Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.     

Enhanced immune‐modulatory effects of thalidomide and dexamethasone co‐treatment on T cell subsets

Thalidomide (TM) has been reported to have anti‐cancer and anti‐inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co‐treatment had an enhanced immune‐modulatory effect on T cells through regulating the expression of co‐stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort‐purified and cultured for CD4⁺ T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4‐1BB, and glucocorticoid‐induced tumour necrosis factor receptor‐related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 μm ) decreased CD4⁺ T cell proliferation in a dose‐dependent manner, whereas TM/DX (0·1 or 1 nm ) co‐treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co‐stimulatory molecules decreased upon TM/DX co‐treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4⁺ T cells isolated from TM‐ and DX‐treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4‐1BB expression in CD4⁺ T cells.     

Myasthenia gravis after allogeneic bone marrow transplantation treated with mycophenolate mofetil monitored by peripheral blood OX40+ CD4+ T cells

A patient who developed myasthenia gravis (MG) 25 months after allogeneic bone marrow transplant was immunologically analyzed. OX40+CD4+ T cells in the peripheral blood prominently increased one month before the onset of MG. CD4/CD8 ratios, usually abnormally inverted in patients with chronic graft-vs.-host disease (cGVHD), showed pseudonormalization during the course of MG. We succeeded in uneventful rapid tapering of prednisolone (PSL) using mycophenolate mofetil (MMF). Monitoring of OX40+CD4+ T cells supported the tapering of PSL and MMF as a marker of cGVHD activity. This case suggested the utility of MMF and monitoring of OX40+CD4+ T cells in the management of cGVHD-associated autoimmune diseases.     

CD40反义RNA对系统性红斑狼疮患者B淋巴细胞功能的影响

目的　探讨瞬间表达的CD4 0反义RNA对EB病毒转染的系统性红斑狼疮 (SLE)患者B淋巴细胞CD4 0分子表达、细胞增生以及免疫球蛋白 (Ig)分泌功能的影响。 方法　构建人CD4 0反义RNA的真核表达载体CD4 0 /pcDNA3,并将其转染入EB病毒转染的SLE患者B淋巴细胞中。应用流式细胞仪 (FACS)检测观察B淋巴细胞膜上CD4 0分子表达的变化 ;应用四甲基偶氮唑盐微量酶反应比色法 (MTT)观察反义CD4RNA对B淋巴细胞增生能力的影响 ;应用酶联免疫吸附试验(ELISA)测定转染后的B淋巴细胞的Ig分泌功能。结果　与转染pcDNA3空载体组相比 ,转染CD4 0 / pcDNA3组的CD4 0分子的表达明显降低 (P <0 0 1) ;细胞的增生能力明显降低 (P <0 0 5 ) ;细胞的Ig分泌功能明显受抑制 (P <0 0 1)。结论　CD4 0反义RNA对SLE患者的B淋巴细胞有明显的免疫调控作用。     

Echocardiographic criteria for aortic root dissection.

Echocardiographic findings from 10 patients without clinical indications of aortic root dissection or aortic valve disease from 1 patient with angiographic confirmation of aortic root dissection are reported and compared. Previously reported echocardiographic findings were confirmed in the patient with aortic root dissection. These include (1) a widened posterior or anterior aortic wall, or both; (2) parallel motion of the separated margins of the aortic walls; and (3) aortic root dilatation (42 mm or more at end-systole). However, all three findings were also noted in 5 of the 10 patients without clinical indications of aortic root dissection or aortic valve disease, and at least two of the three findings were noted in the remaining 5 patients. Echocardiographic detection of aortic root dissection appears to be most reliable when clinical indications of the anomaly are present.     

CD40 在癫痫大鼠大脑皮层及海马中的表达变化

目的：研究CD40炎症分子在癫痫持续状态(status epilepticus,SE)后大鼠大脑皮层及海马的表达。方法：采 用免疫组织化学及免疫荧光双标记方法,观察锂-匹罗卡品癫痫大鼠大脑皮层及海马的不同区域、不同时间点、不同 细胞中CD40的表达情况。结果：癫痫发作显著增加了CD40阳性细胞,以在海马组织中增加为著; SE后CD40主要在 激活的小胶质细胞上表达;CD40阳性细胞在SE后3 d增加达到一个高峰,在SE 7 d后恢复到SE前稍高的水平。结论： CD40在激活的小胶质细胞上高表达,促进了SE大鼠海马炎症反应,提示CD40介导的信号通路参与SE后海马组织的炎 症病理过程。     

IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice

Aim:

To investigate whether the transfer of the IL-37b gene, a newly identified inhibitor of both innate and adaptive immunity, could improve the therapeutic efficacy of mesenchumal stromal cells (MSCs) in inflammatory bowel disease (IBD).

Methods:

The expression of IL-37 in biopsied specimens of the patients with active ulcerative colitis (UC) was detected using RT-PCR and immunohistochemistry. Mice were treated with 3% dextran sulfate sodium (DSS) for 8 days to induce colitis. Before DSS treatment, the mice were injected with MSCs, MSC-eGFP or MSC-IL37b. Their body weight was measured each day, and the colons and spleens were harvested on d 10 for pathological and biochemical analyses.

Results:

In biopsied specimens of the patients with active UC, the expression of IL-37 was dramatically elevated in inflamed mucosa, mainly in epithelial cells and infiltrating immune cells. Compared to MSC-eGFP or MSCs, MSC-IL37b administration significantly attenuated the body weight and colon length reduction, and decreased the histological score in DSS-induced colitis mice. Furthermore, MSC-IL37b administration increased the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells as well as the percentage of regulatory T cells (Tregs) among splenic CD4+ T cells in the mice. Moreover, MSC-IL37b administration increased the IL-2+ cells and decreased the IFN-γ+ cells among splenic CD4+ T cells.

Conclusion:

IL-37 is involved in the pathophysiology of UC. IL-37b gene transfer enhances the therapeutic efficacy of MSCs in DSS-induced colitis mice by inducing Tregs and MDSCs and regulating cytokine production.     

PRAS40活性调节与功能的研究进展

PRAS40是蛋白激酶B(PKB/Akt)的作用底物,亦是m TORC1的特异性结合蛋白,有多个位点可发生磷酸化,其中Thr246磷酸化受Akt调控,而Ser183、Ser212及Ser221等磷酸化主要受m TORC1调控。磷酸化修饰的PRAS40可调节与Raptor及14-3-3等蛋白的结合,参与Akt、m TORC1活性的调控。PRAS40具有调控细胞增殖、参与神经损伤保护等作用,在胰岛素抵抗、神经退行性病变及肿瘤中扮演重要角色,有望成为药物作用的新靶点。