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ABSTRACT: INTRODUCTION: Neural stem cells (NSCs) are among the most promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. One of the remaining obstacles for NSCs therapy is to overcome the alloimmune response on NSCs by the host. METHODS: To investigate the mechanisms of immune modulatory function derived from the interaction of human NSCs with allogeneic T cells, we examined the immune regulatory effects of human NSCs on allogeneic T cells in vitro. RESULTS: Significantly, NSCs induced apoptosis of allogeneic T cells, in particular CD4+ T cells. Interaction of CD70 on NSCs and CD27 on CD4+ T cells mediated apoptosis of T cells. Thus, blocking CD70-CD27 interaction prevented NSCs-mediated death of CD4+ T cells. CONCLUSIONS: Here we present a rational explanation of NSCs-induced immune escape in two consecutive stages. First, CD70 constitutively expressed on NSCs engaged CD27 on CD4+ T cells, which induced FasL expression on CD4+ T cells. Second, CD4+ T cell apoptosis was followed by Fas-FasL interaction in the CD4+ T cells.
Stem Cell Research & Therapy 05/2013; 4(3):56. · 3.21 Impact Factor
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ABSTRACT: Retransplantation is common in allogeneic islet transplantation, and therefore, memory responses in previously sensitized recipients present a distinct obstacle for successful islet transplantation. Given the difficulties in controlling memory responses contributing to allograft rejection, it is worth investigating the effects of new immune-modulating agents against islet allograft rejection in the sensitized recipients. In this study, we investigated immune-modulating agents including 5-azacytidine and IL-2/anti-IL-2 complex to ascertain their suppressive effects on memory responses. In suppression assays, rapamycin effectively suppressed the proliferation of memory T cells, whereas 5-azacytidine, a methylation inhibitor suppressed the survival and proliferation of memory T cells. Combination therapy of anti-CD40L, anti-OX40L, and rapamycin slightly prolonged BALB/c islet allograft survival in sensitized C57BL6 mice, and reduced intragraft infiltration of macrophages, T cells, and B cells. However, the addition of IL-2/anti-IL-2 complex, an inducer of regulatory T cells, did not exhibit additional suppression against rejection in sensitized mice. Although a combination of 5-azacytidine and rapamycin markedly suppressed islet allograft rejection in naïve mice, it failed to achieve long-term graft survival even when combined with anti-CD40L and anti-OX40 in sensitized mice. In short, 5-azacytidine-based or IL-2/anti-IL-2 complex-based regimens can suppress islet allograft rejection in naïve recipients, but fail to control islet allograft rejection in sensitized recipients.
Transplant Immunology 01/2013; · 1.46 Impact Factor
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Jin Ho Hwang,
Hayne Cho Park,
Jong Cheol Jeong,
Seon Baek,
Mi Yeun Han,
Kitae Bang,
Jeong Yeon Cho,
Suk Hee Yu, Jaeseok Yang,
Kook-Hwan Oh,
Young-Hwan Hwang,
Curie Ahn
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ABSTRACT: BACKGROUND: Urinary tract infection (UTI) occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD). However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. METHODS: We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. RESULTS: With a mean follow-up duration of 65.3 months, 176 (68.8%) out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01) and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension). The annual change in estimated glomerular filtration rate ([increment]eGFR) was significantly larger in magnitude in group B than in group A (-2.7+/-4.56 vs. -1.17+/-5.8, respectively; P=0.01). Age and Group B found to be the independent variables for [increment]eGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001). CONCLUSIONS: Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.
BMC Nephrology 01/2013; 14(1):1. · 2.18 Impact Factor
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ABSTRACT: BACKGROUND:: Wide variation in tacrolimus concentrations and low tacrolimus exposure have been reported to be associated with poor renal graft outcomes in non-Asians. The CYP3A5 polymorphism is a representative genetic factor that might affect this association, together with environmental factors. We investigated whether tacrolimus variability or the mean tacrolimus trough concentration can influence kidney allograft outcomes in Asians and whether the CYP3A5 polymorphism (rs776746) can affect this relationship. METHODS:: Data from renal transplant patients between 2000 and 2010 were analyzed retrospectively. The tacrolimus intraindividual variability (IIV) and the mean tacrolimus trough concentration were calculated from the tacrolimus concentrations between 6 and 12 months after transplantation. RESULTS:: A total of 249 renal transplant patients were enrolled. The patients with higher tacrolimus IIV had shorter rejection-free survival (P = 0.002). However, there was no difference in rejection-free survival between CYP3A5 expressers and nonexpressers. The tacrolimus IIV was not associated with the CYP3A5 polymorphism. High IIV of tacrolimus was an independent risk factor of biopsy-proven acute rejection after adjusting for mean tacrolimus concentration, HLA mismatch, induction therapy, donor type, and CYP3A5 polymorphism (hazard ratio 2.655, 95% confidence interval 1.394-5.056). Interestingly, the impact of tacrolimus IIV on acute rejection was significant in CYP3A5 expressers, whereas it was not in CYP3A5 nonexpressers. CONCLUSIONS:: The IIV of tacrolimus trough concentrations had a significant impact on rejection-free survival. The effect was influenced by CYP3A5 polymorphism, although the tacrolimus variability itself was not determined by the CYP3A5 polymorphism.
Therapeutic drug monitoring 12/2012; 34(6):680-685. · 2.43 Impact Factor
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Han Ro,
Juho Hong,
Beom Seok Kim,
Eun Won Lee,
Myung-Gyu Kim,
Kyu Hyun Han,
Hye-Jung Yeom,
Eun Mi Lee,
Jong Cheol Jeong,
Kook-Hwan Oh,
Curie Ahn, Jaeseok Yang
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ABSTRACT: BACKGROUND: Toll-like receptors (TLRs) are involved in the rejection of solid organ allografts. However, the roles of TLRs in islets are still controversial. We investigated the roles of TLRs in donor islets together with those in recipients in allogeneic islet transplantation. METHODS: To assess the roles of TLRs in either donor islets or recipients, allogeneic islet transplantation was performed using myeloid differentiation factor 88 (MyD88)-knockout (KO), TLR4-KO, or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-KO mice. RESULTS: Both polyriboinosinic polyribocytidylic acid and lipopolysaccharide (LPS) stimulation induced the mRNA expression of regulated and normal T cell expressed and secreted, interferon-γ-inducible protein-10, monocyte chemotactic protein-1, interleukin-8, and inducible nitric oxide synthase in murine islets, whereas the induction was attenuated in TRIF-KO, interferon-β promoter stimulator-1-KO, and TLR4-KO mice. When islets from MyD88-KO, TLR4-KO, or TRIF-KO C57BL/6 mice were transplanted to BALB/c recipients, graft survival was not better than that of wild-type (WT) islets. However, the survival of the MyD88-KO islet allograft was significantly prolonged when combined with anti-CD40L. In parallel, LPS stimulation in donor islets interfered with anti-CD40L blockade-mediated long-term survival of islet allografts in TLR4-KO recipients. LPS stimulation increased the perigraft infiltration of both T cells and macrophages. Then again, when islets from WT BALB/c mice were transplanted to MyD88-KO, TRIF-KO, or WT C57BL/6 mice, there was no difference in graft survival, although some of the MyD88-KO recipients obtained long-term graft survival. However, anti-CD40L prolonged graft survival significantly in MyD88-KO recipients. The absence of MyD88 in either donors or recipients decreased the perigraft infiltration of inflammatory cells when combined with anti-CD40L. CONCLUSIONS: TLRs in both donor islets and recipients are involved in islet allograft rejection.
Transplantation 11/2012; 94(10):1005-1012. · 4.00 Impact Factor
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Kitae Bang,
Jinuk Jeong,
Jong Ho Shin,
Ju Hyung Kang,
Chang Nam Kim,
Hye-Jung Yeom,
Myeong Ok Yoon, Jaeseok Yang,
Curie Ahn,
Jong-Ik Hwang,
Mee Young Park,
Joo-Heon Kim,
Kang Wook Lee
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ABSTRACT: BACKGROUND: Epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells has been regarded as an early mechanism of peritoneal fibrosis. A substantial and rapidly growing literature indicates that HO-1 provides the provenance for pathways that can interrupt virtually all major mechanisms of tissue injury. The effects of HO-1 expression on EMT, which plays a critical role in the development of peritoneal membrane (PM) fibrosis, are unknown and its roles in peritoneal fibrosis has not been studied, yet. METHODS: A piece of human omentum obtained from consenting patients undergoing elective abdominal surgery was used for study. We treated the human peritoneal mesothelial cells (HPMCs) with high glucose solution and HO-1 inducer (hemin, 10 μmol/L). To further investigate the pure effect of HO-1 on EMT of mesothelium, gene transfer of recombinant Adenovirus-harboring human HO-1 (Adv-HO-1 gene) to HPMCs was done. RESULTS: Exposure of HPMCs to HG solution resulted in an increase of the expression of mesenchymal markers such as α-smooth muscle actin (α-SMA) and was associated with a decrease in the expression of epithelial markers, E-cadherin. HO-1 protein expression was decreased in the same situation. Treatment of HPMCs with HO-1 inducer, hemin showed a dosage-dependent amelioration of HG induced changes in markers of EMT with increase of expression of HO-1. Human HO-1 gene transfection resulted in a significant increase in HO-1 expression and ameliorated HG-induced changes in expression of E-cadherin and α-SMA. CONCLUSION: Taken together, our results suggest that HO-1 has a critical role in the modulation of peritoneal fibrosis, and, more important, the suppression of EMT. This study is the first to show the beneficial effect of HO-1 on reversing EMT in MC.
Clinical and Experimental Nephrology 11/2012; · 1.37 Impact Factor
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Han Ro,
Eun Won Lee,
Joo Ho Hong,
Kyu Hyun Han,
Hye-Jung Yeom,
Hwa Jung Kim,
Myung-Gyu Kim,
Hye Seung Jung,
Kook-Hwan Oh,
Kyong Soo Park,
Curie Ahn, Jaeseok Yang
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ABSTRACT: Although innate immunity plays important roles in xenograft rejection, there have been few studies on the role of toll-like receptors (TLRs) in xenotransplantation. Furthermore, most studies focused on the recipient's TLRs. Therefore, we investigated whether TLRs in porcine islets can contribute to islet xenograft rejection. Adult porcine islets were isolated and stimulated by polyinosinic:polycytidylic acid (Poly I:C) or lipopolysaccharide (LPS). Both Poly I:C and LPS stimulation in porcine islets induced expression of chemokines (RANTES, MCP-1, IP-10, and IL-8), cytokines (IL-6 and type I interferons), and adhesion molecules (VCAM-1 and ICAM-1). Porcine islet supernatants stimulated by TLR agonists induced chemotaxis of human leukocytes. They also induced procoagulant activation (tissue factor and fgl-2). However, TLR stimulation did not influence insulin secretion. When porcine MyD88 was knocked-down using shRNA lentivirus, TLR-mediated induction of proinflammatory mediators and procoagulants was attenuated. When LPS was injected to MyD88 or TLR4 knockout mice after porcine islet transplantation, LPS stimulation on donor islets interfered with islet xenograft tolerance induction by anti-CD154 antibodies. Inflammatory cell infiltration and expression of proinflammatory chemokines and cytokines in islet xenografts also increased. In conclusion, TLR activation in porcine islets induced both a proinflammatory and procoagulant response, and thereby contributed to xenograft rejection.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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Hee Jung Jeon,
Yoon Jung Kim,
Hyuk Yong Kwon,
Tai Yeon Koo,
Seon Ha Baek,
Hyo-Jin Kim,
Woo Seong Huh,
Kyu Ha Huh,
Myoung Soo Kim,
Yu Seun Kim,
Su-Kil Park,
Curie Ahn, Jaeseok Yang
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ABSTRACT: We performed retrospective, multi-center study of the impacts of parathyroidectomy (PTX) after or before kidney transplantation on allograft outcomes. A total of 63 patients who underwent PTX after kidney transplantation were identified. Deterioration in eGFR by more than 25% at 1 month after PTX occurred in 20% of the patients. The baseline eGFR was significantly lower in impairment group than nonimpairment group [adjusted odds ratio (OR) 0.87, 95% confidence interval (CI) 0.77-0.99, P = 0.033]. Low iPTH concentration after PTX was also a significant risk factor for the renal impairment (OR 0.96, CI 0.94-0.99, P = 0.009). A total of 37 patients who underwent PTX before transplantation were identified. Thirty-six percent of the patients had persistent hyperparathyroidism by 1 year after transplantation. A high iPTH level before PTX was a significant risk factor for persistent post-transplant hyperparathyroidism (adjusted OR 1.002, CI 1.000-1.005, P = 0.039). Finally, eGFR values during the first 5 years after transplantation were significantly lower in the patients who underwent PTX at less than 1 year after transplantation, than the pretransplant PTX patients (P = 0.032). As PTX after kidney transplantation has a risk of deterioration of allograft function, pretransplant PTX should be considered for patients with severe hyperparathyroidism, who could undergo post-transplant PTX.
Transplant International 09/2012; · 2.92 Impact Factor
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Hayne Cho Park,
Jin Ho Hwang,
Ah-Young Kang,
Han Ro,
Myung-Gyu Kim,
Jung Nam An,
Ji In Park,
Seung Hyup Kim, Jaeseok Yang,
Yun Kyu Oh,
Kook-Hwan Oh,
Jung Woo Noh,
Hae Il Cheong,
Young-Hwan Hwang,
Curie Ahn
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ABSTRACT: Renal failure is one of the most serious complications associated with autosomal dominant polycystic kidney disease (ADPKD). To date, early markers have failed to predict renal function deterioration at the early stages. This 1-year prospective study evaluated N-acetyl-β-D-glucosaminidase (NAG) as a new surrogate marker for renal function in ADPKD.
A total of 270 patients were enrolled in the study, and we measured urinary NAG, β2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) prospectively for 1 year to compare their predictive values for renal function.
Baseline urinary NAG/Cr was negatively correlated with estimated glomerular filtration rate (GFR) (r2 = 0.153, P < 0.001) and positively correlated with total kidney volume (TKV) (r2 = 0.113, P < 0.001). Among other biomarkers, urinary NAG/Cr better discriminated patients with decreased renal function from those with conserved renal function, showing the largest area under the curve (AUC 0.794). Immunohistochemical study revealed strong staining along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells. However, both single and repeated measurements of urinary NAG/Cr failed to predict renal function decline in 1 year.
Urinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients.
BMC Nephrology 08/2012; 13:93. · 2.18 Impact Factor
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ABSTRACT: The mortality and morbidity of end-stage renal failure patients remains high despite recent advances in pre-dialysis care. Previous studies suggesting a positive effect of pre-dialysis education were limited by unmatched comparisons between the recipients and non-recipients of education. The present study aimed to clarify the roles of the multidisciplinary pre-dialysis education (MPE) in chronic kidney disease patients.
We performed a retrospective single centre study, enrolling 1218 consecutive pre-dialysis chronic kidney disease patients, between July 2007 and Feb 2008 and followed them up to 30 months. By using propensity score matching, we matched 149 recipient- and non-recipient pairs from 1218 patients. The incidences of renal replacement therapy, mortality, cardiovascular event and infection were compared between recipients and non-recipients of MPE.
Renal replacement therapy was initiated in 62 and 64 patients in the recipients and non-recipients, respectively (P > 0.05). The MPE reduced unplanned urgent dialysis (8.7% vs 24.2%, P < 0.001) and shortened hospital days (2.16 vs 5.05 days/patient per year). MPE recipients had a better metabolic status at the time of initiating renal replacement therapy. Although no significant survival advantage from MPE was exhibited, MPE recipients had lower incidence of cardiovascular events (adjusted hazard ratio, 0.24; 95% confidence interval (CI), 0.08 to 0.78; P = 0.017), and a tendency toward a lower infection rate (adjusted hazard ratio, 0.44; 95% CI, 0.17 to 1.11; P = 0.083).
MPE was associated with better clinical outcomes in terms of urgent dialysis, cardiovascular events and infection.
Nephrology 03/2012; 17(5):472-9. · 1.31 Impact Factor
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Hye-Jung Yeom,
Ok Jae Koo, Jaeseok Yang,
Bumrae Cho,
Jong-Ik Hwang,
Sol Ji Park,
Sunghoon Hurh,
Hwajung Kim,
Eun Mi Lee,
Han Ro,
Jung Taek Kang,
Su Jin Kim,
Jae-Kyung Won,
Philip J O'Connell,
Hyunil Kim,
Charles D Surh,
Byeong-Chun Lee,
Curie Ahn
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ABSTRACT: Xenotransplantation using transgenic pigs as an organ source is a promising strategy to overcome shortage of human organ for transplantation. Various genetic modifications have been tried to ameliorate xenograft rejection. In the present study we assessed effect of transgenic expression of human heme oxygenase-1 (hHO-1), an inducible protein capable of cytoprotection by scavenging reactive oxygen species and preventing apoptosis caused by cellular stress during inflammatory processes, in neonatal porcine islet-like cluster cells (NPCCs). Transduction of NPCCs with adenovirus containing hHO-1 gene significantly reduced apoptosis compared with the GFP-expressing adenovirus control after treatment with either hydrogen peroxide or hTNF-α and cycloheximide. These protective effects were diminished by co-treatment of hHO-1 antagonist, Zinc protoporphyrin IX. We also generated transgenic pigs expressing hHO-1 and analyzed expression and function of the transgene. Human HO-1 was expressed in most tissues, including the heart, kidney, lung, pancreas, spleen and skin, however, expression levels and patterns of the hHO-1 gene are not consistent in each organ. We isolate fibroblast from transgenic pigs to analyze protective effect of the hHO-1. As expected, fibroblasts derived from the hHO-1 transgenic pigs were significantly resistant to both hydrogen peroxide damage and hTNF-α and cycloheximide-mediated apoptosis when compared with wild-type fibroblasts. Furthermore, induction of RANTES in response to hTNF-α or LPS was significantly decreased in fibroblasts obtained from the hHO-1 transgenic pigs. These findings suggest that transgenic expression of hHO-1 can protect xenografts when exposed to oxidative stresses, especially from ischemia/reperfusion injury, and/or acute rejection mediated by cytokines. Accordingly, hHO-1 could be an important candidate molecule in a multi-transgenic pig strategy for xenotransplantation.
PLoS ONE 01/2012; 7(10):e46646. · 4.09 Impact Factor
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ABSTRACT: Pyruvate is an endogenous antioxidant and anti-inflammatory substance. The present study was implemented to investigate the protective effect of ethyl pyruvate (EP) against the development and progression of diabetic nephropathy in an in vivo and in vitro model. Diabetic rats were prepared by injecting streptozotocin (65 mg/kg). Those that developed diabetes after 72 h were treated with EP (40 mg/kg) intraperitoneally. Diabetic rats without pyruvate treatment and nondiabetic rats were used for control. As an in vitro experiment, rat mesangial cells cultured primarily from Sprague-Dawley rats were treated in high-glucose (HG; 50 mM) or normal-glucose (NG; 5 mM) conditions and with or without pyruvate. Pyruvate-treated diabetic rats exhibited decreased albuminuria and attenuated NADPH-dependent reactive oxygen species generation. Immunohistochemistry showed reduced laminin, type IV collagen, and fibronectin deposition in the glomeruli compared with nontreated diabetic rats. Parallel changes were shown in tissue mRNA and protein expression levels of monocyte chemoattractant protein-1, transforming growth factor-β1, laminin, fibronectin, and type IV collagen in the kidney. Concordantly, protective effects were also exhibited in the mesangial cell culture system. These findings suggest that pyruvate protects against kidney injury via NADPH oxidase inhibition. The present study established that activation of NADPH oxidase plays a crucial role in diabetes-induced oxidative stress, glomerular hypertrophy, and ECM molecule expression. Pyruvate exhibited a renoprotective effect in the progression of experimental diabetic nephropathy. Future research is warranted to investigate the protective mechanism of pyruvate more specifically in relation to NADPH oxidase in diabetic nephropathy.
AJP Renal Physiology 11/2011; 302(5):F606-13. · 4.42 Impact Factor
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Kyeong Cheon Jung,
Chung-Gyu Park,
Yoon Kyung Jeon,
Hyo Jin Park,
Young Larn Ban,
Hye Sook Min,
Eun Ji Kim,
Ju Hyun Kim,
Byung Hyun Kang,
Seung Pyo Park, [......],
Il-Hee Yoon,
Yong-Hee Kim,
Jae-Il Lee,
Jung-Sik Kim,
Jun-Seop Shin, Jaeseok Yang,
Sung Joo Kim,
Emily Rostlund,
William A Muller,
Seong Hoe Park
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ABSTRACT: Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti-ICAM-1-induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection.
Journal of Experimental Medicine 11/2011; 208(12):2477-88. · 13.85 Impact Factor
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Bumrae Cho,
Ok Jae Koo,
Jong-Ik Hwang,
Hwajung Kim,
Eun Mi Lee,
Sunghoon Hurh,
Sol Ji Park,
Han Ro, Jaeseok Yang,
Charles D Surh,
Anthony J D'Apice,
Byeong Chun Lee,
Curie Ahn
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ABSTRACT: Acute humoral xenograft rejection (AHXR) is an important barrier to xenograft survival. Human tumor necrosis factor-α (hTNF-α) is one of the essential mediators of AHXR and induces activation of porcine endothelial cells (PECs), resulting in upregulation of major histocompatibility complex molecules, adhesion molecules, and proinflammatory chemokines. We investigated whether introduction of a soluble human tumor necrosis factor receptor I-Fc (shTNFRI-Fc) fusion gene can suppress activation of PECs and, more importantly, produced shTNFRI-Fc transgenic pigs.
The shTNFRI-Fc gene expression vector was constructed and inserted into PECs. The inhibitory effects of shTNFRI-Fc were tested by luciferase assay, reverse-transcriptase polymerase chain reaction, and flow cytometry. A shTNFRI-Fc transgenic pig was generated by somatic cell nuclear transfer. The expression of shTNFRI-Fc in the transgenic pig was evaluated by PCR, western blot, enzyme-linked immunosorbent assay, and immunohistochemistry. The inhibitory effects of shTNFRI-Fc in the serum obtained from the transgenic pig were also tested.
In comparison with control green fluorescent protein, shTNFRI-Fc protein showed much stronger inhibitory effects on NF-κB activation in the HEK293-NF-κB-luciferase reporting cell line, expression of chemokines and adhesion molecules in PECs, and TNF-α-mediated cytotoxicity. We successfully generated shTNFRI-Fc transgenic pig. Sera obtained from the transgenic pig inhibited induction of chemokines, and E-selectin in PECs stimulated with Human TNF-α.
We have generated transgenic pigs producing shTNFRI-Fc protein that can inhibit TNF-α-mediated activation of PECs. Because TNF-α is an important mediator of xenograft rejection, the use of xenografts that can produce shTNFRI-Fc proteins de novo could be an effective approach in overcoming a considerable component of the xenograft rejection process, especially AHXR.
Transplantation 06/2011; 92(2):139-47. · 4.00 Impact Factor
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ABSTRACT: Although both embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) are known to have immunosuppressive effects, the mechanisms of immunosuppression are still controversial. Both types of stem cells suppressed not only the proliferation but also survival of CD4(+) T cells in vitro. They suppressed secretion of various cytokines (IL-2, IL-12, IFN-γ, TNF-α, IL-4, IL-5, IL-1β, and IL-10), whereas there was no change in the levels of TGF-β or IDO. Classic and modified transwell experiments demonstrated that immunosuppressive activities were mainly mediated by cell-to-cell contact. Granzyme B in the ESCs played a significant role in their immunosuppression, whereas PDL-1, Fas ligand, CD30 or perforin was not involved in the contact-dependent immunosuppression. However, none of the above molecules played a significant role in the immunosuppression by the MSCs. Interestingly, both stem cells increased the proportion of Foxp3(+) regulatory T cells. Our results showed that both ESCs and MSCs suppressed the survival as well as the proliferation of T cells by mainly contact-dependent mechanisms and increased the proportion of regulatory T cells. Granzyme B was involved in immunosuppression by the ESCs in a perforin-independent manner.
Transplant Immunology 05/2011; 25(1):7-15. · 1.46 Impact Factor
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Jong Cheol Jeong,
Young-Hwan Hwang,
Hyosang Kim,
Han Ro,
Hayne Cho Park,
Yoon Jung Kim,
Myung-Gyu Kim,
Jongwon Ha,
Myoung Hee Park,
Dong Wan Chae,
Curie Ahn, Jaeseok Yang
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ABSTRACT: Complements play important roles in both rejection and ischemia-reperfusion injury after transplantation. Complement 5 (C5) is a pivotal complement, which initiates the assembly of the membrane attack complex, and mediates chemotaxis of various immune cells. We investigated the impacts of genetic variations in C5 and its receptor (C5aR) of both recipients and donors on renal allograft outcomes.
Seven single-nucleotide polymorphisms (SNPs) in C5 (rs12237774, rs2159776, rs17611, rs25681, rs2241004, rs10985126 and rs10818500) and one SNP (rs10404456) in the C5aR gene were genotyped in 191 recipient-donor pairs. The association of the polymorphisms with allograft outcomes was determined.
Three C5 SNPs (rs2159776, rs17611 and rs25681) in recipients had a tendency toward a reduced glomerular filtration rate at 1 year after transplantation. There were four haplotypes in the H2 linkage disequilibrium block, which was formed by four SNPs (rs2159776, rs17611, rs25681 and rs2241004). The GGCG haplotype in both recipients and donors was associated with lower glomerular filtration rate at 1 year (60.9 ± 15.9 versus 66.4 ± 15.5 mL/min/1.73 m(2), P = 0.020; 60.6 ± 15.3 versus 66.2 ± 15.8 mL/min/1.73 m(2), P = 0.017). The association was sustained over 7 years after transplantation (P = 0.015 in recipients; P = 0.039 in donors). The presence of the GGCG haplotype in recipients was associated with poorer graft survival (logrank test, P = 0.024). However, C5 polymorphisms were not correlated with serum C5 level. C5aR polymorphism had no significant impact on the allograft outcomes.
The GGCG haplotype of C5 in both recipients and donors was associated with lower renal allograft function.
Nephrology Dialysis Transplantation 03/2011; 26(10):3378-85. · 3.40 Impact Factor
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Han Ro,
Young-Hwan Hwang,
Hyunsook Kim,
Jong Cheol Jeong,
Hankyu Lee,
Young-Seok Doh,
Hayne Cho Park,
Kook-Hwan Oh,
Myoung Hee Park,
Jongwon Ha, Jaeseok Yang,
Curie Ahn
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ABSTRACT: Background. Both chemokines and adhesion molecules mediate allograft rejection by recruiting leukocytes into the allograft. We investigated the association of six single nucleotide polymorphisms (SNPs) located in interleukin (IL)-8, CXCR1, CXCR2, and selectin with kidney allograft outcomes.
Methods. The promoter regions of CXCR1 and CXCR2 were sequenced directly to find SNPs. Reporter gene assay was performed to determine the transcriptional activity of CXCR2 promoter polymorphisms. The association of SNPs in IL-8, CXCR1, CXCR2, and selectin with both acute rejection and estimated glomerular filtration rate at 1-year posttransplant was analyzed in 216 donor-recipient pairs of kidney transplantation.
Results. The donor GA/AA genotypes of CXCR1 −2668G/A (rs2671222) were associated with increased risk for acute rejection even after adjusting for covariates such as gender, diabetes, preemptive transplantation, immunosuppressive regimen, relationship with the donor, and human leukocyte antigen mismatch (adjusted odds ratio 3.56; 95% confidence interval 1.37–9.27; P=0.009). Although the transcriptional activity of the CXCR2 variant promoter was 2.6-fold higher than that of the wild-type promoter (P=0.039), no significant association was observed between CXCR2 polymorphisms and kidney allograft outcomes. SNPs of IL-8, L-selectin, and E-selectin were not associated with kidney allograft outcomes.
Conclusion. The donor CXCR1 −2668 GA/AA genotypes were an independent risk factor for acute rejection in kidney transplantation.
Transplantation 01/2011; 91(1):57-64. · 4.00 Impact Factor
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Han Ro,
Young-Hwan Hwang,
Hyunsook Kim,
Jong Cheol Jeong,
Hankyu Lee,
Young-Seok Doh,
Hayne Cho Park,
Kook-Hwan Oh,
Myoung Hee Park,
Jongwon Ha, Jaeseok Yang,
Curie Ahn
[show abstract]
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ABSTRACT: Both chemokines and adhesion molecules mediate allograft rejection by recruiting leukocytes into the allograft. We investigated the association of six single nucleotide polymorphisms (SNPs) located in interleukin (IL)-8, CXCR1, CXCR2, and selectin with kidney allograft outcomes.
The promoter regions of CXCR1 and CXCR2 were sequenced directly to find SNPs. Reporter gene assay was performed to determine the transcriptional activity of CXCR2 promoter polymorphisms. The association of SNPs in IL-8, CXCR1, CXCR2, and selectin with both acute rejection and estimated glomerular filtration rate at 1-year posttransplant was analyzed in 216 donor-recipient pairs of kidney transplantation.
The donor GA/AA genotypes of CXCR1 -2668G/A (rs2671222) were associated with increased risk for acute rejection even after adjusting for covariates such as gender, diabetes, preemptive transplantation, immunosuppressive regimen, relationship with the donor, and human leukocyte antigen mismatch (adjusted odds ratio 3.56; 95% confidence interval 1.37-9.27; P=0.009). Although the transcriptional activity of the CXCR2 variant promoter was 2.6-fold higher than that of the wild-type promoter (P=0.039), no significant association was observed between CXCR2 polymorphisms and kidney allograft outcomes. SNPs of IL-8, L-selectin, and E-selectin were not associated with kidney allograft outcomes.
The donor CXCR1 -2668 GA/AA genotypes were an independent risk factor for acute rejection in kidney transplantation.
Transplantation 01/2011; 91(1):57-64. · 4.00 Impact Factor
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Ji Yong Jung,
Young-Hwan Hwang,
Seong-Woo Lee,
Hajeong Lee,
Dong Ki Kim,
Sejoong Kim,
Yun Gyu Oh, Jaeseok Yang,
Kwon Wook Joo,
Curie Ahn,
Kook-Hwan Oh
[show abstract]
[hide abstract]
ABSTRACT: An increase in aortic stiffness, as reflected by an increase in pulse wave velocity (PWV), is an important predictor of cardiovascular mortality in dialysis patients. Decreased serum concentration of calcification inhibitor, such as fetuin-A, is inversely related to mortality in haemodialysis patients. Our aim is to investigate the factors associated with aortic stiffness and its change over time in peritoneal dialysis (PD) patients.
As a prospective observational study, we analysed 67 PD patients, aged 50 ± 14 years (mean ± SD) and with dialysis duration of 26 (5-58) months (median, interquartile range). At baseline, age, mean arterial pressure (MAP), left ventricular mass (LVM) index, diabetes, serum albumin, calcium (Ca), phosphorus (P) and intact parathyroid hormone (iPTH), uric acid, total bilirubin, high-sensitivity C-reactive protein (hsCRP), fetuin-A, and residual renal function were included in association analysis with aortic stiffness represented by heart-to-femoral PWV (hfPWV). We also evaluated simple vascular calcification score (SVCS) with plain radiograph of the pelvis and both hands. PWV was measured both at baseline and at 1 year. Change of aortic stiffness was determined by △PWV (difference between 1-year PWV and baseline PWV). Time-averaged concentrations were used to evaluate the relation between biologic markers and changes of aortic stiffness.
hfPWV was 1022 ± 276 cm/s at baseline, and hfPWV determined at 1 year was 1069 ± 317 cm/s. Mean serum fetuin-A concentration was 0.34 ± 0.08 g/L. At baseline, aortic PWV positively correlated with age, smoking status, diabetes, MAP, total cholesterol and LDL cholesterol. On the other hand, aortic PWV inversely correlated with fetuin-A, log PTH, haemoglobin and albumin. In a multiple regression model, association of serum fetuin-A (β = -0.329, P = 0.003) with aortic PWV remained significant, along with age (β = 0.512, P < 0.001), MAP (β = 0.215, P = 0.047) and log PTH (β = -0.269, P = 0.025). At follow-up, △MAP (β = 0.500, P < 0.001) and time-averaged TG (aTG) (β = 0.259 P = 0.019) were determinants of △PWV.
For our PD patients, serum fetuin-A was an independent determinant of aortic stiffness, as well as age, MAP and log PTH. Although 1 year is not sufficient to observe the change of aortic stiffness, some patients exhibited >15% increase of PWV during this period. △MAP and aTG were factors affecting the change of PWV. Follow-up over a longer period is necessary to elucidate factors that determine changes of aortic stiffness over time from PD patients.
Nephrology Dialysis Transplantation 12/2010; 25(12):4041-8. · 3.40 Impact Factor
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Kitae Bang,
Han Kyu Lee,
Wooseong Huh,
Yu-ji Lee,
Byun Seung Woon,
Han Ro,
Young-Hwan Hwang,
Jongwon Ha,
Myoung Hee Park,
Sung-Joo Kim,
Su-Kil Park,
Ha-Young Oh, Jaeseok Yang,
Curie Ahn
[show abstract]
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ABSTRACT: Marginal grafts should be used more actively in Asian countries where deceased donor transplantation is unpopular. We modified a quantitative donor scoring system proposed by Nyberg and his colleagues and developed a donor scoring system in order to assess the quality of deceased donor grafts and their prognostic value as an initial effort to promote usage of marginal donors.
We retrospectively evaluated 337 patients.
A scoring system was derived from six donor variables [age, 0-25; renal function, 0-4; history of hypertension, 0-4; Human Leukocyte Antigen (HLA) mismatch, 0-3; body weight, 0- 1; cause of death, 0-3 points]. Donor grafts were stratified by scores: grade A, 0-10; grade B, 11-20; grade C, 21-30; and grade D, 31-40 points. Donor grades significantly correlated with estimated glomerular filtration rate (eGFR) at 6 months (A, 64.0 mL/min/1.73 m(2); B, 57.0 mL/min/1.73 m(2); C, 46.8 mL/min/1.73 m(2); p < 0.001). The five-year graft survival rate was also lower in grade C than grade A (74% vs. 93%, p = 0.002). Donors in grade C and D were regarded as marginal donors. The proportion of marginal donors was much lower in Korea, compared with data from the United Network for Organ Sharing (15.2% vs. 29%).
Considering the scarcity of deceased donor kidneys and the relatively better graft outcome with lower grade-donors in Korea, it is worth increasing the usage of marginal grafts.
Yonsei medical journal 11/2010; 51(6):870-6. · 0.77 Impact Factor
