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Therapeutic And Mechanic Studies Of An Artemisinin Derivative And A BTK Inhibitor In Autoimmune Diseases

Posted on:2022-08-03Degree:DoctorType:Dissertation
Country:ChinaCandidate:Y T LiuFull Text:PDF
GTID:1484306482496764Subject:Pharmacology
Abstract/Summary:PDF Full Text Request
Autoimmune diseases,including systemic lupus erythematosus(SLE),rheumatoid arthritis(RA),psoriasis,inflammatory bowel disease(IBD)and so on,are a series of immune disorders characterized by a failure in self-tolerance to autoantigens.SLE is considered to be the most typical autoimmune diseases due to its complex clinical manifestations,diverse immune abnormalities and multi-organ involvement.B cell abnormality including excessive proliferation of memory B cells and elevated secretion of autoantibodies is the key pathogenic factor of SLE.Recent years,a subset of autoreactive B cells called age-associated B cells(ABCs)has been identified to be highly correlated with the progression and treatment effect of SLE.Therefore,it is essential to further elucidate on the signaling pathways that regulate the differentiation and functions of ABCs in autoimmunity and clarify the influence of drug candidates on the formation and pathological effects of ABCs.These researches will offer new insights into finding the characteristic cell subsets that indicate the prognosis of diseases and predict the efficacy of drugs.It may provide an innovative means into improving the effectiveness of SLE therapeutic interventions.Rheumatoid arthritis(RA)is a chronic autoimmune disease as well as SLE characterized by synovial inflammation and progressive bone destruction caused by over osteoclastogenesis.Self-reactive B cells secrete massive autoantibodies and promote osteoclast precursors differentiation which result in bone destruction through Fcγ receptor cross-linking signals.Meanwhile,the production of receptor activator of nuclear factor-κB ligand(RANKL)by B cell infiltrating in synovium of RA patients may augment osteoclastogenesis in joint.Therefore,searching for small molecule inhibitors of B cell intracellular signal pathway with ideal activity is expected to interdict the pathological process of RA through multiple interventions.SM934,a water-soluble artemisinin derivative,is a new drug candidate for the treatment of SLE,which is currently in phase Ⅱ of clinical research.In this research,we found that SM934 may have a therapeutic effect on MRL/lpr,a classic model of spontaneous lupus,by controlling the expansion of ABCs in lymphoid organs and kidney and ameliorating abnormal cellular energy metabolism.ABCs is a subset of memory B cell which is highly related to disease progression and treatment response in SLE patients.We treated MRL/lpr mice at all stages of disease progression with SM934 and detected the level of autoantibodies,nephritis related biochemical and urine indexes.The results showed that: 1)the number of ABCs cells in spleen and kidney of MRL/lpr increased rapidly,which was positively correlated with the indication of disease activity;2)the glycolysis and mitochondrial respiration of B cells in spleen increased significantly with the progression of the disease,while the metabolic level of B cells infiltrating in kidney was lower than that in normal mice,which showed an opposite trend of energy metabolism;3)SM934 treatment in progression stage of SLE significantly reduced ABCs cells in immune organs and kidney of MRL/lpr mice,which was positively correlated with the therapeutic effect;4)SM934 treatment reversed the abnormal energy metabolism pattern of B cells in immune organs and kidney of MRL/lpr mice.Nearly 95% of SLE patients are complicated with arthritis and pain of joint.The disease features of lupus arthritis are similar to that of early RA.Pristane-induced lupus model is a typical experimental animal model of SLE with RA,which is widely used to study the pathological mechanism of autoimmune response and inflammation.In this study,the model of pristane-induced arthritis(PIA)was used to study the therapeutic effect and mechanism of SM934 on lupus associated arthritis.The results indicated that oral administration of SM934: 1)significantly decreased the clinical score and joint inflammation of PIA model mice;and 2)decreased the levels of serum autoantibodies and anti-Collagen Ⅱ(CⅡ)antibodies.Moreover,further investigation of the mechanism showed that SM934 could regulate the polarization of macrophages and change the inflammatory microenvironment of articular cavity,thus protect against bone destruction.Bruton tyrosine kinase(BTK)is a pivotal regulator of B cell receptor(BCR)and FC gamma receptor(FcγR)signal,which participates in the pathological process of autoimmune diseases including RA.BTK has attracted remarkable interest as therapeutic target,which can regulate the function of a variety of immune cells(B cells and myeloid cells)involved in RA.SOMCL-17-016 is a novel tricyclic BTK inhibitor with high kinase selectivity.In this study,we demonstrated that SOMCL-17-016 presented excellent immunosuppressive activity in vivo and in vitro.It was proved that oral treatment with SOMCL-17-016 significantly ameliorated the joint injury and inflammation in collagen-induced arthritis(CIA)model,and had more potent therapeutic effects than Ibrutinib and Acalabrutinib at the corresponding dosages.Further mechanism studies illustrated that SOMCL-17-016 exerted the following effects by inhibiting BTK: 1)decrease of autoantibodies produced by B cells;2)reduction of the number of RANKL-secreted B cells infiltrated in synovium,which could change the differentiation environment of osteoclasts in joint;3)repression of osteoclastogenesis by inhibiting RANK-BTK-PLCγ2 signal pathway.SOMCL-17-016 relived the symptoms of CIA through interfering with multiple signal pathways and immunological events regulated by BTK,which is expected to be a candidate drug for the treatment of RA.In conclusion,the present study focused on the pathological role and regulatory mechanism of key cell subsets and intracellular signal molecules in the progression and tissue injury of SLE and RA.We confirmed the therapeutic effect of BTK inhibitor SOMCL-17-016 in autoimmune diseases,further explored the mechanism of artemisinin derivative SM934 in the treatment of SLE,and preliminarily established the internal relationship between their therapeutic effects and the regulation of sensitive cell subsets.It will be conducive to reveal and verify new drug candidates and therapeutic targets for autoimmune diseases.
Keywords/Search Tags:Autoimmune disease, Systemic lupus erythematosus, Rheumatoid arthritis, Artemisinin derivative SM934, BTK inhibitor
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