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1.
J Exp Med ; 204(1): 191-201, 2007 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-17210729

RESUMO

Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)-expanded, islet antigen-specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet beta cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5x10(4) of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/terapia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ilhotas Pancreáticas/imunologia , Selectina L/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Fatores de Transcrição Forkhead/metabolismo , Insulina/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Estado Pré-Diabético/sangue , Estado Pré-Diabético/imunologia , Estado Pré-Diabético/terapia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
2.
J Exp Med ; 199(11): 1467-77, 2004 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-15184500

RESUMO

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet beta cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5) polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.


Assuntos
Autoantígenos/imunologia , Antígenos CD4/análise , Células Dendríticas/fisiologia , Diabetes Mellitus Tipo 1/prevenção & controle , Receptores de Interleucina-2/análise , Linfócitos T Reguladores/imunologia , Animais , Apresentação de Antígeno , Feminino , Imunofenotipagem , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD
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