RESUMEN
In spite of considerable therapeutic progress, acute graft-versus-host disease still limits allogeneic hematopoietic cell transplantation. We recently reported that mouse infection with nidovirus lactate dehydrogenase elevating virus impairs disease in non-conditioned B6D2F1 recipients of parental B6 spleen cells. As this virus activates TLR7, we tested a pharmacological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lymphocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presentation by CD11b+ and CD8α+ dendritic cells were inhibited. These inhibitions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 transplantation model, R848 decelerated, but did not abrogate, donor T-cell implantation and activation. However, it decreased interferon-gamma, tumor necrosis factor-alpha and interleukin-27 while upregulating active transforming growth factor-beta 1 plasma levels. In addition, donor and recipient Foxp3+ regulatory T-cell numbers were increased in recipient mice and their elimination compromised disease prevention. R848 also strongly improved survival of lethally irradiated BALB/c recipients of B6 hematopoietic cells and this also correlated with an upregulation of CD4 and CD8 Foxp3+ regulatory T cells that could be further increased by inhibition of interleukin-27. The combination of anti-interleukin-27p28 mono -clonal antibody and R848 showed strong synergy in preventing disease in the B6 to B6D2F1 transplantation model when recipients were sublethally irradiated and this also correlated with upregulation of regulatory T cells. We conclude that R848 modulates multiple aspects of graft-versus-host disease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Enfermedad Injerto contra Huésped/prevención & control , Imidazoles/farmacología , Interleucina-27/antagonistas & inhibidores , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Receptor Toll-Like 7/metabolismo , Animales , Citocinas/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Inmunomodulación/efectos de los fármacos , Ligandos , Melanoma Experimental , Ratones , Trasplante de Neoplasias , Linfocitos T Reguladores/inmunologíaRESUMEN
This is a review looking at anti cytokine therapy in Rheumatoid Arthritis (RA), Psoriatic Arthritis (PSA) and Ankylosing Spondylitis (AS). The review explores the similarities and differences in the clinical features, as well as treatments and cytokines involved in the development and propagation of the disease. Particular attention is paid to TNFα inhibitors IL-1ra, IL-6 and JAK kinase Inhibitors, anti IL23 and IL-12 and the new developments with anti-IL-17.
Asunto(s)
Artritis Psoriásica/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Citocinas/antagonistas & inhibidores , Espondilitis Anquilosante/tratamiento farmacológico , Animales , Artritis Psoriásica/inmunología , Artritis Psoriásica/fisiopatología , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Enfermedad Crónica/tratamiento farmacológico , Citocinas/metabolismo , Humanos , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-12/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Interleucina-27/antagonistas & inhibidores , Interleucina-6/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Ratones , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/fisiopatología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
INTRODUCTION: Previous studies have shown that some cytokines mediate the effect of IGF-1 on inflammation and also association between IGF-1 and vascular endothelial dysfunction. Due to the discrepancies in the inflammatory and anti-inflammatory roles of IL-27 and IL-35, the effects of these cytokines and their IGF-1-mediating role were investigated regarding chronic joint inflammation and synovial blood flow. METHOD: Male rats were divided into two main groups of histopathology (n=80) and blood flow (n=72). These were further divided into ten subgroups of control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1+IL-27 antagonist, and IGF-1+IL-35 antagonist. Inflammation was induced by intra-articular injection of complete Freund adjuvant. Two weeks later (in order to induce chronic inflammation), vehicle or drugs were injected into the joint space every other day until day 28, on which inflammatory indices were assessed histopathologically. In the second subgroups, vehicle or drugs were administered by super-fusion on day 28 and their effects on the joint blood flow (JBF, laser Doppler perfusion method) and the systemic blood pressure were assessed. RESULTS: Endogenous IL-27 and IL-35 had inflammatory roles and IGF-1 had no effect. IL-27 and IL-35 antagonists had the highest anti-inflammatory and anti-angiogenesis effects and these effects were inhibited by IGF-1. Total inflammation score was 4.5 ± 0.42, 3.50 ± 0.5, 2.25 ± 0.45 and 1.50 ± 0.42 for vehicle, IGF-1 antagonist, IL-27 antagonist and IL-35 antagonist respectively. A significant increase was induced in JBF by IGF-1 antagonist and combination of IGF-1+IL-35 antagonist. CONCLUSION: IL-27 and IL-35 antagonists may be suitable goals for the treatment of chronic joint inflammation while their anti-inflammatory effects are not exerted via the changes in JBF.
Asunto(s)
Inflamación/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Interleucina-27/metabolismo , Interleucinas/metabolismo , Articulación de la Rodilla/metabolismo , Animales , Antiinflamatorios/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Enfermedad Crónica , Adyuvante de Freund , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Subunidad p35 de la Interleucina-12/antagonistas & inhibidores , Subunidad p35 de la Interleucina-12/metabolismo , Interleucina-27/antagonistas & inhibidores , Interleucinas/antagonistas & inhibidores , Articulación de la Rodilla/irrigación sanguínea , Articulación de la Rodilla/patología , Masculino , Antígenos de Histocompatibilidad Menor/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Factores de TiempoRESUMEN
UNLABELLED: Interleukin-27 (IL-27) belongs to the IL-6/IL-12 family of cytokines, associated with different inflammatory diseases and orchestrates its biological activity via common heterodimeric receptor composed of WSX-1 (IL-27Rα) and gp130. The present study was aimed to investigate the regulation of CXCL9, CXCL10, and CXCL11 chemokines in hepatic cells (human LX-2 cell line derived from normal human stellate cells (HSC), primary human hepatocytes, HSC, and HepG2 cells) and concanavalin A (ConA)-induced liver inflammation. We demonstrated that IL-27, but not IL-6, induced/up-regulated CXCR3 ligand genes (CXCL9, CXCL10, and CXCL11; out of 26 selected genes) in a STAT1-dependent manner in hepatic cells in vitro both at transcript and protein levels. In ConA-induced T cell-mediated hepatic model, we showed that soluble IL-27/IFNγ was elevated following ConA hepatitis in association with increased CXCL9, CXCL10, and CXCL11 expression in the liver. The exogenous IL-27 administration induced CXCR3 ligands in mouse liver at 4 h with any significant effect on recruitment of CXCR3(+) immune cells in the liver. The neutralization of IL-27 during ConA hepatitis differentially modulated (transcript vs protein expression) CXCR3 ligands and IFNγ during ConA-induced hepatitis with down-regulated expression of CXCL9 and CXCL10 at transcript level. The IFNγ, complementary regulated the expression of CXCR3 ligands as their up-regulation during ConA hepatitis, was abolished in IFNγ KO mice. In summary, IL-27 up-regulated the CXCL9, CXCL10, and CXCL11 chemokine expression in hepatic cells. IL-27 regulated CXCR3 ligand expression in IFNγ-dependent manner during acute hepatitis suggesting a complementary role of IL-27 and IFNγ to moderate liver inflammation via regulation of CXCR3 ligands. KEY MESSAGE: IL-27 up-regulated CXCR3 ligand expression in human hepatic cells in vitro. IL-27 up-regulated CXCR3 ligand expression and secretion in ConA hepatitis in vivo. CXCR3 ligand expression was down-regulated by blocking IL-27 or IFNγ deficiency. IL-27 modulated liver injury by regulation of CXCR3 ligands in IFNγ-dependent manner.