HPV-associated indications, such as anogenital warts and cervical and anal intraepithelial neoplasia. Immunisation approaches such as adjuvanted peptides, virus-like particles and fusion constructs are discussed. Specifically, chimaeric molecules comprised of mycobacterial heat-shock proteins (Hsps) and HPV16 E7 appear promising.
