RESUMO
It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gammadelta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4(+) T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.
Assuntos
Transferência Adotiva , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colite/prevenção & controle , Colo/efeitos dos fármacos , Receptores Imunológicos/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígeno CD11c/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Proteínas de Transporte/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/patologia , Células Dendríticas/imunologia , Modelos Animais de Doenças , Feminino , Antígenos de Histocompatibilidade Classe I/metabolismo , Interferon gama/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Ligantes , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Antígenos de Histocompatibilidade Menor/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Receptores de Células Matadoras NaturaisAssuntos
Asma/terapia , Adolescente , Asma/diagnóstico , Criança , Pré-Escolar , Humanos , Lactente , Guias de Prática Clínica como AssuntoRESUMO
Adhesion molecules of the integrin family are implicated not only in leukocyte migration but also in leukocyte activation. Here we characterize the expression and function of fibronectin receptor integrins on rat mast cells. A rat basophilic leukemia cell line (RBL-2H3) and phorbol ester-stimulated rat peritoneal mast cells adhered to fibronectin (FN), vitronectin and fibrinogen. These mast cells expressed fibronectin receptor integrins, including very late antigen (VLA)-4, VLA-5 and vitronectin receptor (VNR), as estimated by immunofluorescent staining and inhibition of FN adherence by newly established mAbs reactive with the rat alpha 4 (MR alpha 4-1), alpha 5 (HM alpha 5-1) or beta 3 (HM beta 3-1) chains of the integrin molecules. The beta-hexosaminidase release, a marker for mast cell degranulation, triggered by high affinity IgE receptor (Fc epsilon RI)-mediated stimulation, was enhanced by adhesion of RBL-2H3 cells to either immobilized FN, MR alpha 4-1, HM alpha 5-1 or HM beta 3-1. This FN enhancement of beta-hexosaminidase release was inhibited by soluble MR alpha 4-1, HM alpha 5-1 and HM beta 3-1 as well as by GRGDSP and DELPQLVTLPHPNHLGPEILDVPST peptides which abrogate VLA-5/VNR and VLA-4 binding to FN respectively. In vivo, passive cutaneous anaphylaxis induced by IgE anti-DNP and DNP-BSA was inhibited by concurrent s.c. injection of MR alpha 4-1, HM alpha 5-1 and HM beta 3-1. These results demonstrate that FN receptor integrins expressed on rat mast cells play an important role in regulating mast cell activation both in vitro and in vivo.
