RESUMO
BACKGROUND: Nasal instillation is an effective method for inducing antigen-specific immune tolerance. However, it is not clear how a tolerization scheme established in one mouse strain will perform when used in a mouse of a different haplotype. OBJECTIVES: To compare the antigen-specific recall responses in four mouse strains--BALB/c, C57BL/6, NOD, and B10.PL--that were pretreated nasally with 50 micrograms of hen egg-white lysozyme prior to parenteral immunization with homologous antigen. METHODS: Mice were nasally treated with a prototype antigen, HEL, and then immunized with the same antigen emulsified in complete Freund's adjuvant. Spleens and lymph nodes were assayed for T cell proliferation measured by tritiated thymidine incorporation. Cytokine production was measured using ELISPOT assay. Serum antibody response to HEL was measured using an enzyme-linked immunosorbent assay. RESULTS: Proliferative recall responses to HEL in B10.PL, C57BL/6, and BALB/c were greatly reduced compared to control mice, but non-obese diabetic mice were resistant to the tolerization regime. Despite their susceptibility to nasally induced suppression, the mechanisms responsible for tolerance induction differed in BALB/c and C57BL/6 mice. CONCLUSIONS: Our findings demonstrate that while mucosal contacts with specific antigen consistently affect the outcome of subsequent exposure to the same antigen, the observed response will vary non-predictably, depending on the genetic background of the animal.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Modelos Animais de Doenças , Tolerância Imunológica/imunologia , Imunização/métodos , Camundongos Endogâmicos BALB C/imunologia , Camundongos Endogâmicos C57BL/imunologia , Camundongos Endogâmicos NOD/imunologia , Muramidase/imunologia , Muramidase/uso terapêutico , Animais , Doenças Autoimunes/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Epitopos/genética , Epitopos/imunologia , Haplótipos/genética , Haplótipos/imunologia , Tolerância Imunológica/genética , Imunidade nas Mucosas/imunologia , Instilação de Medicamentos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C/genética , Camundongos Endogâmicos C57BL/genética , Camundongos Endogâmicos NOD/genética , Mucosa Nasal , Linfócitos T/imunologiaRESUMO
Nasal installation or oral feeding of antigens can alter the subsequent immune response in animals and humans. Most mucosal treatments with antigens tend to down-regulate disease, inducing full tolerance or immune deviation; however, priming has also been reported. We evaluated the course of experimental autoimmune encephalomyelitis (EAE) in (SJL x B10.PL)F1 mice after nasal instillation of myelin basic protein. There was a tendency towards exacerbation of subsequent disease in animals if they were nasally exposed to gpMBP during the neonatal period (first week of life), compared to exposure during adulthood. Later, at 11 months of age, this tendency to exacerbate disappeared. Our results suggest that mucosal exposure during early life may regularly modulate the anti-self immune response upwards in individuals genetically predisposed to autoimmune diseases.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Imunidade nas Mucosas , Proteína Básica da Mielina/imunologia , Administração Intranasal , Fatores Etários , Animais , Animais Recém-Nascidos , Regulação para Baixo , Cobaias , Humanos , Imunização Secundária , Camundongos , Proteína Básica da Mielina/administração & dosagem , Prevenção Secundária , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Recent studies have suggested the IL-4Ralpha expressed on lung epithelium is necessary for TH2-mediated goblet cell differentiation and mucus hypersecretion in a murine model of allergic lung disease. However, the IL-4Ralpha is expressed on numerous cell types that could contribute to the overall pathology and severity of asthma. The relative role of the receptor on these cells has not yet been conclusively delineated. To dissect the contribution of IL-4Ralpha in the development of pulmonary allergic responses, we generated murine radiation bone marrow (BM) chimeras. BM from IL-4Ralpha(+) or IL-4Ralpha(-) mice was transferred into recipient mice that expressed or lacked IL-4Ralpha. In the absence of IL-4Ralpha in recipient mice, there was no goblet cell metaplasia or mucus hypersecretion in response to OVA, even in the presence of TH2 cells and substantial eosinophilic infiltration. More importantly, we found that expression of the IL-4Ralpha on a nonlymphoid, MHC class II(+), BM-derived cell type contributes to the severity of inflammation and mucus production. These results suggest that IL-4 and IL-13 contribute to the development of allergic inflammation by stimulating a complex interaction between IL-4Ralpha(+) cell types of both bone marrow and non-bone marrow origin.
Assuntos
Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Pulmão/imunologia , Pulmão/patologia , Subunidades Proteicas/fisiologia , Receptores de Interleucina-4/fisiologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Animais , Transplante de Medula Óssea/imunologia , Transplante de Medula Óssea/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Eosinofilia/imunologia , Eosinofilia/patologia , Células Caliciformes/imunologia , Células Caliciformes/patologia , Hiperplasia , Pulmão/metabolismo , Metaplasia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Muco/metabolismo , Subunidades Proteicas/biossíntese , Quimera por Radiação/imunologia , Receptores de Interleucina-4/biossíntese , Índice de Gravidade de Doença , Células Th2/imunologia , Células Th2/transplanteRESUMO
Based on the tolerogenic properties of IgG carriers and B cell Ag presentation, we developed a retrovirally mediated gene expression approach for treatment of autoimmune conditions. In this study, we show that the IgG-Ag retroviral constructs, expressing myelin basic protein (MBP) or glutamic acid decarboxylase in B cells, can be used for the treatment of murine models for multiple sclerosis and diabetes. Transduction of syngeneic B cells with MBP-IgG leads to the amelioration of ongoing experimental allergic encephalomyelitis induced by the transfer of primed cells from PLxSJL F(1) mice with ongoing disease and could be effective even after symptoms appeared. This effect is specific and does not involve bystander suppression because treatment with MBP-IgG does not affect disease induced after immunization with proteolipid protein immunodominant peptide plus MBP. Interestingly, if donor B cells are derived from gld mice (Fas ligand-negative), then tolerance is not induced with a model Ag although there was no evidence for Fas ligand-mediated deletion of target T cells. In spontaneous diabetes in nonobese diabetic mice, we were able to stop the ongoing autoimmune process by treatment at 7-10 wk with glutamic acid decarboxylase-IgG retrovirally transduced B cells, or attenuate it with B cells transduced with an insulin B chain (B9-23) epitope IgG fusion protein. Furthermore, IgG fusion protein gene therapy can also protect primed recipients from Ag-induced anaphylactic shock, and thus does not cause immune deviation. These results demonstrate proof of principle for future efforts to develop this approach in a clinical setting.