RESUMO
Purpose: To determine cellular and temporal expression patterns of herpes virus entry mediator (HVEM, Tnfrsf14) in the murine cornea during the course of herpes simplex virus 1 (HSV-1) infection, the impact of this expression on pathogenesis, and whether alterations in HVEM or downstream HVEM-mediated effects ameliorate corneal disease. Methods: Corneal HVEM levels were assessed in C57BL/6 mice after infection with HSV-1(17). Leukocytic infiltrates and corneal sensitivity loss were measured in the presence, global absence (HVEM knockout [KO] mice; Tnfrsf14-/-), or partial absence of HVEM (HVEM conditional KO). Effects of immune-modifying nanoparticles (IMPs) on viral replication, corneal sensitivity, and corneal infiltrates were measured. Results: Corneal HVEM+ populations, particularly monocytes/macrophages during acute infection (3 days post infection [dpi]) and polymorphonuclear neutrophils (PMN) during the chronic inflammatory phase (14 dpi), increased after HSV-1 infection. Herpes virus entry mediator increased leukocytes in the cornea and corneal sensitivity loss. Ablation of HVEM from CD45+ cells, or intravenous IMP therapy, reduced infiltrates in the chronic phase and maintained corneal sensitivity. Conclusions: Herpes virus entry mediator was expressed on two key populations: corneal monocytes/macrophages and PMNs. Herpes virus entry mediator promoted the recruitment of myeloid cells to the cornea in the chronic phase. Herpes virus entry mediator-associated corneal sensitivity loss preceded leukocytic infiltration, suggesting it may play an active role in recruitment. We propose that HVEM on resident corneal macrophages increases nerve damage and immune cell invasion, and we showed that prevention of late-phase infiltration of PMN and CD4+ T cells by IMP therapy improved clinical symptoms and mortality and reduced corneal sensitivity loss caused by HSV-1.
Assuntos
Infecções Oculares Virais/terapia , Infecções por Herpesviridae/terapia , Herpesvirus Humano 1/patogenicidade , Imunoterapia/métodos , Ceratite Herpética/terapia , Ácido Láctico/administração & dosagem , Ácido Poliglicólico/administração & dosagem , Membro 14 de Receptores do Fator de Necrose Tumoral/administração & dosagem , Animais , Materiais Biocompatíveis/administração & dosagem , Córnea/metabolismo , Córnea/patologia , Córnea/virologia , Modelos Animais de Doenças , Infecções Oculares Virais/diagnóstico , Infecções Oculares Virais/imunologia , Citometria de Fluxo , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/imunologia , Imunidade Celular , Imuno-Histoquímica , Injeções Intravenosas , Ceratite Herpética/diagnóstico , Ceratite Herpética/imunologia , Ceratite Herpética/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F(1) transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases.
Assuntos
Reação Enxerto-Hospedeiro/imunologia , Receptores Imunológicos/antagonistas & inibidores , Membro 14 de Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Transdução de Sinais/imunologia , Transferência Adotiva , Animais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/transplante , Células CHO , Movimento Celular/genética , Movimento Celular/imunologia , Cricetinae , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Endogâmicos Lew , Receptores Imunológicos/fisiologia , Membro 14 de Receptores do Fator de Necrose Tumoral/administração & dosagem , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Baço/citologia , Baço/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/transplanteRESUMO
Previous studies attempting to influence the severity of collagen-induced arthritis (CIA) by modulating the LIGHT (lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator (HVEM) on T cells)/lymphotoxin pathway have yielded conflicting results. To further clarify the role of LIGHT in autoimmune arthritis, a HVEM-Ig fusion protein was used. CIA was induced in DBA1 mice, which were injected i.p. with recombinant HVEM-Ig fusion protein and control Ig at different time points. Severity of clinical arthritis and histologic joint destruction were significantly increased in HVEM-Ig-treated mice compared with control-Ig-treated mice. Collagen II-induced in vitro T cell proliferation and IFN-gamma production was augmented in mice treated with HVEM-Ig, as was the production of IgG2a anti-collagen II Ab. Accordingly, serum concentrations of IFN-gamma and IL-6 were higher in mice treated with HVEM-Ig. In conclusion, HVEM-Ig aggravates autoimmunity in collagen-induced arthritis, which is possibly mediated by interaction with B and T lymphocyte attenuator (BTLA) or CD160, despite the blockade of LIGHT. Hence, HVEM-Ig seems not to be a valid therapeutic option in autoimmune arthritis.