• Biotechnology and Bioprocess Engineering:BBE
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• v.7 no.5
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• pp.303-310
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• 2002

Cell therapy applied to wound healing or tissue regeneration presents a revolutionary realm to which principles of gene engineering and delivery may be applied. One promising application is the transplantation of cells into the wounded tissue to help the tissue repair. However, when cells are transplanted from in vitro to in vivo, immune rejection occurs due to the immune response triggered by the activation of T-cell, and the transplanted cells are destroyed by the attack of activated T-cell and lose their function. Immune suppressant such as FK506 is commonly used to suppress immune rejection during transplantation. However, such kind of immune suppressants not only suppresses immune rejection in the periphery of transplanted cells but also suppresses whole immune response system against pathogenic infection. In order to solve this problem, we developed a method to protect the desired cells from immune rejection without impairing whole immune system during cell transplantation. Previously, we reported the success of constructing glomerular epithelial cells for removal of immune complex, in which complement receptor of type 1 (CR1) was over-expressed on the membrane of renal glomerular epithelial cells and could bind immune complex of DNA/anti-DNA-antibody to remove immune complex through phagocy-tosis [1]. Attempting to apply the CR1-expressing cells to cell therapy and evade immune rejection during cell transplantation, we constructed three plasmids containing genes encoding a soluble fusion protein of cytolytic T lymphocyte associated antigen-4 (CTLA4Ig) and an enhanced green fluorescent protein (EGFP). The plasmids were transfected to the above-mentioned glomerular epithelial cells to express both genes simultaneously. Using the clone cells for cell transplantation showed that mice with autoimmune disease prolonged their life significantly as compared with the control mice, and two injections of the cells at the beginning of two weeks resulted in remarkable survivability, whereas it requires half a year and 50 administrations of proteins purified from the same amount of cells to achieve the same effect.

• Childhood Kidney Diseases
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• v.12 no.1
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• pp.23-29
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• 2008

Kidney allograft transplantation is the most effective method of renal replacement for end stage renal disease patients. Still, it is another kind of 'disease', requiring immunosuppression to keep the allograft from rejection(allograft immune reaction). Immune system of the allograft recipient recognizes the graft as a 'pathogen (foreign or danger)', and the allograft-recognizing commanderin-chief of adaptive immune system, T cell, recruits all the components of immune system for attacking the graft. Proper activation and proliferation of T cell require signals from recognizing proper epitope(processed antigen by antigen presenting cell) via T cell receptor, costimulatory stimuli, and cytokines(IL-2). Thus, most of the immunosuppressive agents suppress the process of T cell activation and proliferation.

• Korean Journal of Transplantation
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• v.28 no.3
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• pp.113-120
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• 2014

Two-signal models are useful in explaining various types of immune responses. In particular, secondary, so-called costimulatory, signals are critically required for the process of T-cell activation, survival, differentiation, and memory formation. Early studies in rodent models showed that targeting T-cell costimulatory pathways elicits immunological tolerance, providing a basis for development of costimulatory therapeutics in allograft rejection. However, as the classic definition of T-cell costimulation continues to evolve, simple blockade of costimulatory pathways has limitations in prevention of allograft rejection. Furthermore, functions of costimulatory molecules are much more diverse than initially anticipated and beyond T cells. In this mini-review, we will discuss CD137-CD137L bidirectional signals as examples showing that two-signals can be applicable to multiple phases of immune responses.

• IMMUNE NETWORK
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• v.4 no.1
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• pp.53-59
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• 2004

Background: Minor histocompatibility HY antigen, as a transplantation antigen, has been known to cause graft rejection in MHC (major histocompatibility complex) matched donor-recipient. The aim of our study is to investigate the role of male antigen (HY) disparity on MHC matched pancreatic islet transplantation and to examine the mechanism of the immune reaction. Methods: Pancreatic islets were isolated and purified by collagen digestion followed by Ficoll gradient. The isolated islets of male C57BL6/J were transplanted underneath the kidney capsule of syngeneic female mice rendered diabetic with streptozotocine. Blood glucose was monitored for the rejection of engrafted islets. After certain period of time, tail to flank skin transplantation was performed either on mouse transplanted with HY mismatched islets or on sham treated mouse. The rejection was monitored by scoring gross pathology of the engrafted skin. Results: HY mismatched islets survived more than 300 days in 14 out of 15 mice. The acceptance of second party graft (male B6 islets) and the rejection of third party graft (male BALB/c islets) in these mice suggested the tolerance to islets with HY disparity. B6 Skin with HY disparity was rejected on day $25{\pm}7$. However, HY mismatched skin transplanted on the mice tolerated to HY mismatched islets survived more than 240 days. Tetramer staining in these mice indicated the CTL recognizing MHC Db/Uty was not deleted or anergized. Conclusion: The islet transplantation across HY disparity induced tolerance to HY antigen in C57BL6 mouse, which in turn induced tolerance to HY mismatched skin, which otherwise would be rejected within 25 days. The MHC tetramer staining suggested the underlying mechanisms would not be clonal deletion or anergy.

• Reproductive and Developmental Biology
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• v.41 no.3
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• pp.57-63
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• 2017

Xenotransplantation is proposed as a solution to the problem of organ shortage. However, transplantation of xenogeneic organs induces an antigen-antibody reaction in ${\alpha}$-1,3-gal structure that are not present in humans and primates, and thus complement is also activated and organs die within minutes or hours. In this study, we used FasL gene, which is involved in the immune response of NK cell, and US11, which suppresses MHC Class I cell membrane surface expression, to inhibit cell mediated rejection in the interspecific immunity rejection, and also hDAF(CD55) was introduced to confirm the response to C3 complement. These genes were tranfeced into Korean native pig fetal fibroblasts using pCAGGS vector. And cytotoxicity of NK cell and human complement was confirmed in each cell line. The US11 inhibited the cytotoxicity of NK cell and, in addition, the simultaneous expression of US11 and Fas ligand showed excellent suppress to T-lymphocyte cytotoxicity, hDAF showed weak resistance to cytotoxicity of natural killer cell but not in CD8+ CTLs. Cytotoxicity study with human complement showed that hDAF was effective for reducing complement reaction. In this studies have demonstrated that each gene is effective in reducing immune rejection.

• 제어로봇시스템학회:학술대회논문집
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• 2004.08a
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• pp.885-890
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• 2004

Strictly maintaining the steam temperature can be difficult due to heating value variation to the fuel source, time delay changes in the main steam temperature, the change of the dynamic characteristics in the reheater. Up to the present time, PID Controller has been used to operate this system. However, it is very difficult to achieve an optimal PID gain with no experience, since the gain of the PID controller has to be manually tuned by trial and error. This paper focuses on tuning of the Controller with disturbance rejection for thermal power plant using immune based multiobjective approach. An ITSE(Integral of time weighted squared error) is used to decide performance of tuning results.

• Journal of Veterinary Clinics
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• v.28 no.1
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• pp.63-70
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• 2011

To consider the iliac fossa as the vascular anastomosis site of kidney transplantation for the short-term study of acute rejection in pigs. Twelve domestic pigs weighing 39~48 kg underwent heterotopic renal allgraft transplantation. The experimental animals were divided into 2 groups in terms of renal vascular anastomosis site; the external iliac artery and vein were used in iliac fossa model (n = 6), the abdominal aorta and the caudal vena cava inferior to the kidney were used in abdominal cavity model (n = 6). Renal function was evaluated by daily measurement of plasma creatinine and BUN concentrations. The experiments' health including postoperative complications was also assessed daily for 8 days after transplantation. After euthanazation gross and histopathologic analysis was performed. All six pigs in iliac fossa model developed neuropraxia and lameness of the ipsilateral pelvic limb. However, no necrosis was observed in any pigs. In the abdominal cavity model, durations of both the surgical operation and the vascular anastomosis were significantly longer than those in the iliac fossa model. Furthermore, ischemia injury of the transplanted kidney was increased in abdominal cavity model, which induced accelerated-acute immune response from day 4 after transplantation. Despite of pelvic limb complication, the iliac fossa model showed more advantages including not only less ischemia time related to easy vascular anastomosis, but also less immune response during the acute rejection period. The results indicate that the iliac fossa model may be appropriate to the study of acute rejection in porcine kidney transplantation.

• IMMUNE NETWORK
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• v.16 no.4
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• pp.219-232
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• 2016

Production of high affinity antibodies for antigens is a critical component for the immune system to fight off infectious pathogens. However, it could be detrimental to our body when the antigens that B cells recognize are of self-origin. Follicular helper T, or Tfh, cells are required for the generation of germinal center reactions, where high affinity antibody-producing B cells and memory B cells predominantly develop. As such, Tfh cells are considered as targets to prevent B cells from producing high affinity antibodies against self-antigens, when high affinity autoantibodies are responsible for immunopathologies in autoimmune disorders. This review article provides an overview of current understanding of Tfh cells and discusses it in the context of animal models of autoimmune diseases and allograft rejections for generation of novel therapeutic interventions.

• IMMUNE NETWORK
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• v.23 no.6
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• pp.44.1-44.16
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• 2023

Mesenchymal stem cells (MSCs) are effective in treating autoimmune diseases and managing various conditions, such as engraftment of allogeneic islets. Additionally, autologous and HLA-matched allogeneic MSCs can aid in the engraftment of human allogeneic kidneys with or without low doses of tacrolimus, respectively. However, HLA alloantigens are problematic because cell therapy uses more HLA-mismatched allogeneic cells than autologous for convenience and standardization. In particular, HLA-mismatched MSCs showed increased Ag-specific T/B cells and reduced viability faster than HLA-matched MSCs. In CRISPR/Cas9-based cell therapy, Cas9 induce T cell activation in the recipient's immune system. Interestingly, despite their immunogenicity being limited to the cells with foreign Ags, the accumulation of HLA alloantigen-sensitized T/B cells may lead to allograft rejection, suggesting that alloantigens may have a greater scope of adverse effects than foreign Ags. To avoid alloantigen recognition, the β2-microglobulin knockout (B2MKO) system, eliminating class-I MHC, was able to avoid rejection by alloreactive CD8 T cells compared to controls. Moreover, universal donor cells in which both B2M and Class II MHC transactivator (CIITA) were knocked out was more effective in avoiding immune rejection than single KO. However, B2MKO and CIITA KO system remain to be controlled and validated for adverse effects such as the development of tumorigenicity due to deficient Ag recognition by CD8 T and CD4 T cells, respectively. Overall, better HLA-matching or depletion of HLA alloantigens prior to cell therapy can reduce repetitive transplantation through the long-term survival of allogeneic cell therapy, which may be especially important for patients seeking allogeneic transplantation.

• Asian-Australasian Journal of Animal Sciences
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• v.22 no.1
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• pp.20-25
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• 2009

Xenotransplantation of pig organs into humans is a potential solution for the shortage of donor organs for transplantation. However, multiple immune barriers preclude its clinical application. In particular, the initial type of rejection in xenotransplantation is an acute cellular rejection by host $CD8^+$ cytotoxic T lymphocyte (CTL) cells that react to donor major histocompatibility complex (MHC) class I. The human cytomegalovirus (HCMV) glycoprotein Unique Short (US) 2 specifically targets MHC class I heavy chains to relocate them from the endoplasmic reticulum (ER) membrane to the cytosol, where they are degraded by the proteasome. In this study we transfected the US2 gene into minipig fetal fibroblasts and established four US2 clonal cell lines. The integration of US2 into transgenic fetal cells was confirmed using PCR and Southern blot assay. The reduction of Swine Leukocyte Antigen (SLA)-I by US2 was also detected using Flow cytometry assay (FACS). The FACS analysis of the US2 clonal cell lines demonstrated a substantial reduction in SLA-I surface expression. The level (44% to 76%) of SLA-I expression in US2 clonal cell lines was decreased relative to the control. In cytotoxicity assay the rate of $CD8^+$ T cell-mediated cytotoxicity was significantly reduced to 23.8${\pm}$15.1% compared to the control (59.8${\pm}$8.4%, p<0.05). In conclusion, US2 can directly protect against $CD8^+$-mediated cell lysis. These results indicate that the expression of US2 in pig cells may provide a new approach to overcome the CTL-mediated immune rejection in xenotransplantation.