Therapeutic Effects Of TACI-Ig On Experimental Autoimmune Encephalomyelitis

Objective: The neuromyelitis optica spectrum disorders(NMOSD)is one of the most recent diseases in the field of neurology,and the positive rate of aquaporin 4(AQP4)is higher than that of aquaporin 4(AQP4)A high group of nervous system autoimmune demyelinating disease.NMOSD is a class of typical diseases of central nervous system demyelinating disease,the disease in young and middle-aged women,the incidence is often severe symptoms,resulting in numbness of the limbs,decreased vision and other symptoms,severe cases,or even transverse paraplegia,serious impact Quality of life of patients.At present,there is no effective treatment for NMOSD treatment,the main treatment drugs,including glucocorticoids,azathioprine and mycophenolate mofetil,but there are still some problems,first of all,not every patient with drugs Sensitivity,followed by long-term medication will be accompanied by side effects of drugs.With the development of NMOSD,the role of B cells in its pathogenesis has been paid more and more attention.In this study,we hope that by using the newly developed B lymphocyte stimulator(BLyS)and a proliferation-inducing ligand(APRIL)inhibitor TACI receptor fusion protein(TACI-Ig)(Autoimmune Encephalomyelitis,EAE)to explore the effectiveness of B-cell-based experimental protocol in demyelinating disease represented by NMOSD,and to provide theoretical basis for clinical application and stand by.Methods: This study firstly collected NMOSD patients according to the clinical diagnosis standards,which were divided into acute stage and remission groups based on the time of blood samples were collected and the clinical symptoms.At the same time,normal control peripheral blood serum were collected consistent with age and sex distribution of disease groups.All groups were performed detection of expression level of BLyS and APRIL.Secondly,we induced EAE models by MOG35-55 and administrated intraperitoneal injection of different doses of TACI-Ig treatment.The scores of clinical sympthon of EAE mice were recorded daily to evaluate the therapeutic effect of TACI-Ig.At the end of the treatment,the mice which were at the peak of inflammation(Day 25)were executed and seperated the spleens to analysis the differentiation of B cells of the peripheral inflammation through flow cytometry staining technic,while those were at the regression period of inflammation(Day 35)were executed and seperated the spinal cord to perform HE as well as LFB staining and evaluate the degree of demyelination and inflammatory infiltration in central nervous system(CNS).Finally,the effects of TACI-Ig on proliferation,apoptosis and subtype differentiation of T and B cells were tested in vitro to provide evidence for the safety of TACI-Ig against normal T and B cells.Results: Firstly,the expression level of BLyS and APRIL in peripheral serum samples from NMOSD patients were significantly higher than those in healthy controls'.The vivo experiments confirmed that TACI-Ig significantly reduced the clinical scores of EAE,alleviated the degree of inflammatory infiltration and demyelination in the central nervous system,and inhibited the proliferation of activated B cells in EAE mice.Finally,the CD4+T cells and CD19+B cells sorted in vitro were co-cultured with TACI-Ig and the results indicated that the low concentration of drug(0nM-100nM)did not affect the proliferation and apoptosis of the two types of cells while the high concentration(100nM-1000nM)will inhibit the cell proliferation.TACI-Ig could significantly reduce the over activation and proliferation of B cells under LPS inflammatory stimuli without affecting the differentiation of T cell subsets.Conclusion: Through the experimental study of the above two parts,this study evaluated the therapeutic effect of TACI-Ig on EAE.Experimental results show that TACI-Ig can significantly improve the EAE behavioral score,inhibition of CNS demyelination and inflammatory infiltration,flow analysis results confirmed that TACI-Ig is inhibited by B cells in the body of abnormal proliferation play a role in the same time in a certain Of the safe concentration range does not affect the normal proliferation and differentiation of T and B lymphocytes.Finally,we detected the peripheral blood BlyS and APRIL in NMOSD patients,and the two target molecules of TACI-Ig were significantly elevated in NMOSD patients,especially in acute patients,suggesting that TACI-Ig Application to NMOSD treatment is a great potential and the development of space.