Effects Of Targeted Regulation Of Monocyte-macrophages On Experimental Autoimmune Encephalomyelitis

The occurrence and development of multiple sclerosis(MS)is accompanied by complex pathological phenomena and immunological events involving a variety of immune cells,resulting in a lot of controversy about the mechanism of MS.Clinical drug development process is also slow.In addition,as no obvious lesion area in the early stage of MS,using of MRI imaging techniques can't effectively achieve the early diagnosis of MS,which is also a reason that MS is difficult for treatment.In recent years,researchers have proposed a strategy based on targeted myeloid cells for the diagnosis and treatment of MS.However,the strategies to target and regulate these cells is still in its infancy and how to directly reveal the role of these cells in the progression of MS in vivo is also an urgent problem to be solved.On the basis of experimental autoimmune encephalomyelitis(EAE),this study proposed that peripheral blood inflammatory monocytes as the target of MS regulation.With the aid of HPPS,which was a peptide mimicking high density lipoprotein developed by our lab,hydrophobic anti-inflammatory drug curcumin can be selectively transferred to inflammatory monocytes.Curcumin could modulate the action of moncyte and delay the progression of EAE.Meanwhile,intravital imaging clearly showed that HPPS loaded with DiR-BOA dye specifically labeled the infiltrated monocytes in the CNS of the EAE mice.Multple common encephalitogenic opitopes(MMPt),a protein antigen drug developed by the department of immunology of the Third Military Medical University,can significantly delay the progression of EAE.Intravital imaging showed that MMPt was located in the CNS perivascular macrophages and could induce autoreactive T cell apoptosis.The main achievements and conclusions of this study are as follows:1)In vivo imaging confirmed that HPPS specifically targeted inflammatory monocytes in the peripheral blood and was carried by monocytes to the CNS pathogenesis area of early EAE mouse model.Compared with other immune cells in the peripheral blood,intravenous injection of HPPS could target more than 90% of monocytes,less than 6% of neutrophils or other cells engulfed HPPS.When inflammatory monocytes carried imaging contrast agents,it can be used to indicate the lesion area in the CNS of EAE mice.2)The nano-drugs Cur-HPPS carrying curcumin specifically immunomodulate monocytes in the peripheral blood inflammatory,and achieved a good therapeutic effect on the EAE mice by inhibiting them across the blood brain barrier.The highly efficient uptake of curcumin hindered inflammatory monocytes across the blood brain barrier in EAE mice,resulting in the reduction of EAE morbidity from 100% to 30%.It attributed to the immunomodulatory effect of Cur-HPPS on inflammatory monocytes,which inhibited NF-?B activation and downregulate the expression of adhesion-and migration-related molecules.3)In vivo imaging confirmed that CNS perivascular macrophages are immunoregulated targets for protein antigens.Intravital imaging showed that MMPt could be effectively ingested by CNS perivascular macrophages in EAE model.Within three hours after intravenous injection of the drug,macrophages formed immune synapses with autoreactive T cells,thus inducing T cells apoptosis and promoting the motor recovery of EAE mice.In summary,we used the EAE model as the animal model.By targeted delivery of imaging contrast agent,we realized early detection of CNS inflammation in EAE.Through targeted delivery of immunotherapy drug,we could regulate the function of monocyte-macrophages,and successfully delay the progression of EAE.This study will provide new strategies for the diagnosis and treatment of clinical MS.