RESUMO
Lipopolysaccharide (LPS) is a well-defined agonist of Toll-like receptor (TLR) 4 that activates innate immune responses and influences the development of the adaptive response during infection with Gram-negative bacteria. Many years ago, Dr. Edgar Ribi separated the adjuvant activity of LPS from its toxic effects, an effort that led to the development of monophosphoryl lipid A (MPL). MPL, derived from Salmonella minnesota R595, has progressed through clinical development and is now used in various product-enabling formulations to support the generation of antigen-specific responses in several commercial and preclinical vaccines. We have generated several synthetic lipid A molecules, foremost glucopyranosyl lipid adjuvant (GLA) and second-generation lipid adjuvant (SLA), and have advanced these to clinical trial for various indications. In this review we summarize the potential and current positioning of TLR4-based adjuvant formulations in approved and emerging vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , Glucosídeos/farmacologia , Imunogenicidade da Vacina , Lipídeo A/análogos & derivados , Tuberculose/prevenção & controle , Adjuvantes Imunológicos/química , Compostos de Alúmen/química , Animais , Glucosídeos/química , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Leishmaniose/imunologia , Leishmaniose/parasitologia , Leishmaniose/prevenção & controle , Hanseníase/imunologia , Hanseníase/parasitologia , Hanseníase/prevenção & controle , Lipídeo A/química , Lipídeo A/farmacologia , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/imunologia , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/prevenção & controle , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/microbiologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinas/administração & dosagem , Vacinas/química , Vacinas/imunologiaRESUMO
A comparison was made on the in situ immunological characteristics of dermal infiltrates of early (24-hour) and late (3-4 weeks) skin reactions in leprosy patients. The skin reactions were induced by armadillo-derived leprosin coupled to liposomes and standard Dharmendra lepromin. Most lymphocytes in the early reaction induced by both antigens were positive for Leu 4, Leu 3a, OKT8 and Ia like antigens indicating thereby the presence of activated T cells. The ratio of Leu 3a/OKT8+ cells were similar. In the late reaction elicited by both antigens, the lymphocytes in the granulomas were predominantly activated T lymphocytes expressing Leu 4, Leu 3a, OKT8 and Ia like antigens. Leu 3a+ cells were scattered diffusely amidst the epithelioid cells. In contrast, the OKT8+ cells were present mainly as 'a ring' in the periphery of the granuloma. A similar ratio of Leu 3a+/OKT8+ cells was observed in these granulomas. Macrophages in the granulomas expressed Ia like antigens. These observations indicate that the immunological characteristics of dermal infiltrates in the skin reaction induced by armadillo-derived leprosin coupled to liposomes and standard Dharmendra lepromin appear to be identical.