RESUMO
The designation of Brown-Norway (BN) rats as resistant to experimental allergic encephalomyelitis (EAE) is an oversimplification. Lewis rats are susceptible and BN rats are usually resistant to EAE after inoculation with guinea pig spinal cord or basic protein in Freund's adjuvant. However, EAE can be produced in BN rats by immunizing with rat cord and carbonyl iron, a particulate adjuvant. In the present work, the possibility that susceptibility of BN rats under these conditions is due only to the special qualities of the adjuvant has been eliminated by producing EAE in them without any adjuvant at all, merely by increasing the absorption and processing of the rat cord antigen. The susceptibility of the F1 hybrids is intermediate with respect to guinea pig cord antigen but it was equal to or greater than either parental strain when tested with rat cord antigen. Histologic evidence that BN rats do not absorb or process neural antigen as well as other strains, and the augmentation of EAE by increasing the dose and absorption of the inoculum, suggest that antigen absorption, processing and presentation is a "bottleneck" for development of EAE in BN rats. Absorption and processing of antigen should be considered along with cellular response, inflammatory mediators and epitope dominance when analyzing susceptibility and resistance to EAE.
Assuntos
Antígenos/administração & dosagem , Encefalomielite Autoimune Experimental/imunologia , Ratos Endogâmicos BN/imunologia , Ratos Endogâmicos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/genética , Feminino , Hibridização Genética , Imunização , Ativação Linfocitária , Proteína Básica da Mielina/imunologia , Ratos , Ratos Endogâmicos Lew , Especificidade da Espécie , Medula Espinal/imunologiaRESUMO
FK506 is the most potent immunosuppressive agent known. Its toxicity is substantial in dogs, minor in rats, and unknown in subhuman primates. In small doses that are nontoxic even in dogs, it can be used in synergistic combination with cyclosporine, steroids, and presumably in other drugs.
Assuntos
Rejeição de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Animais , Ciclosporinas/administração & dosagem , Cães , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Transplante de Coração , Imunossupressores/toxicidade , Nefropatias/induzido quimicamente , Transplante de Rim , Transplante de Fígado , Prednisona/administração & dosagem , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/toxicidade , Ratos , Ratos Endogâmicos ACI/imunologia , Ratos Endogâmicos BN/imunologia , Ratos Endogâmicos Lew/imunologia , Tacrolimo , Transplante Heterólogo , Transplante HomólogoRESUMO
The ability of a new cyclosporine (Cs) derivative, (Nva2)-Cs (CsG), to suppress rejection of lung and heart allografts in rats was determined and compared with that of CsA. Left lungs were transplanted orthotopically; hearts were transplanted heterotopically into the abdomen. (Nva2)-Cs was used in three experimental protocols: (1) single or three (Nva2)-Cs injections given to lung-transplanted rats, (2) daily oral (Nva2)-Cs treatment at different doses compared with similar CsA treatments in heart allografted rats, and (3) An 11-day (Nva2)-Cs treatment starting at increasing intervals after transplantation of hearts. (Nva2)-Cs was found to be immunosuppressive, and effective even when the treatment started as late as four days after transplantation. However, (Nva2)-Cs was less effective than CsA in suppressing rejection of lung and heart allografts at low doses. Because (Nva2)-Cs is possibly not nephrotoxic, it might be a useful drug if used in higher doses than CsA or in combination with other immunosuppressive agents.
Assuntos
Ciclosporina , Ciclosporinas/uso terapêutico , Rejeição de Enxerto/efeitos dos fármacos , Transplante de Coração , Transplante de Coração-Pulmão , Transplante de Pulmão , Animais , Ciclosporinas/sangue , Avaliação Pré-Clínica de Medicamentos , Masculino , Ratos , Ratos Endogâmicos ACI/imunologia , Ratos Endogâmicos BN/imunologia , Ratos Endogâmicos Lew/imunologiaRESUMO
Brown Norway (BN) rats are much less susceptible to experimental allergic encephalomyelitis (EAE) than Lewis rats. Nevertheless, BN rats developed severe EAE, even paralysis, when immunized with rat spinal cord and carbonyl iron adjuvant. Complete Freund's adjuvant (CFA) was much less effective. The use of both CFA and pertussis vaccine with rat cord was moderately, but not consistently, effective. Guinea pig spinal cord was weakly encephalitogenic to BN rats with all adjuvant combinations. We were not able to produce EAE in BN rats with purified myelin basic protein from either rat or guinea pig. Inoculations directly into lymph nodes or into the blood stream proved that the low susceptibility of BN rats was not due to lack of absorption from the site of inoculation, but may be related to peculiarities of processing antigen in draining lymph nodes. The severity of EAE in F1 hybrids was intermediate between the BN and Lewis parental strains when tested with an immunizing procedure of appropriate strength. The fact that F1 hybrids were less reactive than Lewis mandates modification of the theory that susceptibility to EAE is inherited through a single autosomal dominant gene.