RESUMEN
Immunoglobulin G (IgG) is transcytosed across intestinal epithelial cells of suckling mammals by the neonatal Fc receptor (FcRn); however, the contribution of FcRn vs. FcRn-independent uptake to serum IgG levels had not been determined in either rat pups or human (h)FcRn-expressing mice (Tg276 and Tg32). In isoflurane-anesthetized rodents, serum levels were determined after regional intestinal delivery of human monoclonal antibodies (hIgG) with either wild-type (WT) Fc sequences or variants engineered for different FcRn binding affinities. Detection of full-length hIgG was by immunoassay; intestinal hFcRn and hIgG localization was by immunocytochemistry. High (µg/ml) serum levels of hIgG were detected after proximal intestinal delivery (0.1-10 mg/kg) in 2-wk-old rats. Human FcRn was visualized in epithelial cells of Tg276 mice, but low serum hIgG levels (<10 ng/ml) were obtained. In rat pups, intraintestinal hIgG1 WT administration resulted in dose-related and saturable uptake, whereas uptake of a low FcRn-binding affinity variant was nonsaturable. There were no differences in hIgG levels from systemic and hepatic portal vein serum samples, and intense hIgG immunostaining was noted in villi enterocytes and within lymphatic lacteal-like vessels. This study demonstrated that FcRn-mediated uptake in rat pups accounted for ~80% of serum hIgG levels and that IgG enters the circulation via the lymph and not the hepatic portal vein. The remaining uptake though the immature intestine is nonreceptor mediated. Intestinal epithelial cell hFcRn expression occurred in Tg276 mice, but receptor-mediated transport of IgG was not observed. The suckling rat pup intestine is a mechanistic model of FcRn-IgG-mediated transcytosis.
Asunto(s)
Animales Lactantes/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunoglobulina G/metabolismo , Mucosa Intestinal/metabolismo , Receptores Fc/genética , Receptores Fc/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Relación Dosis-Respuesta a Droga , Enterocitos/metabolismo , Células Epiteliales/metabolismo , Femenino , Humanos , Inmunoensayo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Ratas , Transcitosis/fisiologíaRESUMEN
Abatacept is the first in a new class of agents that selectively modulates T-cell activation by attenuating CD28-mediated co-stimulation. This study examined the effects of abatacept on disease development in a rat model of collagen-induced arthritis (CIA). The rats were treated with either abatacept (1mg/kg) or control IgG beginning at the time of induction of CIA. By day 16, significant paw swelling was observed in IgG-treated control animals that continued to increase, reaching a plateau on day 21. Prophylactic treatment with abatacept completely abrogated paw swelling throughout the study. Histopathology demonstrated a significant reduction in inflammation, cartilage destruction, bone resorption and pannus formation. Abatacept treatment resulted in 90% inhibition of circulating collagen-specific antibodies and decreased the serum expression of many cytokines and chemokines that were upregulated in diseased animals. Immunohistochemical analysis of the ankle joints demonstrated that interleukin-6 production was reduced in the tissues and the numbers of osteoclasts present in the joints were also decreased. Ankle microcomputer tomography (micro-CT) analyses dramatically demonstrated the protective effects of abatacept on bone destruction in these animals. Data presented here demonstrate that prophylactic administration of abatacept significantly inhibits the onset and progression of disease in a rat CIA model, with reductions in inflammation, inflammatory mediators, and bone and joint destruction.