Targeted treatment strategy for patients with severe pulmonary hypertension secondary to connective tissue diseases

Background:Pulmonary arterial hypertension(PAH)associated with connective tissue diseases(CTD)(CTD-PAH)remains a difficult challenge in clinical practice.We aimed to evaluate the effects of targeted vasodilators in patients with severe CTD-PAH.Methods:The data of 53 patients with severe CTD-PAH hospitalized at the Department of Rheumatology and Immunology,The Affiliated Drum Tower Hospital of Nanjing University Medical School,were retrospectively reviewed.Patients were followed up for an average of 2 years to track their outcomes.The efficacy of treatment and the survival rate of patients with severe CTD-PAH were determined.Results:Among the causes of severe CTD-PAH,systemic lupus erythematosus(SLE)was the most common(39.6%),and the age at onset in patients with SLE-PAH was younger than that of patients with other CTD.Bosentan was more effective than sildenafil in reducing pulmonary artery pressure,improving cardiac function,and increasing survival time.Combination therapy with targeted vasodilators significantly improved the prognosis of patients with severe CTD-PAH compared with monotherapy.Conclusions:Patients with severe CTD-PAH should be treated early with targeted vasodilators.In this study,bosentan was superior to sildenafil.Combined treatment might be an option for severe CTD-PAH.

Transplantation of Human Bone Marrow Mesenchymal Stem Cell Ameliorates the Autoimmune Pathogenesis in MRL/lpr Mice

Recent evidence indicates that mesenchymal stem cells （MSC） possess immunosuppressive properties both in vitro and in vivo. We previously demonstrated the functional abnormality of bone marrow derived MSC in patients with systemic lupus erythematosus （SLE）. In this study, we aimed to investigate whether transplantation of human bone marrow derived MSC affects the autoimmune pathogenesis in MRL/Ipr mice. We found that human MSC from healthy donors reduced the proliferation of T lymphocytes from MRL/Ipr mice in a dose-dependent fashion. Two weeks after in vivo transfer of MSC, we detected significantly reduced serum levels of anti ds-DNA antibodies and 24 hour proteinuria in MRL/Ipr mice as compared with control groups without MSC transplantation. Moreover, flow cytometric analysis revealed markedly reduced number of CD4＋ T cells while increased Thl subpopulation in MSC group and MSC ＋ CTX group when compared with controls. Histopathological examination showed significantly reduced renal pathology in MSC-treated mice. Immunohistochemical studies further revealed reduced expression of TGF-~, FN, VEGF and the deposition of complement C3 in renal tissue after MSC and MSC ＋ CTX treatment. Taken together, we have demonstrated that transplantation of human MSC can significantly inhibit the autoimmune progression in MRL/Ipr mice. Cellular ＆ Molecular Immunology. 2008;5（6）：417-424.

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Mesenchymal stem cells(MSCs)are critical for immune regulation.Although several microRNAs(miRNAs)have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function,the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear.Here,we show that patients with systemic lupus erythematosus(SLE)display a unique miRNA signature in bone marrow-derived MSCs(BMSCs)compared with normal controls,among which miR-663 is closely associated with SLE disease activity.MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper(Tfh)cells and upregulation of regulatory T(Treg)cells by targeting transforming growth factorβ1(TGF-β1).MiR-663 overexpression weakens the therapeutic effect of BMSCs,while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice.Thus,miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

A Pilot Study of the Therapeutic Efficacy and Mechanism of Artesunate in the MRL/lpr Murine Model of Systemic Lupus Erythematosus

Recent evidence indicates that artesunate has immunomodulatory properties that might be useful for treating autoimmune disease.In this study,we conducted a pilot study and explored the effect and mechanism of artesunate on the treatment of systemic lupus erythematosus using an MRL/lpr murine model.MRL/lpr mice were divided into control,cyclophosphamide(CTX)and artesunate treatment groups.Blood was collected to measure serum levels of creatinine,antinuclear antibody(ANA)and anti-double-stranded DNA(anti-dsDNA)antibody.Twenty-four-hour urine was collected to measure levels of proteinuria.The concentration of monocyte chemotactic protein-1(MCP-1)in serum and urine was measured.The expression of MCP-1 in kidney was detected by Western blot and immunohistochemistry assay,respectively.The expression of B cell activating factor(BAFF)in spleen was determined by real time-PCR and immunoblotting.We found that artesunate significantly increased the survival rate,body weight and blood leukocyte counts,and reduced the serum levels of ANA and anti-dsDNA antibody titer,24 h urinary protein,and serum creatinine.Our results indicated that artesunate could decrease MCP-1,major pro-inflammation cytokine,in serum,urine and kidney.We also found that the level of BAFF,the major B cell activation factor,was decreased in artesunate treated MRL/lpr mice.Its efficacy was comparable with that of CTX in this study.Taken together,we have demonstrated that artesunate can inhibit the progression of disease and reverse the pathologic lesion of lupus nephritis.