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Clin Cancer Res ; 12(14 Pt 1): 4294-305, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16857805

RESUMO

PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens. RESULTS: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.


Assuntos
Anticorpos Monoclonais/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioma/metabolismo , Glioma/terapia , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Linfócitos T Reguladores/metabolismo , Animais , Células da Medula Óssea/metabolismo , Antígenos CD4/biossíntese , Linhagem Celular Tumoral , Células Dendríticas/metabolismo , Citometria de Fluxo , Interferon gama/metabolismo , Subunidade alfa de Receptor de Interleucina-2/química , Linfócitos/metabolismo , Camundongos , Linfócitos T/metabolismo
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