评估IFN-γ调控型启动子(CIITA-pIV)驱动的MHC II类分子反式激活因子突变体(MHC class II transactivator mu-tant,CIITAm)重组腺病毒Ad-pIV-CIITAm对小鼠实验性自身免疫性甲状腺炎(experimental autoimmune thyroiditis,EAT)的治疗效果...评估IFN-γ调控型启动子(CIITA-pIV)驱动的MHC II类分子反式激活因子突变体(MHC class II transactivator mu-tant,CIITAm)重组腺病毒Ad-pIV-CIITAm对小鼠实验性自身免疫性甲状腺炎(experimental autoimmune thyroiditis,EAT)的治疗效果,并探讨其可能的作用机制。34只健康雌性CBA/J小鼠随机分成CIITAm治疗组(n=9)、GFP对照组(n=9)、EAT模型组(n=8)和正常对照组(n=8)共四组。正常对照组不做特殊处理,其余三组均以猪甲状腺球蛋白(porcinethyroglobulin,pTg)+弗氏佐剂(complete or incomplete Freund adjuvant,CFA/IFA)建立EAT小鼠模型,并分别静脉注射重组腺病毒Ad-pIV-CIITAm、Ad-GFP及等体积生理盐水。首次免疫后第29天处死小鼠,进行H-E染色观察甲状腺病理形态;免疫组织化学染色测定甲状腺MHC II类分子表达;分析pTg刺激下脾脏淋巴细胞的增殖及其上清液中IFN-γ的分泌水平;ELISA法检测血浆中抗-pTg自身抗体滴度;流式细胞术分析外周血和脾脏淋巴细胞中T细胞亚群。结果:H-E染色结果表明,CIITAm治疗组甲状腺淋巴细胞浸润指数(0.5±0.5)低于GFP对照组(1.5±0.2)和EAT模型组(1.4±0.4,P<0.01)。免疫组化结果显示,GFP对照组和EAT模型组甲状腺组织有弥漫性MHC II类分子表达,而CIITAm治疗组未见明显表达,正常对照组表达呈阴性。80μg/ml pTg刺激下,CIITAm治疗组小鼠淋巴细胞刺激指数(SI)明显低于GFP对照组或EAT模型组(P<0.01);培养上清各组IFN-γ分泌水平结果类似(P<0.01)。CIITAm治疗组血浆抗-pTg自身抗体滴度显著低于GFP对照组或EAT模型组(P<0.05);CIITAm治疗组外周血和脾脏CD4+T细胞百分率亦显著低于GFP对照组或EAT模型组(P<0.05)。重组腺病毒Ad-pIV-CIITAm能抑制EAT小鼠甲状腺组织MHC II类分子表达,抑制自身反应性T细胞增殖,减轻甲状腺炎性细胞浸润,降低自身抗体滴度,对EAT有一定的治疗作用。展开更多
Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory enshea...Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.展开更多
Immunomodulation has been considered a potential therapeutic approach for chronic kidney disease(CKD).Although it has been previously reported that CD4+T cells contribute to the development of renal fibrosis after UUO...Immunomodulation has been considered a potential therapeutic approach for chronic kidney disease(CKD).Although it has been previously reported that CD4+T cells contribute to the development of renal fibrosis after UUO,the role of MHC class Ⅱ(MHCII)in UUO-induced renal fibrosis remains largely uncharacterized.The present study reports that the expressions of MHCII molecules in renal cortical tubules are upregulated in a mouse unilateral ureter obstruction(UUO)model.Global or renal tubule-specific ablation of MHCII significantly alleviates renal fibrosis following UUO.Additionally,renal expression of profibrotic genes showcased consistent reduction in both MHCII gene deficient mouse lines.These results demonstrate that renal tubular MHCII plays an important role in pathogenesis of renal fibrosis.展开更多
基金supported by grants from The National Natural Science Foundation of China(81801548,82071736)the Fundamental Research Funds for the Central Universities(WK9110000149)。
基金supported by the Spanish Ministry of Economy and Competitiveness,No.PID2019-106498GB-I00(to MVS)the Instituto de Salud CarlosⅢ,Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”,No.PI19/00071(to MAB)+1 种基金Ministerio de Ciencia e Innovación Project,No.SAF2017-82736-C2-1-R(to MTMF)in Universidad Autónoma de MadridFundación Universidad Francisco de Vitoria(to JS)。
文摘Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.
基金This work was supported by grants from the Natural Science Foundation of China(91639201,81390351,91742103 and 81770868)the Medical Scientific Research Foundation of Guangdong Province(A2020260)+4 种基金the Natural Science Foundation of Guangdong Province of China(2018A030313134)the Guangdong Provincial Science and Technology Program(2019B030301009)the Innovation-driven Project of CSU(2020CX015)the Shenzhen Basic Research Project(JCYJ20170818141928220,JCYJ2019073015124040376)the Shenzhen University Medical Science Cross Innovation(860000002100142).
文摘Immunomodulation has been considered a potential therapeutic approach for chronic kidney disease(CKD).Although it has been previously reported that CD4+T cells contribute to the development of renal fibrosis after UUO,the role of MHC class Ⅱ(MHCII)in UUO-induced renal fibrosis remains largely uncharacterized.The present study reports that the expressions of MHCII molecules in renal cortical tubules are upregulated in a mouse unilateral ureter obstruction(UUO)model.Global or renal tubule-specific ablation of MHCII significantly alleviates renal fibrosis following UUO.Additionally,renal expression of profibrotic genes showcased consistent reduction in both MHCII gene deficient mouse lines.These results demonstrate that renal tubular MHCII plays an important role in pathogenesis of renal fibrosis.
