RESUMO
Herein we demonstrate that ultraviolet light-inactivated Herpes Simplex Virus-1 (UV-HSV-1) stimulates peripheral blood mononuclear cells (PBMCs) to lyse both androgen-sensitive and androgen-independent prostate cancer (PrCA) cell lines, but not the benign prostatic hyperplastic epithelial cell line, BPH-1, and is 1000-10,000-fold more potent at stimulating this killing than ultraviolet light-inactivated Vesicular Stomatitis Virus, adenovirus, reovirus or cytomegalovirus. Among PBMCs, natural killer (NK) cells appear to be a major cell type involved in this killing and UV-HSV-1 appears to directly and potently stimulate NK cell expression of CD69, degranulation, cytokine production, and migration to IL-8 in PC3 conditioned medium. We also found that UV-HSV-1 stimulates glycolysis in PBMCs and NK cells, and that 2-deoxyglucose and the protein kinase C inhibitor, Go6976, and the NFκB inhibitor, Bay 11-7082, all abrogate UV-HSV-1 activated killing of PC3 cells by PBMCs and NK cells. Using neutralizing anti-Toll-like receptor 2 (TLR2) we found that UV-HSV-1, like HSV-1, activates NK cells via TLR2. Taken together, these results are consistent with Toll-like receptor 2 ligands on UV-HSV-1 stimulating TLR2 on NK cells to activate protein kinase C, leading to enhanced glycolysis and NFκB activation, both of which play a critical role in this anti-PrCA innate immune response. Importantly, UV-HSV-1 synergizes with IL-15 to increase the cytolytic activity of PBMCs against PC3 cells and there was considerable donor-to-donor variation in killing ability. These results support the preclinical development of UV-HSV-1 as an adjuvant, in combination with IL-15, for cell infusions of healthy, preselected NK cells to treat PrCA.
Assuntos
Citotoxicidade Imunológica , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/efeitos da radiação , Células Matadoras Naturais/imunologia , Raios Ultravioleta , Inativação de Vírus/efeitos da radiação , Biomarcadores , Linhagem Celular Tumoral , Citocinas/metabolismo , Glicólise , Humanos , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/metabolismo , Receptor 2 Toll-Like/metabolismoRESUMO
The use of low-level laser to suppress infections caused by Herpes simplex viruses 1 and 2 was evaluated after one to five applications. A gradual reduction in replication of Herpes simplex viruses 1 and 2 was observed, with 68.4% and 57.3% inhibition, respectively, after five applications, thus favoring its clinical use.
Assuntos
Herpesvirus Humano 1/efeitos da radiação , Herpesvirus Humano 2/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Animais , Chlorocebus aethiops , Herpes Simples/radioterapia , Humanos , Células Vero , Replicação Viral/efeitos da radiaçãoRESUMO
O uso do laser de baixa intensidade na supressão de infecções pelos vírus Herpes simplex 1 e 2 foi avaliado após uma a cinco aplicações, sendo observada uma redução gradual na replicação dos vírus Herpes simplex 1 e 2 com 68,4 por cento e 57,3 por cento de inibição, respectivamente, após 5 aplicações, indicando o seu uso clínico.
The use of low-level laser to suppress infections caused by Herpes simplex viruses 1 and 2 was evaluated after one to five applications. A gradual reduction in replication of Herpes simplex viruses 1 and 2 was observed, with 68.4 percent and 57.3 percent inhibition, respectively, after five applications, thus favoring its clinical use.