RESUMEN
We developed a novel trimeric sTNFRII fusion protein, named sTNFRII-gAD, which exhibited a higher in vitro antagonistic efficacy for TNFα in comparison with sTNFRII-Fc. This study aimed to investigate the arthritic protection of sTNFRII-gAD in a rat collagen-induced arthritis (CIA). The rats were injected intradermally with collagen type II at days 0 and 7. Three days after the second injection (day 10), the rats were intraperitoneally given sTNFRII-gAD or sTNFRII-Fc, or PBS. Effects of treatments were examined with respect of CIA incidence, severity and pathological changes. Serum TNFα, IL-17A and regulatory T cell (Treg) in periphery were determined at days 10 and 16, respectively. Our results showed that sTNFRIIgAD significantly reduced CIA incidence and severity (p < 0.05); meanwhile it led to a dramatic improvement in cartilage and bone damage. Moreover, the increase in serum anti-CII and IL-17A, and the reduction in Treg population were inhibited (p < 0.05) by sTNFRII-gAD or sTNFRII-Fc. Serum TNFα was found to be accumulated in the groups treated with sTNFRII-gAD or sTNFRII-Fc compared with the group treated with PBS (p < 0.05). It is noteworthy that sTNFRII-gAD displayed a better efficacy than sTNFRII-Fc in CIA incidence, pathological changes in cartilage and the elevation of anti-CII antibody, indicating that sTNFRII-gAD is potentially a more efficacious anti-TNFα agent for rheumatoid arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Receptores Tipo II del Factor de Necrosis Tumoral/uso terapéutico , Animales , Anticuerpos/sangre , Artritis Experimental/sangre , Artritis Experimental/patología , Cartílago/patología , Colágeno Tipo II/inmunología , Colágeno Tipo II/toxicidad , Evaluación Preclínica de Medicamentos , Femenino , Inyecciones Intraperitoneales , Interleucina-17/sangre , Articulación de la Rodilla/patología , Recuento de Linfocitos , Ratas , Ratas Wistar , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/uso terapéutico , Solubilidad , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/análisisRESUMEN
To validate its efficacy in the context of the human immune system, a novel therapeutic vaccine of hGM-CSF/hTNFα surface-modified PC-3 cells against human prostate cancer was evaluated in the human peripheral blood lymphocytes-severe combined immunodeficiency (huPBL-SCID) chimeric mouse model. The hGM-CSF or/and hTNFα modified vaccines inhibited prostate cancer growth effectively so as to prolong the mouse survival significantly. The splenocytes from the hGM-CSF/hTNFα vaccine-inoculated mice showed the strongest tumor-specific cytotoxicity against PC-3 cells and the highest production of IFNɤ. These features indicated that type 1 protective immune response was induced efficiently against human prostate cancer and further enhanced through synergetic adjuvant effects of hGM-CSF and hTNFα.