Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Recuperação de Função Fisiológica/imunologia , Adolescente , Adulto , Idoso , Aloenxertos , Biomarcadores/sangue , Citomegalovirus/imunologia , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/imunologia , Feminino , Antígenos HLA , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Accumulating experimental and clinical evidence has been obtained over recent years in support of the notion that the immune system has the potential to cure cancer. The most convincing example is the graft versus leukaemia effect observed after allogeneic haematopoietic stem cell transplantation. In the autologous setting, however, the isolation and expansion of naturally occurring tumour-specific T cells is a challenging task. Cancer antigens are often self-antigens and cancer-specific T cells are thus subject to selective mechanisms of central and peripheral tolerance. The significant advances in gene-transfer technologies developed over the last decade have offered new tools to overcome these limitations. Natural T cells can be genetically modified to generate high numbers of 'supernatural' tumour-reactive T cells from virtually every cancer patient. Supernatural T cells may express clonal receptors providing new specificities, factors increasing T-cell performance or safety factors enabling their elimination in case of toxicity. Technological improvements applied to novel concepts of T-cell biology and oncogenesis will allow to simultaneously equip T cells with different transgenes and expand a real 'army' of lymphocytes trained to selectively eradicate cancer cells.
Assuntos
Antígenos de Neoplasias , Engenharia Genética , Efeito Enxerto vs Leucemia/genética , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Linfócitos T , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Linfócitos T/metabolismo , Linfócitos T/transplante , Transplante HomólogoAssuntos
Genes Virais , Marcadores Genéticos , Vetores Genéticos/efeitos adversos , Receptor de Fator de Crescimento Neural/análise , Retroviridae/genética , Animais , Transplante de Medula Óssea , Cães , Humanos , Leucemia/etiologia , Leucemia/prevenção & controle , Camundongos , Ratos , Transdução GenéticaRESUMO
Individuals with a negative intradermal reaction to tuberculin PPD have long been described in the Mycobacterium tuberculosis exposed, immune-competent population. Here, we studied PPD-specific blood T lymphocytes from these subjects for phenotypic markers relevant to skin migration, including the expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen (CLA). Out of 82 patients with active tuberculosis we identified four subjects who were repeatedly PPD skin test-negative. CD4 T lymphocytes specific to mycobacterial antigens were derived from these individuals, which (i) proliferated in vitro to M. tuberculosis antigens comparably to those from PPD+ patients; (ii) secreted comparable amounts of IL-2 but lower amounts of IFN-gamma; (iii) were confined within the CLA-negative T cell subset. We conclude that the negative tuberculin reaction in a small subset of patients exposed to mycobacteria is associated with impaired production of IFN-gamma by circulating PPD-specific T cells that are lacking CLA expression. On this basis in vitro proliferation to PPD can discriminate bona fide non-responders from infected patients with a deficit in the margination of M. tuberculosis-specific T lymphocytes.
Assuntos
Interferon gama/biossíntese , Glicoproteínas de Membrana/deficiência , Mycobacterium tuberculosis/imunologia , Receptores de Retorno de Linfócitos/deficiência , Linfócitos T/imunologia , Tuberculose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Diferenciação de Linfócitos T , Antígenos de Neoplasias , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Feminino , Humanos , Técnicas In Vitro , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Teste Tuberculínico , Tuberculose/diagnósticoRESUMO
In this work, an ELISA for the quantitative determination of IgG anti-CD4 autoantibodies was validated and utilized in the follow-up of two cohorts of HIV-1-exposed seronegative subjects. A serum with an arbitrarily assigned concentration of 100,000 units/ml was used as a reference, and the detection limit, inter- and intraassay variability, and analytical recovery were calculated. The study subjects included adults sexually exposed to HIV-1-infected partners and the newborns of HIV-1+ mothers who seroreverted by 18 months of age. Some of these individuals were studied over an 18- to 24-month period. The detection limit of the assay was 2000 AU/ml. Intra- and interassay variability was, respectively, 3.92 and 3.90%. Analytical recovery in an assay in which a fixed amount of anti-CD4 antibodies was added to different samples was 98%. A proportion of adults (16 of 47, 34.0%) and babies (12 of 27, 44.4%) had significantly higher concentrations of anti-CD4 antibodies. Among them, 8 adults maintained the same concentration as that found in the first determination; on the other hand, 12 babies born to seronegative mothers showed a significant increase in the concentration of anti-CD4 antibodies during their first months of life. In conclusion, anti-CD4 antibodies can be measured using a validated ELISA. They represent a serologic trait that is quantitatively conserved in HIV-1-exposed seronegative adult individuals and is actively acquired by newborns to HIV+ mothers.
Assuntos
Autoanticorpos/sangue , Antígenos CD4/imunologia , Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects. OBJECTIVE: We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86). METHODS: Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents. RESULTS: Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% +/- 14.8% vs 1.4% +/- 1.2%; P <.001), whereas no difference was observed in CD86 expression (2.0% +/- 2.3% vs 1.1% +/- 0.6; P >.1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner. CONCLUSION: Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects.
Assuntos
Células Apresentadoras de Antígenos/fisiologia , Asma/metabolismo , Antígeno B7-1/biossíntese , Macrófagos Alveolares/metabolismo , Células Th2/imunologia , Adolescente , Adulto , Antígenos CD/biossíntese , Antígeno B7-1/fisiologia , Antígeno B7-2 , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/biossíntese , Feminino , Humanos , Interleucina-4/biossíntese , Interleucina-5/biossíntese , Masculino , Glicoproteínas de Membrana/biossíntese , Testes de Função RespiratóriaRESUMO
Anti-CD4 antibodies have been documented in about 10-20% of HIV-infected patients. This autoimmune response could be triggered by increased CD4 processing and unveiling of hidden (cryptic) epitopes. Multiple markers of exposure to HIV have been described in exposed uninfected individuals. Here, we investigated the mechanisms underlying the generation of anti-CD4 antibodies in a cohort of 54 seronegative exposed uninfected individuals. We identified anti-CD4 antibodies above normal levels in 16 of 47 (34%) exposed uninfected subjects. The fine specificity of these antibodies was different in this cohort when compared with those found in HIV+ patients. This suggested the possibility of different mechanisms underlying the generation of anti-CD4 antibodies in these two groups. Indeed, in exposed uninfected subjects, we found circulating CD4 T cells specific for gp120, but not for CD4. In contrast, HIV-1-seropositive patients had peripheral blood T cells specific for both molecules. Noncovalent binding of gp120 to soluble CD4 enhanced activation of gp120-specific T lymphocytes in exposed uninfected subjects, but not in HIV+ subjects. Moreover, gp120-specific T cells isolated from exposed uninfected, but not from HIV+, subjects provided help for anti-CD4 antibody production by B cells pulsed with CD4-gp120 complex. We conclude that gp120-specific T cells are present in exposed uninfected individuals, and can provide intermolecular help for anti-CD4 antibody production. This mechanism is distinct from that found in HIV-1-seropositive patients and may play a protective role against HIV-1 infection in vivo.