RESUMEN
Animals that have recovered from adoptively transferred EAE develop clinical disease signs 2-3days earlier than controls when challenged with encephalitogen. This may be due to the reactivation of donor-derived memory cells or stimulation of recipient-derived memory cells primed during the adoptive disease episode. In order to determine the origin of the memory cell subset, we used a donor-recipient model where donor cells are rejected in recipients following a course of adoptively transferred disease. Our results suggest the early onset of disease seen in recipients recovered from adoptively transferred disease and challenged with encephalitogen is due to the sustained presence of donor-derived memory cells.
Asunto(s)
Traslado Adoptivo/métodos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Memoria Inmunológica/fisiología , Proteína Básica de Mielina/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Adyuvante de Freund/toxicidad , Masculino , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Caracteres Sexuales , Bazo/metabolismo , Bazo/patología , Factores de TiempoRESUMEN
We have used a peptide derived from Acanthamoeba castellanii (ACA) to treat the relapsing phase of EAE that develops in SJL mice following immunization with the PLP 139-151 peptide. The native sequence of the ACA 81-95 peptide that shares key residues with the PLP 139-151 peptide is weakly encephalitogenic in SJL mice but is not recognized by antiserum from SJL mice immunized with PLP 139-151. A single amino acid change to the ACA 81-95 peptide sequence significantly enhanced its encephalitogenicity. When administered to SJL mice as a nonlinear peptide octamer, the modified ACA peptide prevented relapsing episodes of EAE in SJL mice previously immunized with the PLP 139-151 encephalitogenic peptide.
Asunto(s)
Anafilaxia/inmunología , Anafilaxia/prevención & control , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Proteína Proteolipídica de la Mielina/inmunología , Proteína Proteolipídica de la Mielina/farmacología , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Acanthamoeba castellanii/genética , Acanthamoeba castellanii/inmunología , Secuencia de Aminoácidos , Animales , Especificidad de Anticuerpos/inmunología , Modelos Animales de Enfermedad , Femenino , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Imitación Molecular/inmunología , Datos de Secuencia Molecular , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Proteína Proteolipídica de la Mielina/genética , Fragmentos de Péptidos/genética , Linfocitos T/inmunologíaRESUMEN
Leishmania major and all other parasitic protozoa are unable to synthesize purines de novo and are therefore reliant upon uptake of preformed purines from their hosts via nucleobase and nucleoside transporters. L. major expresses two nucleobase permeases, NT3 that is a high affinity transporter for purine nucleobases and NT4 that is a low affinity transporter for adenine. nt3((-/-)) null mutant promastigotes were unable to replicate in medium containing 10 microM hypoxanthine, guanine, or xanthine and replicated slowly in 10 microM adenine due to residual low affinity uptake of that purine. The NT3 transporter mediated the uptake of the anti-leishmanial drug allopurinol, and the nt3((-/-)) mutants were resistant to killing by this drug. Expression of the NT3 permease was profoundly downregulated at the protein but not the mRNA level in stationary phase compared with logarithmic phase promastigotes. The nt4((-/-)) null mutant was quantitatively impaired in survival within murine bone marrow-derived macrophages. Extensive efforts to generate an nt3((-/-))/nt4((-/-)) dual null mutant were not successful, suggesting that one of the two nucleobase permeases must be retained for robust growth of the parasite. The phenotypes of these null mutants underscore the importance of purine nucleobase transporters in the Leishmania life cycle and pharmacology.
Asunto(s)
Leishmania major/genética , Proteínas de Transporte de Nucleobases/genética , Proteínas de Transporte de Nucleobases/metabolismo , Animales , Transporte Biológico/genética , Genes Protozoarios , Proteínas Fluorescentes Verdes/metabolismo , Leishmania major/metabolismo , Mutación , Purinas/metabolismoRESUMEN
In this study we evaluated the efficacy of DNA vaccination of IFN-gamma knockout (GKO) mice against Listeria monocytogenes, as these immunodeficient mice are highly susceptible to infection with low numbers of this intracellular bacterial pathogen. Following intramuscular immunization of BALB/c GKO mice with plasmid DNA constructs encoding recombinant forms of the L. monocytogenes hemolysin, listeriolysin O (LLO), we detected the in vivo induction of a LLO(91-99) peptide-specific, protective immune CTL response equivalent to that observed following similar DNA vaccination of normal BALB/c mice. The observed protection represented greatly enhanced immunity for the GKO host, suggesting that DNA vaccination may provide a useful vaccine alternative for certain immunocompromised host populations.