동종면역반응에서 배아줄기세포와 중간엽줄기세포의 면역억제현상 규명

학위논문 (박사)-- 서울대학교 대학원 : 의학과 면역학 전공, 2013. 2. 안규리.Introduction: Embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) are known to have immunosuppressive effects. However, its immunosuppressive mechanisms still remain controversial. We therefore conducted this study to examine the immunosuppressive mechanisms of ESCs and MSCs in an in vitro environment and in an animal experimental model of the allograft transplantation of skin and pancreatic islet for in vivo environment. Methods: To analyze the in vitro immunosuppressive effect of stem cells, naïve T cells or memory T cells from C57BL/6 mice and antigen presenting cells from BALB/c mice with ESCs or MSCs were co-cultured for 3 days and thymidine uptake, ELISA (enzyme-linked immunosorbent assay), CFSE (carboxyfluorescein succinimidyl ester) and 7-AAD staining were conducted. Transwell experiment and RT-PCR (reverse transcription-polymerase chain reaction) on immunosuppressive molecules such as PDL-1, Fas-L, CD30, CD70, perforin and granzyme B for the immunosuppressive mechanism were performed. For the functional assay, blocking antibodies or inhibitors on each molecule were treated. To analyze the in vivo immunosuppressive effect of both stem cells, we performed the allogeneic skin and pancreatic transplantation by intravenous injection or co-transplantation of stem cells with anti-CD40L antibodies or mycophenolate mofetil (MMF). Results: ESCs or MSCs did not stimulate alloimmune response and synchronously suppressed the proliferation, survival, activation of naïve CD4+ T cells in an in vitro alloimmune response. They also suppressed the release of cytokines such as IL-2, IL-12, IFN-γ, TNF-α, IL-4, IL-5, IL-1β and IL-10. But there were no significant changes in the expression of TGF-β or IDO (indoleamine 2,3-dioxygenase). In addition, they also suppressed CD44+ memory T cells or T cell activation markers and induced regulatory T cells. The transwell assay revealed that the immunosuppressive effects of both types of stem cells originated from the cell-to-cell contact. Both types of stem cells strongly expressed PDL-1, Fas-L, CD30, perforin and granzyme B, but weakly expressed CD70. When blocking agents on granzyme B of ESCs, the immunosuppressive effect of ESCs was significantly reduced. Both ESCs and MSCs by intravenous injection or co-transplantation did not strongly suppress the immune rejection of the allogeneic skin tissue and pancreatic islet. Despite the concomitant use of them with immunosuppressant, there was no additional effect. Significant immunological changes of immune cells by stem cells were not shown in transplanted recipients. Conclusions: Murine ESCs or MSCs showed the low immunogenicity and the significant immunosuppressive effect such as the suppression of both proliferation and survival of naïve T cells and memory T cells, cytokine release reduction, the induction of Tregs in an in vitro environment. The main mechanism of immunosuppression was by cell-to-cell and granzyme B on ESCs played a key role. However, both stem cells did not suppress allogeneic rejection in the allogeneic skin and pancreatic islet transplantation. This discrepancy in the immunosuppressive effects of stem cells between an in vitro environment and an in vivo one showed that it has to be considered for the establishment of optimal transplantation condition and for the successful clinical application of stem cells in the field of organ transplantation.Abstract i Contents iii List of Tables and Figures iv List of Abbreviations vi Introduction 1 Material and Methods 6 Results 12 Discussion 51 References 58 Abstract in Korean 67Docto

Low-Frequency Noise in HighTc Superconductors : Y1Ba2Cu3O7-δ thin films and Bi2Sr2Ca1CusOx single crystals

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라인 생산시스템의 계층적 생산계획에 관한 연구

학위논문(석사) - 한국과학기술원 : 산업공학과, 1995.2, [ ii, 43 p. ]This thesis deals a hierarchical production planning problem for a line production system. A hierarchical procedure is proposed for the following three phases : aggregated production planning, family disaggregation and item disaggregation. For the first phase problem, an LP formulation is developed with the objective of minimizing the sum of inventory holding cost and overtime labor cost, which can be solved on a rolling horizon basis. For the second phase problem, the first period``s solution of the aggregated plan is disaggregated to families in a way which maximizes line efficiency. For the last phase, the family production quantity is disaggregated to items such that the flow time is minimized. In this regard, item-flow model and batch-flow model are proposed to determine the batch size and operation sequence of each item. In the item-flow model, the case with two items is solved optimally, whereas a heuristic procedure is presented for the case with multi-item. And in the batchflow model, a heuristic and a way to find a lower bound are proposed. A example problem is solved to illustrate the above models.한국과학기술원 : 산업공학과