RESUMEN
Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematurely degraded. Because of the inherent complexity of the pathogenetic mechanisms involved in CF, which include impaired chloride permeability and persistent lung inflammation, a multidrug approach is required for efficacious CF therapy. To date, no individual drug with pleiotropic beneficial effects is available for CF. Here we report on the ability of thymosin alpha 1 (Tα1)-a naturally occurring polypeptide with an excellent safety profile in the clinic when used as an adjuvant or an immunotherapeutic agent-to rectify the multiple tissue defects in mice with CF as well as in cells from subjects with the p.Phe508del mutation. Tα1 displayed two combined properties that favorably opposed CF symptomatology: it reduced inflammation and increased CFTR maturation, stability and activity. By virtue of this two-pronged action, Tα1 has strong potential to be an efficacious single-molecule-based therapeutic agent for CF.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Fibrosis Quística/genética , Citocinas/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Timosina/análogos & derivados , Animales , Autofagia/efectos de los fármacos , Western Blotting , Línea Celular , Canales de Cloruro/efectos de los fármacos , Canales de Cloruro/metabolismo , Fibrosis Quística/inmunología , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Inmunoprecipitación , Indolamina-Pirrol 2,3,-Dioxigenasa/efectos de los fármacos , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Inflamación , Ratones , Ratones Endogámicos CFTR , Técnicas de Placa-Clamp , Estabilidad Proteica/efectos de los fármacos , Células RAW 264.7 , Mucosa Respiratoria/citología , Timalfasina , Timosina/farmacología , Ubiquitina Tiolesterasa/efectos de los fármacos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-ß. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-ß, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.