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1.
Blood ; 113(19): 4681-9, 2009 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-19252140

RESUMO

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from a hematopoietic stem cell expressing the BCR/ABL fusion protein. Leukemic and dendritic cells (DCs) develop from the same transformed hematopoietic progenitors. How BCR/ABL interferes with the immunoregulatory function of DCs in vivo is unknown. We analyzed the function of BCR/ABL-expressing DCs in a retroviral-induced murine CML model using the glycoprotein of lymphocytic choriomeningitis virus as a model leukemia antigen. BCR/ABL-expressing DCs were found in bone marrow, thymus, spleen, lymph nodes, and blood of CML mice. They were characterized by a low maturation status and induced only limited expansion of naive and memory cytotoxic T lymphocytes (CTLs). In addition, immunization with in vitro-generated BCR/ABL-expressing DCs induced lower frequencies of specific CTLs than immunization with control DCs. BCR/ABL-expressing DCs preferentially homed to the thymus, whereas only few BCR/ABL-expressing DCs reached the spleen. Our results indicate that BCR/ABL-expressing DCs do not efficiently induce CML-specific T-cell responses resulting from low DC maturation and impaired homing to secondary lymphoid organs. In addition, BCR/ABL-expressing DCs in the thymus may contribute to CML-specific tolerance induction of specific CTLs.


Assuntos
Células Dendríticas/fisiologia , Proteínas de Fusão bcr-abl/metabolismo , Glicoproteínas/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Modelos Animais de Doenças , Citometria de Fluxo , Imunização , Memória Imunológica/imunologia , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Retroviridae/genética , Células Tumorais Cultivadas , Irradiação Corporal Total
2.
Eur J Immunol ; 39(3): 704-16, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19189311

RESUMO

CTL are induced by two pathways, i.e. direct priming, where tumor cells present tumor antigens to naïve specific CTL, and cross-priming, where professional APC cross-present captured tumor antigens to CTL. Here, we examined direct priming versus cross-priming after immunizing (H-2(b) x H-2(d)) F1 mice with either H-2(b) or H-2(d) positive tumor cells transfected with the GP or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV). Cross-priming was observed for the immunodominant epitopes LCMV-gp33 and -np118, although direct induction resulted in higher CTL frequencies. In contrast, CTL specific for the subdominant epitopes LCMV-gp283 or -np396 were induced only if epitopes were presented directly on MHC class I molecules of the immunizing cell. The broader repertoire and the higher CTL frequencies induced after vaccination with haplotype-matched tumor cells resulted in more efficient anti-tumor and antiviral protection. Firstly, our results indicate that certain virus and tumor antigens may not be detected by CD8(+) T cells because of impaired cross-priming. Secondly, efficient cross-priming contributes to the immunodominant nature of a tumor-specific CTL epitope. Thirdly, vaccine strategies using autologous or syngenic antigen-expressing cells induce a broader repertoire of tumor-specific CTL and higher CTL frequencies.


Assuntos
Antígenos Virais/imunologia , Apresentação Cruzada/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Epitopos Imunodominantes/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos Virais/metabolismo , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Epitopos Imunodominantes/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/metabolismo , Transfecção
3.
Cancer Res ; 67(15): 7467-76, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17671217

RESUMO

The effect of cancer immunotherapy on the endogenous immune response against tumors is largely unknown. Therefore, we studied immune responses against murine tumors expressing the glycoprotein (GP) and/or nucleoprotein of lymphocytic choriomeningitis virus (LCMV) with or without adoptive T-cell therapy. In nontreated animals, CTLs specific for different epitopes as well as LCMV-GP-specific antibodies contributed to tumor surveillance. Adoptive immunotherapy with monoclonal CTLs specific for LCMV-gp33 impaired the endogenous tumor-specific antibody and CTL response by targeting antigen cross-presenting cells. As a consequence and in contrast to expectations, immunotherapy enhanced tumor growth. Thus, for certain immunogenic tumors, a reduction of tumor-specific B- and T-cell responses and enhanced tumor growth may be an unwanted consequence of adoptive immunotherapy.


Assuntos
Fibrossarcoma/terapia , Imunoterapia Adotiva/métodos , Melanoma Experimental/terapia , Linfócitos T/transplante , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Cromo/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Epitopos de Linfócito T/imunologia , Fibrossarcoma/imunologia , Citometria de Fluxo , Glicoproteínas/imunologia , Glicoproteínas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nucleoproteínas/imunologia , Nucleoproteínas/metabolismo , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
4.
Blood ; 108(10): 3406-13, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16873671

RESUMO

Imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (TKs) and is effective in the treatment of malignancies characterized by constitutive activation of these TKs such as chronic myeloid leukemia and gastrointestinal stromal tumors. TKs also play an important role in T-cell receptor (TCR) signal transduction. Inhibitory as well as stimulating effects of imatinib on T cells and dendritic cells have been described. Here, we analyzed the effects of imatinib treatment on antiviral immune responses in vivo. Primary cytotoxic T-cell (CTL) responses were not impaired in imatinib-treated mice after infection with lymphocytic choriomeningitis virus (LCMV) or after immunization with a tumor cell line expressing LCMV glycoprotein (LCMV-GP). Similarly, neutralizing antibody responses to vesicular stomatitis virus (VSV) were not affected. In contrast, secondary expansion of LCMV-specific memory CTLs was reduced in vitro and in vivo, resulting in impaired protection against reinfection. In addition, imatinib treatment delayed the onset of diabetes in a CTL-induced diabetes model. In summary, imatinib treatment in vivo selectively inhibits the expansion of antigen-experienced memory CTLs without affecting primary T- or B-cell responses. Therefore, imatinib may be efficacious in the suppression of CTL-mediated immunopathology in autoimmune diseases without the risk of acquiring viral infections.


Assuntos
Memória Imunológica/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Viroses/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Benzamidas , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Mesilato de Imatinib , Imunidade/efeitos dos fármacos , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico
5.
Eur J Immunol ; 35(11): 3229-39, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16231287

RESUMO

Different viruses elicit distinct phenotypes of memory cytotoxic T lymphocytes (CTL). This is reflected in differential expression of homing receptors and costimulatory molecules like CD27. Memory CTL retained CD27 following lymphocytic choriomeningitis virus (LCMV) infection, but not after immunization with recombinant vaccinia virus or tumor cells expressing LCMV glycoprotein. Stable CD27 expression on memory CTL required ligation by CD70 expressed on polyclonally activated B cells during the contraction phase. The functional consequence of CD27 expressed on virus-specific CTL was analyzed in CD27-deficient mice. LCMV infection of CD27(-/-) mice revealed that primary CTL activation and expansion as well as elimination of the virus were independent of CD27 expression. In contrast, ligation of CD27 on memory CTL upon secondary antigen encounter increased clonal expansion and improved protection against re-infection. This points to novel B cell-CTL interactions during viral infection and to a beneficial role of polyclonal B cell activation that represents a characteristic of murine LCMV, human immunodeficiency virus and human hepatitis B and C virus infection.


Assuntos
Subpopulações de Linfócitos B/imunologia , Memória Imunológica , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/imunologia , Subpopulações de Linfócitos B/metabolismo , Ligante CD27 , Proliferação de Células , Células Clonais , Humanos , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Fatores de Necrose Tumoral/biossíntese , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/imunologia
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