Induction of liver transplant immune tolerance in an outbred rat strain model using tacrolimus.

Background: Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Post-transplant immunosuppressive therapy is important to prevent graft failure. We investigated the effectiveness of tacrolimus (FK506) and their mechanisms for liver transplant immune tolerance in an outbred rat LT model.

Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients.

Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients.

Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.

Programmed Death-Ligand 1 Expression Potentiates the Immune Modulatory Function Of Myeloid-Derived Suppressor Cells in Systemic Lupus Erythematosus.

Multiple studies have explored the potential role of programmed death-ligand 1 (PD-L1) as a mediator of Myeloid-derived suppressor cells (MDSCs) effects in various cancers. However, the role PD-L1 expression in MDSCs on autoimmune disease is still largely unknown.This study was undertaken to whether MDSC expressing PD-L1 have more potent immunoregulatory activity and control autoimmunity more effectively in two murine models of lupus (MRL/ mice and Roquin mice).

Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host disease with combination of regulatory T cells.

Background: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting.

FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition.

Background: Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD.

Daurinol Attenuates Autoimmune Arthritis via Stabilization of Nrp1-PTEN-Foxp3 Signaling in Regulatory T Cells.

Optimizing Treg function and improving Treg stability are attractive treatment strategies for treating autoimmune rheumatoid arthritis (RA). However, the limited number of circulating Tregs and questions about the functional stability of -expanded Tregs are potential limitations of Treg-based cell therapy. The aim of this study was to analyze the regulatory effect of daurinol, a catalytic inhibitor of topoisomerase IIα, on Th cell differentiation and to evaluate their therapeutic potential in a preclinical experimental model of RA.

Metformin Augments Anti-Inflammatory and Chondroprotective Properties of Mesenchymal Stem Cells in Experimental Osteoarthritis.

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA.

The Therapeutic Effect of STAT3 Signaling-Suppressed MSC on Pain and Articular Cartilage Damage in a Rat Model of Monosodium Iodoacetate-Induced Osteoarthritis.

Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation.

Ro60 Inhibits Colonic Inflammation and Fibrosis in a Mouse Model of Dextran Sulfate Sodium-Induced Colitis.

Inflammatory bowel disease (IBD) is caused by chronic inflammation of the gastrointestinal tract. The pathogenesis of IBD remains unclear. The inflammation is associated with activation of T helper (Th) lymphocytes and chronic production of inflammatory cytokines.

Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice.

Myeloid-derived suppressor cells (MDSCs) are heterogenous populations of immature myeloid progenitor cells with immunoregulatory function. MDSCs play critical roles in controlling the processes of autoimmunity but their roles in rheumatoid arthritis (RA) are controversial. The present study was undertaken to investigate whether MDSCs have therapeutic impact in mice with collagen-induced arthritis (CIA), an animal model of RA.

Clean-Up Human Embryonic Stem Cell Lines Using Humanized Culture Condition.

Human embryonic stem cell (hESC) culture system has been changing culture conditions from conventional to xeno-free for therapeutic cell applications, and -glycolylneuraminic acid (Neu5Gc) could be a useful indicator of xenogeneic contaminations in hESCs because human cells can no longer produce it genetically. We set up the humanized culture condition using commercially available humanized materials and two different adaptation methods: sequential or direct. SNUhES4 and H1 hESC lines, previously established in conventional culture conditions, were maintained using the humanized culture condition and were examined for the presence of Neu5Gc.

Propagation of Human Embryonic Stem Cells on Human Amniotic Fluid Cells as Feeder Cells in Xeno-Free Culture Conditions.

Human embryonic stem cells (hESCs) have been routinely cultured on mouse embryonic fibroblast feederlayers with a medium containing animal materials. For clinical application of hESCs, animal-derived products from the animal feeder cells, animal substrates such as gelatin or Matrigel and animal serum are strictly to be eliminated in the culture system. In this study, we performed that SNUhES32 and H1 were cultured on human amniotic fluid cells (hAFCs) with KOSR XenoFree and a humanized substrate.

Extracts of Magnoliae flos inhibit inducible nitric oxide synthase via ERK in human respiratory epithelial cells.

Nitric oxide (NO) is a marker of pulmonary inflammation. In asthma, the levels of exhaled NO are elevated and the source of this increased NO is inducible nitric oxide synthase (iNOS) within airway epithelial cells. Epimagnolin and fargesin are compounds isolated from the ethanol extract of Magnoliae flos, the seed of the Magnolia plant and are used to treat nasal congestion, headache and sinusitis in Asian countries.

Separation and maintenance of normal cells from human embryonic stem cells with trisomy 12 mosaicism.

Human embryonic stem cells (hESCs) are pluripotent and hold great promise as useful tools in basic scientific research and in the field of regenerative medicine. However, several studies have recently reported chromosomal abnormalities such as gains of chromosomes 12, 17 and X in hESCs. This genetic instability presents an obstacle in the application of hESCs as sources of cell therapies.

7-Ketocholesterol predisposes human aorta smooth muscle cells to Fas-mediated death.

Human vascular smooth muscle cells (HVSMCs) are resistant to Fas-mediated death under normal physiological conditions. However, HVSMC death by activation of the receptor pathway was reported in the atherosclerotic lesions. In this study, we investigated whether 7-ketocholesterol, one of the major cholesterol oxides in the lesions, altered resistance of HVSMC to Fas-mediated death pathway.

TNF-alpha activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol.

This study was undertaken to investigate whether a physiologically compatible concentration of 7-ketocholesterol had any effect on human vascular smooth muscle cells (HVSMCs). We found that 7-ketocholesterol changed the viability of human aorta smooth muscle cells (HAoSMC) not by cytotoxicity but by activation of tumor necrosis factor-alpha receptor (TNFR)-mediated death. Whereas TNF-alpha did not affect the viability in the presence of 7alpha-hydroxycholesterol or cholesterol, the cytokine induced HAoSMC death in the presence of 7-ketocholesterol as detected by morphology, viability, and fragmentation of chromosomal DNA.

Kurarinone isolated from Sophora flavescens Ait inhibited MCP-1-induced chemotaxis.

The accumulation of circulating monocytes in the arterial wall is an early in atherosclerotic plaque formation. Monocyte chemoattractant protein-1 (MCP-1) promotes the migration of monocytes and would play a role in the development of atherosclerotic lesions. Searching for inhibitors of MCP-1-induced cell migration from natural sources, we isolated one active compound through active-guided fractionations from the MeOH extracts of Sophora flavescens Ait (Leguminosae).

Pheophorbide A-methyl ester, Acyl-CoA: cholesterol acyltransferase inhibitor from Diospyros kaki.

In the course of our search for Acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors from natural sources, a new type of ACAT inhibitor was isolated from a methanol extract of Diospyros kaki. On the basis of spectral and structural evidence, the compound was identified as pheophorbide A-methyl ester. Pheophorbide A-methyl ester inhibited ACAT activity in a dose dependent manner with an IC50 value of 1.