Non-myeloablative transplantation of bone marrow expressing self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice.
Gene Ther
; 19(11): 1075-84, 2012 Nov.
Article
em En
| MEDLINE
| ID: mdl-22071968
ABSTRACT
Myeloablative transplantation of bone marrow (BM) engineered to express myelin oligodendrocyte glycoprotein (MOG) establishes central intrathymic tolerance and completely prevents MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. Here we asked whether non-myeloablative transplantation of MOG expressing BM (pMOG-bone marrow transplantation (BMT)) can also provide the same protection. Using stepwise reduction of irradiation doses, 275 cGy irradiation with pMOG-BMT protected 100% of mice from EAE development even with two subsequent re-challenge with MOG. Irradiation doses <275 cGy produced dose-dependent partial protection with significant disease protection still evident at 50 cGy. Splenocytes from 275 cGy recipients proliferated to MOG stimulation in vitro, indicating that MOG-reactive cells are present in the periphery but failed to induce disease. MOG-stimulated splenocytes produced little or no interleukin-17, interferon-γ, granulocyte-monocyte colony stimulating factor and tumor necrosis factor-α compared with EAE control. Adoptive transfer of CD4 T cells from EAE-resistant mice into Rag2(-/-) mice devoid of MOG expression resulted in MOG-induced EAE in ~74% of mice. Treatment of EAE-resistant mice with anti-programmed death 1 (PD-1) monoclonal antibody-induced EAE in 67% of mice. We conclude that non-myeloablative transplantation of self-antigen expressing BM induces robust peripheral tolerance that completely prevented EAE development. Our findings implicate clonal anergy and the PD-1 pathway in the maintenance of peripheral tolerance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autoantígenos
/
Autoimunidade
/
Transplante de Medula Óssea
/
Condicionamento Pré-Transplante
/
Tolerância Periférica
Limite:
Animals
Idioma:
En
Revista:
Gene Ther
Assunto da revista:
GENETICA MEDICA
/
TERAPEUTICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Austrália