LAP+ Treg is a better biomarker than total Treg in viral myocarditis

Latency associated peptide (LAP) is a protein expressed on the membrane of some regulatory T cells (Treg). LAP⁺ Treg have a greater immunomodulatory effect than that of their negative counterparts. In this study, we presented the data on the proportion of LAP⁺ Treg out of CD4⁺ cells in mice with viral myocarditis, which we believed was more sensitive and specific than that of the ratio of total Treg in CD4⁺ cells. Comparing with the previously recognized total Treg, LAP⁺ Treg was a better biomarker on myocardial inflammation.     

Cytokine-targeted therapy for the management of solid organ transplant recipients

IntroductionThe number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects.BodyCytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn’s, and multiple sclerosis.ConclusionThis article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.     

B cell MHC class II signaling: A story of life and death

MHC class II regulates B cell activation, proliferation, and differentiation during cognate B cell-T cell interaction. This is, in part, due to the MHC class II signaling in B cells. Activation of MHC Class II in human B cells or “primed” murine B cells leads to tyrosine phosphorylation, calcium mobilization, AKT, ERK, JNK activation. In addition, crosslinking MHC class II with monoclonal Abs kill malignant human B cells. Several humanized anti-HLA-DR/MHC class II monoclonal Abs entered clinical trials for lymphoma/leukemia and MHC class II-expressing melanomas. Mechanistically, MHC class II is associated with a wealth of transmembrane proteins including the B cell-specific signaling proteins CD79a/b, CD19 and a group of four-transmembrane proteins including tetraspanins and the apoptotic protein MPYS/STING. Furthermore, MHC class II signals are compartmentalized in the tetraspanin-enriched microdomains. In this review, we discuss our current understanding of MHC class II signaling in B cells focusing on its physiological significance and the therapeutic potential.     

Dexamethasone turns tumor antigen-presenting cells into tolerogenic dendritic cells with T cell inhibitory functions

BackgroundDendritic cells (DCs) are usually immunogenic, but they are also capable of inducing tolerance under anti-inflammatory conditions. Immunotherapy based on autologous DCs loaded with an allogeneic melanoma cell lysate (TRIMEL/DCs) induces immunological responses and increases melanoma patient survival. Glucocorticoids can suppress DC maturation and function, leading to a DC-mediated inhibition of T cell responses.MethodsThe effect of dexamethasone, a glucocorticoid extensively used in cancer therapies, on TRIMEL/DCs phenotype and immunogenicity was examined.ResultsDexamethasone induced a semi-mature phenotype on TRIMEL/DC with low maturation surface marker expressions, decreased pro-inflammatory cytokine induction (IL-1β and IL-12) and increased release of regulatory cytokines (IL-10 and TGF-β). Dexamethasone-treated TRIMEL/DCs inhibited allogeneic CD4⁺ T cell proliferation and cytokine release (IFNγ, TNF-α and IL-17). Co-culturing melanoma-specific memory tumor-infiltrating lymphocytes with dexamethasone-treated TRIMEL/DC inhibited proliferation and effector T cell activities, including cytokine secretion and anti-melanoma cytotoxicity.ConclusionsThese findings suggest that dexamethasone repressed melanoma cell lysate-mediated DC maturation, generating a potent tolerogenic-like DC phenotype that inhibited melanoma-specific effector T cell activities. These results suggest that dexamethasone-induced immunosuppression may interfere with the clinical efficacy of DC-based melanoma vaccines, and must be taken into account for optimal design of cellular therapy against cancer.     

Enhanced Anti-Leukemic Effects through Induction of Immunomodulating Microenvironment by Blocking CXCR4 and PD-L1 in an AML Mouse Model

Previously, we found that dual therapy by the CXCR4 inhibitor Plerixafor and cytosine arabinoside (Ara-C) effectively eradicated leukemia cells and concurrently activated immune cells in acute myeloid leukemia (AML). To reveal the significance of programmed death-ligand1 (PD-L1) in AML and as a strategic approach, we investigated the anti-leukemic effect of a triple combinational therapy by utilizing Plerixafor and anti-PD-L1 in combination with chemotherapy in an AML mouse model. We examined leukemic myeloid blast cells in multiple organs after the successive treatment with Ara-C, Plerixafor, and anti-PD-L1. The results showed that noticeable benefits of triple combinational therapy for eradication of myeloid blast cells in vivo with prolonged survival rates. The frequencies of regulatory T cells (Tregs), monocytic-myeloid-derived suppressor cells (M-MDSCs), and granulocytic-myeloid-derived suppressor cells (G-MDSCs), in the peripheral blood of leukemic mice were consistently decreased, even when mice were sacrificed alive at D + 26 after completion of the triple combinational therapy, compared to the other subgroups. These findings imply that the modulation by the triple combinational therapy may lead to more efficient leukemic myeloid blast cell ablation through the suppression of Tregs or M-MDSCs and G-MDSCs in AML. Although Plerixafor and PD-L1 antagonist do not have a direct anti-leukemic role, our results provide some clues and guidelines to develop clinically therapeutic strategies for chemotherapy-resistant patients by the modulation of leukemic microenvironments.     

二巯基丁二酸修饰的Fe3O4纳米颗粒对人血管内皮细胞的作用研究

目的研究二巯基丁二酸修饰的Fe3O4纳米颗粒(dimercaptosuccinic acid-magnetite nanoparticles,DMSA-Fe3O4)对人脐静脉内皮细胞(human umbilical vein endothelial cells,HUVECs)功能的影响。方法利用动态光散射法表征DMSA-Fe3O4的粒径及表面电荷;采用普鲁士蓝染色、邻二氮菲铁定量和透射电镜观察方法研究HUVECs对DMSA-Fe3O4的摄取规律;利用细胞计数试剂盒(Cell Counting Kit-8,CCK-8)检测DMSA-Fe3O4对内皮细胞活性的影响;通过酶联免疫吸附试剂盒测定DMSA-Fe3O4对内皮细胞血管内皮生长因子(vascular endothelial growth factor,VEGF)分泌量的影响。结果HUVECs能够大量吞噬DMSA-Fe3O4,其吞噬量具有孵育时间和剂量依赖性;短时间内所测剂量范围DMSA-Fe3O4对细胞活性无显著影响,但长时间高剂量条件使细胞活性明显降低。此外,在高剂量DMSA-Fe3O4暴露下(200μg/mL),内皮细胞分泌VEGF的量约为对照组的3倍。结论DMSA-Fe3O4易于被HUVECs吞噬;高浓度DMSA-Fe3O4与HUVECs长时间培养使细胞活性降低,并刺激内皮细胞分泌VEGF。     

Effect of Aryl Substituents and Fluorine Addition on the Optoelectronic Properties and Organic Solar Cell Performance of a High Efficiency Indacenodithienothiophene‐alt‐Quinoxaline π‐Conjugated Polymer

A series of donor‐acceptor (D‐A) π‐conjugated polymers, based on indacenodithienothiophene (IDTT) as an electron‐donating unit and quinoxaline as an electron‐deficient moiety, are synthesized via a Pd‐catalyzed Stille cross‐coupling polymerization. Molecular characteristics, photovoltaic parameters, and optoelectronic properties are examined through structural differences corresponding to thienyl versus phenyl side group substitutions on the IDTT and the non‐fluorinated versus the monofluoro quinoxaline derivatives. One of the most important outcome is that the power conversion efficiency (PCE) in the studied polymers is more device architecture dependent (conventional vs inverted) rather than chemical structure dependent. From single junction solar cells based on bulk heterojunction polymer:[6,6]‐phenyl‐C₇₁‐butyric acid methyl ester (PC₇₁BM) systems as the active layer, a maximum PCE of 5.33% has been achieved from the polymer containing the thienyl substituent on the IDTT and one fluorine atom on the quinoxaline. This demonstrates that finding the optimum molecular weight of ThIDTT‐QF or introducing the monofluoro‐quinoxaline in a regioregular motif in the polymer backbone significantly higher PCE can be expected versus the fully optimized high performance PhIDTT‐Q conjugated polymer.