Seog Woon Kwon

The effect of VEGF on the myogenic differentiation of adipose tissue derived stem cells within thermosensitive hydrogel matrices.

We investigated the combination of human adipose tissue derived stem cells (ADSC) and in vivo gel-forming methoxy poly (ethyleneglycol)-poly (epsilon-caprolactone) (MPEG-PCL) as a muscle regeneration matrix, with and without inclusion of vascular endothelial cell growth factor (VEGF). VEGF(165)-treated stem cell grafts showed significant proliferation and differentiation into muscle tissue in vivo. Importantly, the inclusion of VEGF enhanced vascularization. This scaffold supported preconditioned ADSC, and allowed them to differentiate into mature muscle tissues in vivo, indicating that ADSC of human origin and MPEG-PCL scaffolds provided an appropriate environment for cellular growth and expansion. Our results thus provide a potential solution to the major obstacle encountered in the engineering of thick complex tissues, which require an adequate blood supply to maintain cell viability during tissue growth and to induce appropriate structural organization. Therefore, the combination of ADSC and in vivo gel-forming MPEG-PCL with VEGF(165) might serve as a suitable non-invasive biomaterial for clinical muscle regeneration applications.

Haploidentical haematopoietic stem cell transplantation using CD3 or CD3/CD19 depletion and conditioning with fludarabine, cyclophosphamide and antithymocyte globulin for acquired severe aplastic anaemia

Fitzgibbon, J., Iqbal, S., Davies, A., O’Shea, D.,Carlotti, E., Chaplin, T., Matthews, J., Raghavan,M., Norton, A., Lister, T.A. & Young, B.D.(2007) Genome-wide detection of recurring sitesof uniparental disomy in follicular and trans-formed follicular lymphoma. Leukemia, 21,1514–1520.Mao, Z., Quintanilla-Martinez, L., Raffeld, M.,Richter, M., Krugmann, J., Burek, C., Hartmann,E., Rudiger, T., Jaffe, E.S., Muller-Hermelink,H.K., Ott, G., Fend, F. & Rosenwald, A. (2007)IgVH mutational status and clonality analysis ofRichter’s transformation: diffuse large B-celllymphoma and Hodgkin lymphoma in associa-tion with B-cell chronic lymphocytic leukemia(B-CLL) represent 2 different pathways of diseaseevolution. American Journal of Surgical Pathology,31, 1605–1614.Rossi, D. & Gaidano, G. (2009) Richter syndrome:molecular insights and clinical perspectives.Hematologcal Oncology ,27, 1–10.Scandurra, M., Rossi, D., Deambrogi, C., Rancoita,P.M., Chigrinova, E., Mian, M., Cerri, M., Rasi,S., Sozzi, E., Forconi, F., Ponzoni, M., Moreno,S.M., Piris, M.A., Inghirami, G., Zucca, E., Gattei,V., Rinaldi, A., Kwee, I., Gaidano, G. & Bertoni,F. (2010) Genomic profiling of Richter’ssyndrome: recurrent lesions and differences withde novo diffuse large B-cell lymphomas. Hema-tologcal Oncology, 28, 62–67.Smit, L.A., van Maldegem, F., Langerak, A.W., vander Schoot, C.E., de Wit, M.J., Bea, S., Campo,E., Bende, R.J. & van Noesel, C.J. (2006) Anti-gen receptors and somatic hypermutation inB-cell chronic lymphocytic leukemia with Rich-ter’s transformation. Haematologica 91, 903–911.Timar, B., Fulop, Z., Csernus, B., Angster, C., Bog-nar, A., Szepesi, A., Kopper, L. & Matolcsy, A.(2004) Relationship between the mutational sta-tus of VH genes and pathogenesis of diffuse largeB-cell lymphoma in Richter’s syndrome. Leuke-mia, 18, 326–330.

Establishment of a national on-line registry for apheresis in Korea.

National apheresis registries can be used to evaluate changes in technology, clinical indications, and applications over the years. Since the establishment of the Korean Society of Apheresis (KSFA) in 1999, basic data on the status of apheresis have been collected using letters and e-mails on a biennial basis. In February 2006, a KSFA homepage and an on-line apheresis registry were constructed (http://www.apheresis.or.kr/). The registry consists of two sub-registries, one addressing overall aspects, e.g., the numbers and types of apheresis machines, total numbers of apheresis procedures, and the other addressing therapeutic plasmapheresis, e.g., diagnoses, modes of treatment, instrument used, replacement fluids, volumes processed, vascular access, anticoagulants, complications, and clinical responses. Data registered on-line is presumed to represent about 95% of total apheresis procedures performed in Korea. In this report, we introduce our on-line registry system and compared the data obtained by on-line registry with the previous ones.

Current status of therapeutic plasma exchange in Korea

Abstract:  A nationwide survey on the status of plasma exchange in Korea was performed during the 2 year period 2001–02. Data from 496 patients were collected from 15 major hospitals. The most common indication was myasthenia gravis (15.3%), followed by thrombotic thrombocytopenic purpura (14.5%) and hemolytic uremic syndrome (9.7%). Clinical improvement was noted in 70.1% of the 415 cases. Plasma exchange by centrifugation alone accounted for 92.4%. Postcentrifugal filtration was carried out in 5.6% and double filtration in 2.0% of treatments. The most common instruments for the centrifugation were Cobe Spectra (71.3%) and Fenwal CS3000 (15.8%). Filtration was performed by either Kuraray KM8300 or Kuraray KM8800. The overall frequency of complications was 11.1% (293/2647 cases), of which symptomatic hypocalcemia was the most common (2.3%).

Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis

Eosinophils play a major pathologic role in the pathogenesis of diverse inflammatory diseases including chronic rhinosinusitis (CRS). Dysregulated production of prostaglandin (PG), particularly PGD2, is considered to be an important contributing factor to eosinophilic inflammation in CRS primarily through proinflammatory and chemotactic effects on eosinophils. Here, we provide evidence that PGD2 can promote eosinophilic inflammation through a suppression of Natural killer (NK) cell effector function and NK cell-mediated eosinophil regulation. Eosinophil apoptosis mediated by NK cells was significantly decreased in CRS patients compared with healthy controls. This decrease was associated with NK cell dysfunction and eosinophilic inflammation. Tissue eosinophils were positively correlated with blood eosinophils in CRS patients. In a murine model of CRS, NK cell depletion caused an exacerbation of blood eosinophilia and eosinophilic inflammation in the sinonasal tissue. PGD2 and its metabolite, but not PGE2 and a panel of cytokines including TGF-β, were increased in CRS patients compared with controls. Effector functions of NK cells were potently suppressed by PGD2-dependent, rather than PGE2-dependent, pathway in controls and CRS patients. Thus, our results suggest decreased NK cell-mediated eosinophil regulation, possibly through an increased level of PGD2, as a previously unrecognized link between PG dysregulation and eosinophilic inflammation in CRS.

Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1- independent mechanism

The assessment of the biological activity of capsaicin, the compound responsible for the spicy flavor of chili pepper, produced controversial results, showing either carcinogenicity or cancer prevention. The innate immune system plays a pivotal role in cancer pathology and prevention; yet, the effect of capsaicin on natural killer (NK) cells, which function in cancer surveillance, is unclear. This study found that capsaicin inhibited NK cell-mediated cytotoxicity and cytokine production (interferon-γ and tumor necrosis factor-α). Capsaicin impaired the cytotoxicity of NK cells, thereby inhibiting lysis of standard target cells and gastric cancer cells by modulating calcium mobilization in NK cells. Capsaicin also induced apoptosis in gastric cancer cells, but that effect required higher concentrations and longer exposure times than those required to trigger NK cell dysfunction. Furthermore, capsaicin inhibited the cytotoxicity of isolated NK cells and of an NK cell line, suggesting a direct effect on NK cells. Antagonists of transient receptor potential vanilloid subfamily member 1 (TRPV1), a cognate capsaicin receptor, or deficiency in TRPV1 expression failed to prevent the defects induced by capsaicin in NK cells expressing functional TRPV1. Thus, the mechanism of action of capsaicin on NK cells is largely independent of TRPV1. Taken together, capsaicin may have chemotherapeutic potential but may impair NK cell function, which plays a central role in tumor surveillance.

NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3β

Activation of NK cells is triggered by combined signals from multiple activating receptors that belong to different families. Several NK cell activating receptors have been identified, but their role in the regulation of effector functions is primarily understood in the context of their individual engagement. Therefore, little is known about the signaling pathways broadly implicated by the multiple NK cell activation cues. Here we provide evidence pointing to glycogen synthase kinase (GSK)-3β as a negative regulator of multiple NK cell activating signals. Using an activation model that combines NKG2D and 2B4 and tests different signaling molecules, we found that GSK-3 undergoes inhibitory phosphorylation at regulatory serine residues by the engagement of NKG2D and 2B4, either individually or in combination. The extent of such phosphorylation was closely correlated with the degree of NK cell activation. NK cell functions, such as cytokine production and cytotoxicity, were consistently enhanced by the knockdown of GSK-3β or its inhibition with different pharmacological inhibitors, whereas inhibition of the GSK-3α isoform had no effect. In addition, NK cell function was augmented by the overexpression of a catalytically inactive form of GSK-3β. Importantly, the regulation of NK cell function by GSK-3β was common to diverse activating receptors that signal through both ITAM and non-ITAM pathways. Thus, our results suggest that GSK-3β negatively regulates NK cell activation and that modulation of GSK-3β function could be used to enhance NK cell activation.

Evaluation of parameters obtained from the Sysmex XN-2000 for predicting the recovery of the absolute neutrophil count and platelets after hematopoietic stem cell transplantation

We analyzed abilities of parameters from Sysmex XN‐2000 (Sysmex, Kobe, Japan) to predict absolute neutrophil count (ANC) and platelet recovery after hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies.

Reconstitution of T and NK cells after haploidentical hematopoietic cell transplantation using αβ T cell-depleted grafts and the clinical implication of γδ T cells

To investigate reconstitution of T and NK cells after αβ T lymphocyte–depleted haploidentical hematopoietic cell transplantation (HHCT) and the clinical implications of γδ T cells, we analyzed 50 pediatric patients who received 55 HHCTs using αβ T cell–depleted grafts. The number of CD3+ T cells and CD8+ T cells recovered rapidly and reached donor levels at days 180 and 60, respectively. Recovery of NK cells was rapid, and the median of NK cells at day 14 was comparable to the donor level. At day 14, median percentage of γδ T lymphocytes was 70.5%. After day 14, the percentage of γδ T cells gradually decreased, while the percentage of αβ T cells gradually increased. Patients with a low percentage (≤21%) of γδ T cells at day 30 had significantly higher incidence of cytomegalovirus (CMV) reactivation compared to patients with a high percentage (>70%) of γδ T cells (P < .01). In patients with acute leukemia, patients with high percentage of γδ T cells at day 30 showed significantly higher relapse‐free survival compared to those with low percentage of γδ T cells (P = .02). Data suggest that early recovery of γδ T cells decreases the risk of CMV reactivation and leukemia relapse.