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1.
Immunobiology ; 217(9): 912-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22356938

RESUMO

Mast cells (MC) are key effector cells in allergic reactions but also involved in host defence, tissue remodeling, angiogenesis, and fibrogenesis. Here, we show that human intestinal fibroblasts (FB) suppress apoptosis in human intestinal MC dependent on IL-6. Intestinal FB produced IL-6 upon direct stimulation by intestinal MC in co-culture or by MC mediators such as TNF-α, IL-1ß, tryptase or histamine. MC incubated with IL-6 survived for up to 3 weeks similar to MC co-cultured with FB and MC survival could be blocked by neutralizing anti-IL-6 Abs. Moreover, FB stimulated by MC mediators upregulated their expression of matrix metalloproteinase-1 (MMP-1), a key fibrolytic enzyme. Noteworthy, FB co-cultured with MC or treated with MMP-1 lost confluence and showed increased numbers of apoptotic cells. Our data indicate an intimate cross talk between mucosal MC and FB resulting in MC survival and induction of a fibrolytic rather than a profibrotic state in FB.


Assuntos
Fibroblastos/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/metabolismo , Mastócitos/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Receptor Cross-Talk , Apoptose/efeitos dos fármacos , Comunicação Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Flavonoides/farmacologia , Humanos , Interleucina-6/farmacologia , Mastócitos/efeitos dos fármacos , Metaloproteinase 1 da Matriz/farmacologia , Inibidores de Proteínas Quinases/farmacologia
2.
Blood ; 118(18): 4853-62, 2011 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-21908423

RESUMO

Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8(+) T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8(+) T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8(+) T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44(high)) and activated (ICOS(+)) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8(+) T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Receptores CCR4/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Autoantígenos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Terapia Combinada , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Especificidade do Receptor de Antígeno de Linfócitos T/efeitos dos fármacos , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Evasão Tumoral/imunologia
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