• IMMUNE NETWORK
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• 제3권4호
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• pp.302-309
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• 2003

Background: CTLA4 (CD152), which is expressed on the surface of T cells following activation, has a much higher affinity for B7 molecules comparing to CD28, and is a negative regulator of T cell activation. In contrast to stimulating and agonistic capabilities of monoclonal antibodies specific to CTLA-4, CTLA4Ig fusion protein appears to act as CD28 antagonist and inhibits in vitro and in vivo T cell priming in variety of immunological conditions. We've set out to confirm whether inhibition of the CD28-B7 costimulatory response using a soluble form of human CTLA4Ig fusion protein would lead to persistent inhibition of alloreactive T cell activation. Methods: We have used CHO-$dhfr^-$ cell-line to produce CTLA4Ig fusion protein. After serum free culture of transfected cell line we purified this recombinant molecule by using protein A column. To confirm characterization of fusion protein, we carried out a series of Western blot, SDS-PAGE and silver staining analyses. We have also investigated the efficacy of CTLA4Ig in vitro such as mixed lymphocyte reaction (MLR) & cytotoxic T lymphocyte (CTL) response and in vivo such as experimental autoimmune encephalomyelitis (EAE), graft versus host disease (GVHD) and skin-graft whether this fusion protein could inhibit alloreactive T cell activation and lead to immunosuppression of activated T cell. Results: In vitro assay, CTLA4Ig fusion protein inhibited immune response in T cell-specific manner: 1) Human CTLA4Ig inhibited allogeneic stimulation in murine MLR; 2) CTLA4Ig prevented the specific killing activity of CTL. In vivo assay, human CTLA4Ig revealed the capacities to induce alloantigen-specific hyporesponsiveness in mouse model: 1) GVHD was efficiently blocked by dose-dependent manner; 2) Clinical score of EAE was significantly decreased compared to nomal control; 3) The time of skin-graft rejection was not different between CTLA4Ig treated and control group. Conclusion: Human CTLA4Ig suppress the T cell-mediated immune response and efficiently inhibit the EAE, GVHD in mouse model. The mechanism of T cell suppression by human CTLA4Ig fusion protein may be originated from the suppression of activity of cytotoxic T cell. Human CTLA4Ig could not suppress the rejection in mouse skin-graft, this finding suggests that other mechanism except the suppression of cytotoxic T cell may exist on the suppression of graft rejection.

• 대한한방부인과학회지
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• 제23권2호
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• pp.71-84
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• 2010

Purpose: In the theory of traditional medicine, Glenditsia spina(GS) can resolve carbuncle, relive swelling, dispel wind and destroy parasites. This study was designed to investigate the effects of GS on gene expression of ovarian tissue in polycystic ovary syndrome(PCOS) rats. Methods: In this experiment, female rats injected with a single dose of 2 mg estradiol valerate(EV) and GS was given for 5 weeks. The genetic profile for the effects on ovarian tissue in PCOS rats was measured using microarray technique, and the functional analysis on these genes was conducted. Results: 985 genes were increased in control and restored to normal level in GS group. (B), 733 genes were decreased in control group and restored to normal level in GS group. (F). Metabolic pathways related in B group genes were Graft-versus-host disease, Allograft rejection, Autoimmune thyroid disease, Cytokine-cytokine receptor interaction, Small cell lung cancer, Type I diabetes mellitus. Metabolic pathways related in F group genes were Antigen processing and present, Adipocytokine signalling pathway, Focal adhesion, ECM-receptor interaction, Pancreatic cancer, Notch signalling pathway, Tight junction. The network of total protein interactions was measured using cytoscape program, and some key molecules, such as c-Fos, c-Myc, ABL1 related in B group, MAPK8, RASA1, CALR related in F group that can be used for elucidation of therapeutical mechanism of medicine in future were identified. Conclusion: These results suggest possibility of GS as anti-cancer and anti-hyperplasia drug in PCOS. In addition, the present author also suggests that related mechanisms are involved in suppression of proto-oncogene such as c-Fos, c-Myc and ABL1, and in regulation of cell cycle such as RASA1.

• Journal of Dental Anesthesia and Pain Medicine
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• 제17권3호
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• pp.163-181
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• 2017

In the field of orofacial surgery, a red blood cell transfusion (RBCT) is occasionally required during double jaw and oral cancer surgery. However, the question remains whether the effect of RBCT during the perioperative period is beneficial or harmful. The answer to this question remains challenging. In the field of orofacial surgery, transfusion is performed for the purpose of oxygen transfer to hypoxic tissues and plasma volume expansion when there is bleeding. However, there are various risks, such as infectious complications (viral and bacterial), transfusion-related acute lung injury, ABO and non-ABO associated hemolytic transfusion reactions, febrile non-hemolytic transfusion reactions, transfusion associated graft-versus-host disease, transfusion associated circulatory overload, and hypersensitivity transfusion reaction including anaphylaxis and transfusion-related immune-modulation. Many studies and guidelines have suggested RBCT is considered when hemoglobin levels recorded are 7 g/dL for general patients and 8-9 g/dL for patients with cardiovascular disease or hemodynamically unstable patients. However, RBCT is occasionally an essential treatment during surgeries and it is often required in emergency cases. We need to comprehensively consider postoperative bleeding, different clinical situations, the level of intra- and postoperative patient monitoring, and various problems that may arise from a transfusion, in the perspective of patient safety. Since orofacial surgery has an especially high risk of bleeding due to the complex structures involved and the extensive vascular distribution, measures to prevent bleeding should be taken and the conditions for a transfusion should be optimized and appropriate in order to promote patient safety.

• Clinical and Experimental Pediatrics
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• 제53권4호
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• pp.538-547
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• 2010

목 적 : 본 연구의 목적은 소아백혈병 환자에서 이식 전처치로서 전신방사선조사(total body irradiation, TBI)군과 비방사선조사(non-TBI)군과의 이식 성적 및 예후를 비교하고자 하였다. 방 법: 1996년 1월에서 2007년 12월까지 전남대학교병원에서 조혈모세포이식을 시행 받은 소아백혈병 환자 77명을 TBI군(n=40)과 non-TBI군(n=37)으로 나누어 각 군 간의 이식 유형, 이식 시 질병상태, 전처치 방법, 이식 세포 수, 생착 속도, 이식편대숙주반응(graft-versus-host disease, GVHD)의 발생빈도, 이식 합병증, 사망원인, 전체생존율(overall survival, OS)과 무사건생존율(event free survival, EFS) 및 후기 합병증을 비교 분석하였다. 결 과 : 급성림프구성백혈병(acute lymphoblastic leukemia, ALL) 환자의 82.4% (28/34)는 TBI를 받았고, 골수계열 백혈병 환자의 72.7% (24/33)는 non-TBI 군이었다. 전체 환자를 대상으로 TBI 여부에 따른 5년 EFS은 두 군간 차이는 없었으나 (62% vs. 63%), ALL 환자에서는 TBI군이 non-TBI군에 비해 통계적으로 유의하게 우수한 5년 EFS을 보였다(65% vs. 17%; $P$=0.005). AML (acute myelogenous leukemia) 환자에서는 non-TBI군이 TBI군보다 더 높은 5년 EFS을 보였으나 통계적인 유의성은 없었다(73% vs. 38 %; $P$=0.089). GVHD 발생률, 생착, 사망원인과 후기 합병증은 두 군간 차이는 없었다. 결 론 : 전처치로서 TBI군과 non-TBI군은 비슷한 결과를 보였으나, ALL환자에서는 TBI군이 non-TBI군에 비하여 유의하게 우수한 5년 EFS을 보였다. 두 군간 후기 합병증의 발생 및 사회경제적 삶의 질을 비교하기 위하여는 많은 환자를 대상으로한 전향적 무작위 연구가 필요하리라 사료된다.

• Tuberculosis and Respiratory Diseases
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• 제49권2호
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• pp.207-216
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• 2000

연구배경 : 동종골수이식은 난치성 혈액질환의 효과적인 치료법이나 약 40%에서 치료와 관련된 합병증으로 사망하고, 그중 10-40%가 폐합병증이 주된 사인이므로 폐합병증의 발생유무는 동종골수이식 치료성적에 중요한 영향을 미친다. 국내에서는 이식편대숙주질환이 서구보다 적고 CMV감염률이 높아 폐합병중이 서구와는 다른 양상으로 나타나리라 사료되어 국내에서 동종 골수이식 후 발생한 폐합병증의 임상양상을 알아보고자 본 연구를 시행하였다. 방법 : 1993년 12월부터 1999년 5월까지 서울중앙병원에서 동종골수이식을 시행한 100명의 성인환자를 대상으로 후향적 코호트법으로 연구하였다. 패합병증은 발생시기에 따라 골수가 생착하는 시기인 30일 전후로 나누고 다시 병인에 따라 감염성 혹은 비감염성으로 분류하였다. 감염성 합병증은 혈액이나 BAL액, 흉막액, 객담검사등에서 병원체가 증명된 경우에서나 임상적으로 감염성 합병증이 의심되는 경우에서 항균제 혹은 항진균제를 사용하여 임상적, 방사선학적 호전이 있는 경우로 정의하였다. 결과 : 1) 폐합병증은 100명중 54명에서 83건이 발생하였다. 2) 30일 이전에는 비감염성 합병증이, 30일 이후에는 감염성 합병증이 더 많이 발생 하였고, 기저질환이 재발되거나 만성 이식편대숙주질환이 없으면 1년 이후에는 감염성 합병증은 발생하지 않았다. 3) 비감염성 합병증으로는 흉막액이 27건으로 가장 많았고, 그 외 비감염성 합병증으로는 폐부종 8건, 미만성 폐포출혈 1 건, BO 2건, BOOP 1건이 있었다. 4) 감염성 합병증은 세균성 폐렴 9 건, 바이러스성 폐렴 4건, 폐결핵 3건, PCP 1건, 진균성 폐렴 5건, 결핵성 흉막염 3건이 있었다. 5) CMV감염과 호중구 회복지연은 폐합병증과 관련된 위험인자로 확인되었다. 6) 폐합병증이 발생한 경우 동종골수이식 후 사망률이 유의하게 높았다. 결론 : 동종골수이식 후 폐합병증은 54%에서 발생하였고, 폐합병증이 발생한 경우에 이식 후 사망률이 증가하였다.

• Clinical and Experimental Pediatrics
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• 제55권3호
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• pp.93-99
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• 2012

Purpose: This study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD). Methods: This retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41). Results: Neutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD ($p$ <0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; $p$=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; $p$ <0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; $p$ <0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; $p$ <0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; $p$=0.04). Conclusion: Survival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative.

• Clinical and Experimental Pediatrics
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• 제55권3호
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• pp.100-106
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• 2012

Purpose: The survival rate for childhood acute lymphoblastic leukemia (ALL) has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR). Methods: Fifty-three ALL patients (42 men, 79%) who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%). Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD), relapse, 1-year transplant-related mortality (TRM), disease-free survival (DFS), and overall survival (OS). Results: Cumulative incidences of acute GVHD (grade 2 or above) and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was $45.2{\pm}6.8%$ and $48.3{\pm}7%$, respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis ($p$=0.010). The rates of relapse and 1 year TRM were $28.9{\pm}6.4%$ and $26.4{\pm}6.1%$, respectively, and unrelated donor HSCT ($p$=0.002) and HLA mismatch ($p$=0.022) were significantly correlated with increased TRM in univariate analysis. Conclusion: In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

• 한국임상약학회지
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• 제20권3호
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• pp.193-199
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• 2010

Tacrolimus, an immunosuppressant prescribed against graft-versus-host disease (GVHD) in patients with allogeneichematopoietic stem cell transplantation (HSCT), is affected to change its pharmacokinetic properties by various factors. For this reason, it is needed a close monitoring to adjust dosage amount in order to optimize the blood concentration of tacrolimus is located within the effective range. According to our in-house study, 62% of HSCT-patients were needed dosage-adjustment and it is necessary to optimize the current immunosuppressive regimen in clinical settings. A retrospective study was designed to evaluate the dosing regimen (converting ratio of IV:PO=1:4) of tacrolimus in HSCT patients (n=62). After collecting data from patient's profile and medical record, pharmacokinetic parameters were calculate and compared between the estimated and the actual values in the selected subjects (n=58). It was found that the bioavailabilty (BA) of oral tacrolimus was 40.5% very much different from that is known as 25%. It implies that the current protocol has a potent risk causes dose-related toxicities to the patients. Furthermore, analyses among factors demonstrated that there was no statistical significance between BA of tacrolimus and the variable factors. In the clinical perspectives, the current converting ratio of tacrolimus in patients with HSCT to be re-considered and an appropriate and optimal alternative regimen should be adopted to prevent GVHD and to increase the quality of life of patients.

• 한국임상약학회지
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• 제28권1호
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• pp.24-29
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• 2018

Background: Cyclosporine is an immunosuppressive agent used to treat and prevent graft versus host reaction (GVHR)-a complication associated with stem cell transplantation. This study aimed to develop a population pharmacokinetic model of cyclosporine and investigate factors affecting cyclosporine clearance in pediatric hematopoietic stem cell transplant patients. Methods: A total of 650 cyclosporine concentrations recorded in 65 patients who underwent hematopoietic stem cell transplantation were used. Data including age, sex, weight, height, body surface area (BSA), type of disease, chemotherapy before stem cell transplantation, type of donor, serum creatinine levels, total bilirubin concentration, hematocrit value, and type of concomitant anti-fungal agents and methylprednisolone used were retrospectively collected. Data related to cyclosporine dosage, administration time, and blood concentration were also collected. All data were analyzed using the non-linear mixed effect model; a two-compartment model with first-order elimination was used. Results: The population pharmacokinetic model of cyclosporine using the NONMEM program was as follows: $CL(L/h)=5.9{\times}(BSA/1.2)^{0.9}$, V2 (L) = 54.5, Q (L/h) = 3.5, V3 (L) = 1080.0, $k_a(h^{-1})=0.000377$. BSA was selected as a covariate of cyclosporine clearance, which increased with an increase in BSA. Conclusion: A population pharmacokinetic model for Korean pediatric hematopoietic stem cell transplant patients was developed, and the important factor affecting cyclosporine clearance was found to be BSA. The model might contribute to the development of the most appropriate dosing regimen for cyclosporine. Further studies on population pharmacokinetics should be carried out, prospectively targeting pediatric patients.

• Asian Pacific Journal of Cancer Prevention
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• 제15권15호
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• pp.6127-6130
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• 2014

Objective: Explore the feasibility of allo-hemopietic stem cell transplants in treating patients with B cell acute lymphocytic leukemia. Methods: Between september 2006 and February 2011, fifteen patients with B cell acute lymphocytic leukemia (ALL) were treated by allo-hemopietic stem cell transplants (HSCT). Stem cell sources were peripheral blood. Six patients were conditioned by busulfan (BU) and cyclophosphamide (CY) and nine patients were conditioned with TBI and cyclophosphamide (CY). Graft versus host disease (GVHD) prophylaxis regimen consisted of cyclosporine A (CSA), methotrex ate (MTX) and mycophenolatemofetil (MMF). Results: Patients received a median of $7.98{\times}10^8{\cdot}kg^{-1}$ ($5.36-12.30{\times}10^8{\cdot}kg^{-1}$) mononuclear cells (MNC). The median time of ANC> $0.5{\times}10^9/L$ was day 12 (10-15), and PLT> $20.0{\times}10^9/L$ was day 13 (11-16). Extensive acute GVHD occurred in 6 (40.0%) patients, and extensive chronic GVHD was recorded in 6 (40.0%) patients. Nine patients were alive after 2.5-65 months follow-up. Conclusion: Allogeneic stem cell transplant could be effective in treating patients with B cell acute lymphocytic leukemia.