Sun-Woo Kang

The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation

The generation of tryptophan (Trp) metabolites by indoleamine 2,3-dioxygenase (IDO) is an effective mechanism for T cell suppression. However, the effect of Trp metabolites on dendritic cells (DCs) remains unclear. Here, we investigated whether the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) directly inhibits DC activation and is responsible for T cell suppression. We found that 3-HAA treatment significantly reduced IL-12, IL-6, and TNF-α production in bone marrow-derived DCs (BMDCs) stimulated with LPS. Maturation markers CD40, CD80, CD86, and I-A were also significantly reduced. Moreover, treatment with 3-HAA decreased the ability of DCs to stimulate T cell activation and differentiation in vitro and in vivo. Finally, we observed that phospho-JNK and phospho-38 levels were reduced in 3-HAA-treated DC2.4 cells and BMDCs. These results suggest that the tryptophan metabolite 3-HAA suppresses T cell responses by inhibiting DC activation.

Reuse of a Previously Transplanted Kidney From a Deceased Donor Using Luminex Virtual Crossmatching: A Case Report

Kidney transplantation is the most desired modality of renal replacement therapy for patients with end-stage renal disease (ESRD). We have attempted to expand the organ donor pool through several methods, including the use of expanded donor criteria. Although previously transplanted kidneys are rarely reused, they can be suitable for transplantation into patients in need. We report a case of successful reuse of a previously transplanted kidney from a deceased donor by means of Luminex virtual crossmatching with the first donor and actual crossmatching with the second donor.

Therapeutic activity of the histone deacetylase inhibitor SB939 on renal fibrosis.

Abstract Fibrosis is the final pathological outcome of many chronic kidney diseases and is quite common. Thus, development of effective anti‐fibrotic agents is urgently needed. Although histone deacetylases (HDACs) have been reported to be involved in renal fibrosis, current HDAC inhibitors are unsatisfactory anti‐fibrosis drugs. Therefore, more potentially relevant anti‐renal fibrosis HDAC inhibitors are needed. We initially found that non‐cytotoxic concentrations of SB939 (pracinostat) had strong anti‐fibrotic activity, drastically decreasing TGF‐&bgr;1‐induced alpha smooth muscle actin (&agr;‐SMA) expression in the NRK renal fibroblast cell line. Similar anti‐fibrotic activity of SB939 on epithelial‐to‐mesenchymal transition (EMT) was confirmed using the HK‐2 human renal proximal tubular epithelial cell line. SB939 inhibited Smad‐independent TGF‐&bgr; signaling involving the MAPK and PI3K/AKT pathways. To evaluate in vivo anti‐fibrotic activity, we administered SB939 in a unilateral ureteric obstruction (UUO) model. SB939 treatment markedly inhibited the accumulation of &agr;‐SMA and tissue injury. Inflammatory and pro‐fibrotic cytokines in the obstructed kidney were also significantly decreased by SB939 treatment. Our results suggest that SB939 might be a promising therapeutic drug for preventing renal fibrosis. HighlightsPan‐HDAC inhibitor SB939 was investigated on renal fibrosis.SB939 inhibits TGF‐&bgr;1‐induced myofibroblast generation.SB939 inhibits Smad‐independent pathways in TGF‐&bgr; signaling.Administration of SB939 into UUO model reduces renal fibrosis and inflammation.

Effect of upregulated TLR2 expression from G-CSF-mobilized donor grafts on acute graft-versus-host disease.

Our previous study demonstrated that G-CSF treatment increased the expression of TLR2 in donor grafts; this contributed to rapid engraftment after allogeneic hematopoietic stem cell transplantation (HSCT) in mice. In the current study, we investigated the effects of upregulated TLR2 expression in G-CSF-mobilized donor grafts on acute graft-versus-host disease (GVHD). We found that TLR2 was highly expressed on myeloid cell populations but not T and B cells from the spleens of G-CSF-treated donor mice. After transplantation, the mortality and disease severity in recipients were not significantly different between G-CSF-treated TLR2-/- and wt donor grafts. Although endogenous TLR2 ligand was detected in the serum of both recipients, T cells from TLR2-/- and wt donors have the same ability regarding alloreactivity. Moreover, the blockade of TLR2 signaling in recipients by administering anti-TLR2 blocking antibody after BMT did not lead to a significant difference in acute GVHD compared with control IgG treatment. However, the hematopoietic ability of G-CSF-mobilized lin−c-kit+ HSCs from TLR2-/- donor grafts was lower than that from wt donor grafts. Our results demonstrate that upregulated TLR2 expression in G-CSF-mobilized donor grafts has no effect on acute GVHD, suggesting that TLR2 is a valuable target for increasing HSCT efficiency in order to enhance engraftment without exacerbating acute GVHD.

Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

Significance Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the metabolism of tryptophan and plays critical roles in immune regulation to avoid severe immunopathology. We demonstrate that IFN-γ signaling in lung parenchyma prevents idiopathic pneumonia syndrome by inducing IDO expression; inhibition of deacetylation of STAT3 potentiates IDO expression induced by IL-6 in an IFN-γ–independent manner; inhibition of IDO expression by immunosuppressants can be reversed by a histone deacetylase inhibitor; and finally, l-kynurenine acts on lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor to suppress their inflammatory activities. Our results indicate that proinflammatory IFN-γ and IL-6 expressed within a short time range early after pulmonary inflammation is indispensable in protecting the lung from devastating immunopathology. The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ–dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ–independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

Matrix Metalloproteinase Gene Polymorphisms and New-Onset Diabetes After Kidney Transplantation in Korean Renal Transplant Subjects

BACKGROUND New-onset diabetes after transplantation (NODAT) is a serious metabolic complication that may follow renal transplantation. Matrix metalloproteinases (MMPs) contribute to insulin insufficiency and beta-cell dysfunction in a rat model. The MMP-2 concentrations were lower in patients with type 2 diabetes mellitus, and the plasma MMPs levels were related to diabetes. Similar to the pathogenesis of type 2 diabetes mellitus, insulin resistance and insulin secretion dysfunction occur in patients with the development of NODAT. Therefore, we examined the association between NODAT and 11 single-nucleotide polymorphisms (SNPs) located within the 3 genes of MMPs that might be related to NODAT. METHODS A total of 309 renal transplant recipients without a history of diabetes were included in this study. DNA was extracted from the blood samples of recipients, and we analyzed the association between the development of NODAT and a panel of 11 SNPs within 3 MMP genes (MMP-1, MMP-2, and MMP-3). RESULTS In terms of allele frequencies, rs243849*C (MMP-2) was significantly higher in patients with NODAT. Two of the 11 (18.1%) SNPs were significantly associated with NODAT development after adjusting for age, sex, and tacrolimus usage: MMP-2 (rs1132896) and MMP-2 (rs243849). In the multiple logistic regression analysis, these 2 SNPs were significantly associated with the development of NODAT in the codominant and recessive or codominant and dominant models. CONCLUSIONS MMP-2 gene rs1132896 and rs243849 polymorphisms may serve as genetic markers for the development of NODAT. The exact molecular mechanisms still must be clarified.