RESUMO
Therapeutic efficacy of P277 against type 1 diabetes was extensively investigated and clinically evidenced. Clinical trials Phases I and II concluded promising results, while the data of P277 immunogenicity in Phase III trials represented weak responses that led to abolish medical use. But, a therapeutic performance of P277 cannot be forgotten. So, in order to exploit its therapeutic benefits and improve its immunogenicity, we developed a new analogue VP to optimize therapeutic efficacy and enhancing immunosuppressive modulations. However, new analogue was purified, and then used to immunize diabetic NOD mice to investigate antidiabetic effects through modulation of immunological status. So, DCs immune responses, relative TLRs, MyD88, and NF-Kß1 mRNA expression on DCs and splenocytes under VP effect were tested. Circulating and intracellular cytokines were also evaluated at treated and non-treated mice. Splenic T lymphocytes proliferation (Th1 and Treg cells) were also determined. Results revealed that VP significantly down regulates DCs maturation through TLR2, TLR4, and MyD88 pathways. It also shifts DCs to a tolerogenic polarization through NF-Kß1 pathway that mediates Th1 immunosuppression and enhances iTreg expanding in type1diabetes mice. Meanwhile, we noticed that VP significantly enhances iTreg CD25 + FoxP3+ proliferation. In conclusion, VP showed promising immune potential to modulate immune regulatory responses and shifts DCs to suppress autoreactive Th1 cells which ameliorated immunosuppressive potency in the type1 diabetic mice.
Assuntos
Autoimunidade/efeitos dos fármacos , Chaperonina 60/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Tolerância Imunológica/efeitos dos fármacos , Imunossupressores/farmacologia , Fragmentos de Peptídeos/farmacologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Comunicação Celular/imunologia , Chaperonina 60/genética , Chaperonina 60/imunologia , Chaperonina 60/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito B/genética , Feminino , Humanos , Imunossupressores/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Mutagênese , Subunidade p50 de NF-kappa B/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismoRESUMO
Objective: To understand the effect of dobutamine on the integrated backscatter of myocardium. Methods: Nineteen open-chest dogs were detected by HP Sonos 5500 with S8 transducer, and the WT, AIBS and CVIB were measured before and after the dobutamine stress. Results: During the dobutamine stress, following the increase of WT, the transmural, subepicardial and subendocardial CVIB all increased. And the increase of subepicardial CVIB was greater than that of subendocardial CVIB, leading to the decrease of TGI. But the AIBS didn't change significantly in the whole process. Conclusion: Dobutamine can enhance myocardium CVIB but has no obvious infleunce on AIBS.
RESUMO
Objective: To understand the effect of dobutamine on the integrated backscatter of myocardium. Methods: Nineteen open chest dogs were detected by HP Sonos 5500 with S8 transducer, and the WT, AIBS and CVIB were measured before and after the dobutamine stress. Results: During the dobutamine stress, following the increase of WT, the transmural, subepicardial and subendocardial CVIB all increased. And the increase of subepicardial CVIB was greater than that of subendocardial CVIB, leading to the decrease of TGI. But the AIBS didn't change significantly in the whole process. Conclusion: Dobutamine can enhance myocardium CVIB but has no obvious infleunce on AIBS. [
