Selective ERK activation differentiates mouse and human tolerogenic dendritic cells, expands antigen-specific regulatory T cells, and suppresses experimental inflammatory arthritis.
Arthritis Rheum
; 63(1): 84-95, 2011 Jan.
Article
em En
| MEDLINE
| ID: mdl-20967853
ABSTRACT
OBJECTIVE:
Most therapeutic treatments for autoimmune arthritis rely on immunosuppressive drugs, which have side effects. Although a previous study by our group showed that specific ERK activation suppressed immune responses, its application in a therapeutic setting has never been tested. The aim of the present study was to define the ERK-dependent immunosuppressive mechanisms and to apply selective ERK activation for the treatment of experimental inflammatory arthritis.METHODS:
A constitutively active ERK activator was coexpressed with a model antigen using lentivectors. Immunosuppressive mechanisms were characterized at the level of dendritic cell (DC) function, differentiation of antigen-specific Treg cells, and inhibition of inflammatory T cells. Administration of the ERK activator with antigen as a strategy to suppress inflammatory arthritis was tested in an experimental mouse model.RESULTS:
Selective ERK activation induced mouse and human DCs to secrete bioactive transforming growth factor ß, a process required for suppression of T cell responses and differentiation of antigen-specific Treg cells. Treg cells strongly proliferated after antigen reencounter in inflammatory conditions, and these cells exhibited antigen-dependent suppressive activities. Inflammatory arthritis was effectively inhibited through antigen-specific mechanisms. Importantly, this strategy did not rely on identification of the initiating arthritogenic antigen. Equivalent mechanisms were demonstrated in human monocyte-derived DCs, setting the scene for a possible rapid translation of this approach to patients with rheumatoid arthritis.CONCLUSION:
This strategy of selective ERK activation resulted in an effective therapeutic protocol, with substantial advantages over DC or T cell vaccination.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Experimental
/
Células Dendríticas
/
Linfócitos T Reguladores
/
MAP Quinases Reguladas por Sinal Extracelular
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Arthritis Rheum
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Reino Unido