RESUMO
BACKGROUND: Blocking the activity of IL-6 can inhibit autoimmune diseases such as rheumatoid arthritis and Crohn's disease. OBJECTIVE: We examined whether an antibody against IL-6, tocilizumab (TCZ) (Actemra®), used clinically in rheumatoid arthritis (RA) would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHOD: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TCZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or TCZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) TCZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TCZ fed donors protected against actively induced disease and decreased inflammation. There was a decrease in IL-6 in actively treated spleen, decrease in TNF-α, Th1-like cytokine IL-12 and increase in Th2-like cytokine IL-10 in active fed and adoptively treated recipients. CONCLUSIONS: Ingested (orally administered) TCZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like cytokines and increase Th2-like anti-inflammatory cytokines.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Administração Oral , Transferência Adotiva , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CD11b/metabolismo , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunização , Inflamação/patologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos Endogâmicos C57BL , Baço/patologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Ingested immunoactive proteins, type I IFN, SIRS peptide 1-21, α-MSH, ACTH, and SST inhibit clinical attacks and inflammation in acute EAE by decreasing Th1-like cytokines, increasing Th2-like cytokines or increasing T(reg) cell frequencies. OBJECTIVE: We examined whether another protein, neuropeptide Y, would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or NPY during ongoing disease. Splenocytes from mock fed or NPY fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. RESULTS: Ingested (oral) NPY inhibited ongoing disease, and decreased inflammation. Adoptively transferred cells from NPY fed donors protected against actively induced disease and decreased inflammation. In actively fed mice, oral NPY decreased Th1-like cytokines and increased Th2-like IL-13 cytokines in both the spleen and the CNS. In recipients of donor cells from NPY fed mice there was a reduction of Th1 and Th17 and induction of Th2-like IL-13 cytokines in both the spleen and CNS. Oral NPY decreased clinical score and decreased inflammatory foci in both actively fed and recipients of actively fed mice. There was no significant increase in T(reg) cell frequencies in actively fed or recipients of NPY fed donor cells. CONCLUSIONS: Ingested (orally administered) NPY can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS.