RESUMO
Accumulation of amyloid-ß peptide (Aß) is considered the triggering factor of pathogenic lesions in Alzheimer's disease (AD), and vaccines targeting Aß are promising therapeutic options. However, the occurrence of meningoencephalitides attributed to T cell responses in 6% of Aß-immunized patients underscores the need for a better understanding of T cell responses to Aß. We characterized the parameters controlling the magnitude of Aß-specific CD4(+) T cell responses in mice. T cell responsiveness to Aß1-42 was highly heterogeneous between mouse strains of different H-2 haplotypes, with SJL/J (H-2(s)) mice displaying a strong response, mainly specific for Aß10-24, and C57BL/6 (H-2(b)) mice displaying a weak response to Aß16-30. Surprisingly, C57BL/6 mice congenic for the H-2(s) haplotype (B6.H-2(S)), which display a "permissive" MHC class II allele for presentation of the immunodominant Aß10-24 epitope, showed a very weak CD4(+) T cell response to Aß, suggesting that MHC-independent genes downmodulate Aß-specific CD4(+) T cell responses in C57BL/6 background. Vaccine-induced CD4(+) T cell responses to Aß were significantly enhanced in both C57BL/6 and B6.H-2(S) mice upon depletion of regulatory T cells (Tregs), whereas Treg-depleted SJL/J mice displayed unaltered Aß-specific T cell responses. Finally, Treg depletion in C57BL/6 transgenic APPPS1 mice, a mouse model of AD, results in enhanced vaccine-induced CD4(+) T cell responses in AD compared with wild-type animals. We concluded that the magnitude of Aß-specific CD4(+) T cell responses is critically controlled in both physiological and pathological settings by MHC-independent genetic factors that determine the overall potency of Aß-specific Treg responses.
Assuntos
Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/antagonistas & inibidores , Linfócitos T CD4-Positivos/imunologia , Antígenos H-2/genética , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Peptídeos beta-Amiloides/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/patologia , Relação Dose-Resposta Imunológica , Epitopos de Linfócito T/imunologia , Antígenos H-2/imunologia , Antígenos de Histocompatibilidade Classe II/administração & dosagem , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Dados de Sequência Molecular , Fragmentos de Peptídeos/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/patologiaRESUMO
Prion diseases are caused by the transconformation of the host cellular prion protein PrP(c) into an infectious neurotoxic isoform called PrP(Sc). While vaccine-induced PrP-specific CD4(+) T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8(+) cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrP(c)-specific CTL was evaluated by stimulating a CD8(+) T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2D(b) and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNγ secreting CD8(+) T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8(+) T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3(+) T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNγ-secreting CD8(+) T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8(+) T cells interact with prions into the CNS during the clinical phase of the disease.
Assuntos
Sistema Nervoso Central/patologia , Doenças Priônicas/imunologia , Complexo Receptor-CD3 de Antígeno de Linfócitos T/imunologia , Scrapie/patologia , Linfócitos T/imunologia , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Sobrevivência Celular , Sistema Nervoso Central/imunologia , Radioisótopos de Cromo , Imunofluorescência , Imunização , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Peptídeos/imunologia , Plasmídeos/genética , Proteínas PrPC/genética , Proteínas PrPC/imunologia , Scrapie/imunologiaRESUMO
Prion diseases are associated with the conversion of the normal host cellular prion protein to an abnormal protease-resistant (PrPres) associated with infectivity. No specific immune response against prions develops during infection due to the strong tolerance to cellular prion protein. We examined the protective potential on prion diseases of immune responses elicited in C57BL/6 mice with PrP peptides 98-127 (P5) or 158-187 (P9) with CpG. After immunization, P5-treated mice developed high titer and long-lasting Abs, and P9-treated mice developed transient IFN-gamma secreting T cells and poor and variable Ab responses. Both treatments impaired early accumulation of PrPres in the spleen and prolonged survival of mice infected with 139A scrapie. Additional P9 boosts after 139A infection sustained the T cell response and partially inhibited PrPres early accumulation but did not improve the survival. Surprisingly, when P9 injections were started 1 mo after infection and repeated subsequently, specific T cell and Ab responses were impaired and no beneficial effect on prion disease was observed. After a single injection of P9, the number of IFN-gamma secreting CD4+ T cells was also reduced in mice 8- to 10-wk postinfection compared with healthy mice. In vivo and in vitro removal of CD4+CD25+ T cells restored the T cell response to P9 in infected mice. In conclusion, CD4+ T cells as well as Abs might participate to the protection against scrapie. Of importance, the peripheral accumulation of PrPres during infection negatively interferes with the development of T and B cell responses to PrP and regulatory T cells might contribute to this phenomenon.
Assuntos
Anticorpos/imunologia , Peptídeos/imunologia , Príons/imunologia , Scrapie/imunologia , Scrapie/patologia , Linfócitos T/imunologia , Vacinas contra a AIDS , Animais , Progressão da Doença , Feminino , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Príons/patogenicidade , Scrapie/classificação , Taxa de Sobrevida , Linfócitos T/metabolismoRESUMO
Intravenous immunoglobulins (IVIg) are therapeutic preparations of normal human polyclonal Ig G (IgG) that exert immunomodulatory effects in patients with autoimmune or systemic inflammatory diseases. Two different IgG subfractions were evaluated for their respective immunomodulatory effects in the treatment of experimental autoimmune diseases: a fraction enriched in antibodies that recognize the F(ab')(2) portion of IVIg and a fraction of natural polyreactive autoantibodies purified on a dinitrophenyl (DNP)-Affiprep immunoadsorbent. A very small fraction of IgG interacting with DNP but not with F(ab')(2) fragments expressed an increased ability to bind to self-antigens. The anti-DNP fraction, but not the anti-idiotype fraction, protected against inflammation observed in collagen-induced arthritis and experimental autoimmune encephalomyelitis in rats. Furthermore, it was able to reduce the occurrence of spontaneous diabetes mellitus in nonobese diabetic mice at lower concentrations than unfractionated IVIg. The therapeutic benefit of the anti-DNP fraction was associated with the inhibition of secretion of proinflammatory cytokines and stimulation of secretion of IL-1 receptor antagonist. Our results provide evidence that polyreactive autoantibodies play a role in the protective effect of IVIg in experimental models of autoimmune diseases in which inflammatory reactions are part of the disease process.