• Journal of Microbiology and Biotechnology
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• 제22권8호
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• pp.1066-1076
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• 2012

Previous observations demonstrated that various immunosuppressive agents and their combination therapies can increase allograft survival rates. However, these treatments may have serious side effects and cannot substantially improve or prolong graft survival in acute graft-versus-host disease (GVHD). To improve the therapeutic potency of divalent immunoadhesins, we have constructed and produced several tetravalent forms of immunoadhesins comprising each of cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), CD2, and lymphocyte activation gene-3 (LAG3). Flow cytometric and T cell proliferation analyses displayed that tetravalent immunoadhesins have a higher binding affinity and more potent efficacy than divalent immunoadhesins. Although all tetravalent immunoadhesins possess better efficacies, tetravalent forms of CTLA4-Ig and LAG3-Ig revealed higher inhibitory effects on T cell proliferation than tetravalent forms of TNFR2-Ig and CD2-Ig. In vitro mixed lymphocytes reaction (MLR) showed that combined treatment with tetravalent CTLA4-Ig and tetravalent LAG3-Ig was highly effective for inhibiting T cell proliferation in both human and murine allogeneic stimulation. In addition, both single tetravalent-form and combination treatments can prevent the lethality of murine acute GVHD. The results of this study demonstrated that co-blockade of the major histocompatibility complex class (MHC)II:T cell receptor (TCR) and CD28:B7 pathways by using tetravalent human LAG3-Ig and CTLA4-Ig synergistically prevented murine acute GVHD.

• 한국식품영양과학회지
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• 제29권1호
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• pp.134-139
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• 2000

Angelica gigas Nakai (danggui) is a popular herb which has been used as a blood-building decoction for recovery from weakness in the Chinese medicine. Its demand increased in functional foods and pharmaceutical industries. For its hygiene, fumigation has been used, but the use of fumigants are going to be prohibited for food processing. In order to investigate gamma irradiation technique for hygiene of danggui, the immunomodulation activity of danggui after irradiation was examined. The water extract of irradiated danggui showed a strong mitogenic effect on splenocytes in vitro to the same level of lipopolysaccharide (LPS) and phytohemagglutinin (PHA). The effect was not different from that of non-danggui. It was tested whether there was any difference between irradiated and non-irradiated danggui in effects on the secretion of antibodies and graft versus host reaction in vivo. It turned out that intraperitoneal (i.p.) administration of the extract of irradiated danggui for 4 days remarkably increased the number of antibody-secreting cells in mice injected with sheep red blood cells (SRBC). Splenomegaly, due to graft versus host reacton, was also increased after 7 days i.p. administration of the extract of danggui in mice injected with allogeneic splenocytes. In these two in vivo test, the effect were not different from those of non-irradiated danggui. These results indicated that immunomodulation activity of danggui might be preserved after irradiation. In the other experiments (data not shown), the irradiated danggui was stable in active component analysis and safe in genetic toxicity test. In further research, the stability in other physiological activity of irradiated danggui will have to be proved before practical application of irradiation for hygiene.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.63-67
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• 2016

Severe graft-versus-host disease (GVHD) is an often lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). The safety of clinical-grade mesenchymal stem cells (MSCs) has been validated, but mixed results have been obtained due to heterogeneity of the MSCs. In this phase I study, the safety of bone marrow-derived homogeneous clonal MSCs (cMSCs) isolated by a new subfractionation culturing method was evaluated. cMSCs were produced in a GMP facility and intravenously administered to patients who had refractory GVHD to standard treatment resulting after allogeneic HSCT for hematologic malignancies. After administration of a single dose ($1{\times}10^6cells/kg$), 11 patients were evaluated for cMSC treatment safety and efficacy. During the trial, nine patients had 85 total adverse events and the rate of serious adverse events was 27.3% (3/11 patients). The only one adverse drug reaction related to cMSC administration was grade 2 myalgia in one patient. Treatment response was observed in four patients: one with acute GVHD (partial response) and three with chronic GVHD. The other chronic patients maintained stable disease during the observation period. This study demonstrates single cMSC infusion to have an acceptable safety profile and promising efficacy, suggesting that we can proceed with the next stage of the clinical trial.

• 한국독성학회:학술대회논문집
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• 한국독성학회 2002년도 Molecular and Cellular Response to Toxic Substances
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• pp.181-181
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• 2002

The herbal combination allergina has been used for the treatment of inflammatory diseases in South Korea. In this study, we investigated the immunosuppressive activities of allergina in more detail. Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients undergoing allogeneic bone marrow transplantation.(omitted)

• 대한미생물학회지
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• 제21권1호
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• pp.133-144
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• 1986

This study was undertaken to assess the effect of ginseng administration on T lymphocyte induced local xenogenic graft-versus-host(GVM) reactions which were induced with thymocyte, spleen cell and lymph node cell of ICR mice. Mice received daily 10mg of 70% alcohol ginseng extract oral1y for 100days and control mice remained untreated for the same period of time. The cells from donor mice were injected intradermally into the closely shaven abdominal skin of Sprague-Dawley rats for GVH tests. The thymocyte from control(ginseng-untreated) mice showed a negative local GVH reaction, whereas thymocyte from experimental(ginseng-treated) mice showed a positive reaction with the rate of 17.4%. When spleen cells were injected, the incidence of positive local GVH reaction was 66.7% among ginseng-treated mice, as opposed to incidence of 45.5% of positive local GVH reaction among control mice. The incidence of positive local GVH reaction of the lymph node cells when injected into a recipient was 71.4% among ginseng-treated mice as compared with that of 18.9% among control mice. The relationship between spleen cell inoculum and intensity of the local GVH reaction was assessed in ginseng-untreated mice. The intensity of GVH reaction clearly appears to be dose related. In ginseng-treated mice, a minimum of $1{\times}10^7$ spleen cell was required for production of positive local GVH reaction with almost linear relationship up to an inoculum of $5{\times}10^8$ cells. In control mice, however, a minimum of $1{\times}10^8$ spleen cells was required for positive GVH reaction. These results strongly suggest that the ginseng administration augments significantly the local xenogenic GVH reaction which was used to assess T lymphocyte function and immunocompetence of mice and in addition to this, these results appear to support previous suggestions that the local GVH reaction consitutes a qualitative test of the functional activity of T lymphocytes. These results may be the first to induce local GVH reaction, employing rats as recipient and mice as donor. This study was also desingned to investigate some of the effects of ginseng extract on lymphocyte-macrophage interactions. This was accomplished by in vitro quantification of 1) migratory inhibitory factor(MIF) synthetic capacity of splenic lymphocytes in mice previously primed with ginseng 2) MIF responsiveness of mouse peritoneal macrophages or chicken peripheral leucocytes under the presence of ginseng extract 3) migration ability of chicken peripheral leucocytes by direct stimulation of ginseng extract or ginseng saponin and 4) immunosuppressive effects of immunosuppressants such as cyclophosphamide, cyclosporin A or dexamethasone. Mice divided equally into the ginseng and the saline groups, which received intraperitoneally daily 0.2ml of ginseng absolute alcohol-extract(5mg/ml) and same amount of saline for 15 days, respectively. The cellular immune responsiveness of these mice was assayed 15 days after ginseng pretreatment. Splenic lymphocytes of mice treated with ginseng, when stimulated with sensitized specific-antigen such as sheep red blood cells or toxoplasmin, or with polyclonal activator concanavalin A, produced significantly more MIF than those of control saline group. MIF responsiveness of normal mouse macrophages was significantly augmented when assayed under the presence of ginseng extract (1mg/ml). The migratory ability of normal chicken leucocytes in the absence of MIF was significantly decreased by the stimulation of ginseng extract alone. MIF response was significantly decreased by immunosuppressants and this impaired response was not restored by ginseng pretreatment. This study was additionally performed to evaluate the effect of ginseng on the expulsion of adult Trichinella spiralis in mice. ICR mice were infected experimentally by esophageal incubation of 300 T. spiralis infective muscle larvae prepared by acid-pepsin digestion of infected mice. and received oral administration of 70% alcohol ginseng extract(10mg/mouse/day) for the indicated days plus 4 days before infection. At various times after infection, the number of adult T. spiralis worms in small intestines was determined. Interestingly, ginseng-treatment was accompanied by accelerated expulson of T. spiralis. These results led to the conclusion that Panax ginseng caused some enhancing effect on GVH reaction, macrophage migration inhibition reaction and expulsion of T. spiralis. In addition these results suggested that the mechanisms responsible for this enhancement of ginseng may be chiefly or partially due to nonspecific stimulation of cell-mediated immune response.

• Toxicological Research
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• 제17권
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• pp.217-218
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• 2001

In a series of our screening for immunomodulating substances, we isolated prodigiosin from the culture broth qf Serratia marcescens B-1231. This compound inhibited the T cell-mediated immune responses such as concanavalin A-induced proliferation, mixed lymphocyte response, local graft versus host reaction and T-dependent antibody response at nontoxic concentrations. However. prodigiosin did not effect B cell-mediated immune functions such as lipopolysaccharide-induced proliferation and -activated polyclonal antibody production at the same concentrations. Prodigiosin did not cause death in vitro to lymphocytes at effective concentrations (＜100 nM) and also did not show toxicity in vivo to lymphoid organs at effective dos-ages (10 and 30 mg/kg). The pharmacological potencies were comparable to the activities of well-known T-cell specific immunosuppressants such as cyclosporin A. In our continuing study, mechanism of action of PDG is investigated with respect to the effect of PDG on IL-2/IL-2R pathway and transcription factor.

• 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.

• 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.

• 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.

• Journal of Oral Medicine and Pain
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• 제25권2호
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• pp.159-165
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• 2000

Subsequent to an allogenic stem cell transplantation(ASCT) on patients with hematologic malignancy(AML, ALL, CML, multiple myeloma, lymphoma etc.), chronic GVHD(graft versus host disease), which is an immunological reaction, occurs. With treatment results from patients who were diagnosed with ALL(acute lymphocytic leukemia), undergone BMT(bone marrow transplantation) and showed oral and skin lesions due to GVHD, treatment of oral manifestations of leukemia and its general management were studied. 90% of patients with chronic GVHD show change in the oral mucosa causing oral manifestations such as leukoplakia, lichenoid change of the oral mucosa, mucosal atrophy, erythema, ulceration and xerostomia. In treating GVHD, extensive systemic immunosuppression cause bacterial, viral, fungal infection that are fatal, and even if the treatment is successful, the patient is already in a severe immunosuppressed state. Therefore, localized target therapy is preferred. In another words, topical application(rinse, cream, ointment etc.) of cyclosporin and steroid in treating oral chronic GVHD is highly recommended, and the use of PUVA(Psoralen Ultraviolet A) and thalidomide is reported to be effective. In treating such diseases, dental treatment to control pain and prevent secondary infection of oral manifestations is very important. To those patients with systemic diseases who show limited effect by general dental treatment, non-invasive treatment such as the dental laser, in addition to the use of drugs, may be necessary to actively treat pain and help the healing process. For greater results, new effective methods are to be developed for treatment.