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1.
J Immunol ; 167(7): 3565-9, 2001 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-11564767

RESUMO

Monocyte-derived dendritic cells (DC) were found to be cytotoxic for several tumor cell lines including Jurkat cells, which were killed through a calcium-independent pathway. K562 cells were resistant, excluding a NK cell-like activity. DC-mediated apoptosis did not involve classical death receptors because it was not reversed by blocking TNF/TNFR, CD95/CD95 ligand, or TNF-related apoptosis-inducing ligand/TNF-related apoptosis-inducing ligand receptor interactions. Fas-associated death domain-deficient, but not caspase-8 deficient, Jurkat cells were killed by DC. Indeed, caspase-8 cleavage was demonstrated in Jurkat cells cocultured with DC, and the use of specific caspase inhibitors confirmed that apoptosis triggered by DC was caspase-8 dependent. Furthermore, the involvement of Bcl-2 family members in the control of DC-mediated apoptosis was demonstrated by Bid cleavage in Jurkat cells cocultured with DC and resistance of Jurkat cells overexpressing Bcl-2 to DC-mediated cytotoxicity. Overall, these data indicate that monocyte-derived DC exert a caspase-8-dependent, Fas associated death domain-independent tumoricidal activity, a finding that could be relevant to their therapeutic use in cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/fisiologia , Caspases/fisiologia , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Monócitos/imunologia , Neoplasias/imunologia , Apoptose , Proteínas Reguladoras de Apoptose , Caspase 8 , Caspase 9 , Células Cultivadas , Proteína Ligante Fas , Proteína de Domínio de Morte Associada a Fas , Humanos , Células Jurkat , Glicoproteínas de Membrana/fisiologia , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/fisiologia
2.
J Soc Biol ; 195(1): 19-23, 2001.
Artigo em Francês | MEDLINE | ID: mdl-11530495

RESUMO

In cancer immunotherapy, the use of dendritic cells (DC) loaded with tumor-associated antigens (TAA) emerged as a promising strategy. We initiated 3 pilot clinical trials with immunological endpoints using TAA loaded autologous DC. These trials showed that this approach was safe and associated with the induction of potent TAA specific IFN-gamma responses, which were transient despite the providing a further help through KLH presentation. Subcutaneous (s.c.) IL-2 administration was associated with long-lasting TAA specific IL-5 production. Clinical responses were observed in about 1/3 of the patients. Further improvements will take advantage of the use of a new type of DC cells (IL-3/IFN-beta DC) and of tumor cell-DC hybrids.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/transplante , Imunoterapia Adotiva , Neoplasias/terapia , Apresentação de Antígeno , Ensaios Clínicos como Assunto , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hemocianinas/imunologia , Humanos , Células Híbridas , Injeções Subcutâneas , Interferon beta/farmacologia , Interferon gama/biossíntese , Interleucina-2/administração & dosagem , Interleucina-2/farmacologia , Interleucina-2/uso terapêutico , Interleucina-3/farmacologia , Interleucina-4/farmacologia , Interleucina-5/biossíntese , Interleucina-5/genética , Antígenos Específicos de Melanoma , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Projetos Piloto , Resultado do Tratamento , Vacinação
3.
Blood ; 95(11): 3478-82, 2000 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-10828032

RESUMO

To gain insight into the mechanisms controlling apoptosis of dendritic cells (DC), human monocyte-derived DC were analyzed for their expression of CD95 (Fas/Apo-1) and their response to CD95 ligation. Although DC expressed the CD95 molecule on their membrane, they did not undergo apoptosis on CD95 ligation unless sensitized by cycloheximide. In parallel, DC synthesized c-FLIP(L), an inhibitor of the CD95-mediated death-signaling cascade. We also demonstrated that bisindolylmaleimide down-regulates c-FLIP(L) expression in DC and, in parallel, allows CD95-mediated apoptosis in these cells. In contrast, Bcl-2, Bcl-x(L), and Bax levels were not affected by bisindolylmaleimide. We conclude that DC resist CD95- mediated apoptosis in association with c-FLIP(L) expression and that the immunosuppressive potential of bisindolylmaleimide previously observed at the T-cell level also involves facilitation of CD95-mediated DC apoptosis.


Assuntos
Proteínas de Transporte/biossíntese , Células Dendríticas/citologia , Células Dendríticas/fisiologia , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Maleimidas/farmacologia , Monócitos/citologia , Receptor fas/fisiologia , Antígenos CD/fisiologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Células Cultivadas , Cicloeximida/farmacologia , Células Dendríticas/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteína X Associada a bcl-2 , Proteína bcl-X
4.
Infect Immun ; 67(8): 4033-40, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10417171

RESUMO

Trypanosoma cruzi, a parasitic protozoan, is the etiological agent of Chagas' disease. Despite the many immune system disorders recognized in this infection and the crucial role played by dendritic cells (DC) in acquired immune responses, it was not known whether these cells could be infected by T. cruzi trypomastigotes and the consequences of such an infection on their immune functions. We now provide evidence that human monocyte-derived DC can be infected by T. cruzi and can support its intracellular multiplication. Interestingly, this infection has functional consequences on immature DC and on their maturation induced by lipopolysaccharide (LPS). First, after T. cruzi infection, the basal synthesis of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) was impaired. Furthermore, the process of maturation of DC induced by LPS was drastically affected by T. cruzi infection. Indeed, secretion of cytokines such as IL-12, TNF-alpha, and IL-6, which are released normally at high levels by LPS-activated DC, as well as the up-regulation of HLA-DR and CD40 molecules, was significantly reduced after this infection. The same effects could be induced by T. cruzi-conditioned medium, indicating that at least these inhibitory effects were mediated by soluble factors released by T. cruzi. Taken together, these results provide new insights into a novel efficient mechanism, directly involving the alteration of DC function, which might be used by T. cruzi to escape the host immune responses in Chagas' disease and thus might favor persistent infection.


Assuntos
Citocinas/biossíntese , Células Dendríticas/parasitologia , Antígenos HLA-DR/análise , Trypanosoma cruzi/fisiologia , Animais , Antígenos CD40/análise , Células Dendríticas/fisiologia , Humanos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos F344
5.
Transplantation ; 67(10): 1342-7, 1999 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-10360588

RESUMO

BACKGROUND: The aim of this study was to better define how glucocorticoids influence primary human T cell responses. Dendritic cells (DC*) are the most effective antigen presenting cells able to activate naive T cells. Previous studies have shown that dexamethasone impaired the function of murine DC. Here, we analyzed how methylprednisolone (MP) might affect the function and maturation of human DC. METHODS: Human DC were generated from peripheral blood mononuclear cells cultured in granulocyte macrophage-colony stimulating factor and interleukin (IL)4. DC maturation was induced either by lipopolysaccharide (LPS) or by fibroblast transfected with the CD40-ligand gene (3T6-CD40L). DC phenotype was characterized by flow cytometric analysis, their cytokine production by ELISA. The ability of DC to activate naive T cells was evaluated in mixed leukocyte reactivity. RESULTS: Although MP did not affect viability of DC, it enhanced their antigen uptake and down-regulated their basal expression of CD86. The expression of CD80 and CD54 by DC was slightly decreased and HLA-DR expression was not modified. MP prevented LPS-induced DC maturation as assessed by the inhibition of CD86, CD80 and CD54 up-regulation, CD83 induction and production of TNF-alpha, IL-6, and IL-12. In contrast, when DC were stimulated by 3T6-CD40L, MP prevented only the synthesis of IL-12. Moreover, MP-treated DC were deficient in their ability to elicit proliferative responses of CD4+CD45RA+ allogeneic T cells as well as their synthesis of interferon (IFN)-gamma, IL-5, and IL-13. CONCLUSION. Glucocorticoids exert potent suppressive effects on human DC and thereby inhibit the induction of primary T cell responses.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Metilprednisolona/farmacologia , Antígenos/metabolismo , Antígenos CD/biossíntese , Antígenos de Superfície/biossíntese , Antígeno B7-1/biossíntese , Antígeno B7-2 , Sobrevivência Celular/efeitos dos fármacos , Células Dendríticas/citologia , Endocitose/imunologia , Antígenos HLA-DR/biossíntese , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Interleucina-12/metabolismo , Isoanticorpos/imunologia , Glicoproteínas de Membrana/biossíntese , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo
6.
J Immunol ; 162(5): 2569-74, 1999 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10072497

RESUMO

N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.


Assuntos
Acetilcisteína/farmacologia , Células Dendríticas/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Ligante de CD40 , Células Cultivadas , Citocinas/biossíntese , Células Dendríticas/fisiologia , Glutationa/análise , Antígenos HLA-DR/análise , Humanos , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/farmacologia , Linfócitos T/fisiologia
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