• IMMUNE NETWORK
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• 제10권4호
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• pp.120-125
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• 2010

Dysfunction of the virus-specific T cells is a cardinal feature in chronic persistent viral infections such as one caused by hepatitis C virus (HCV). In chronic HCV infection, virus-specific dysfunctional CD8 T cells often overexpress various inhibitory receptors. Programmed cell death 1 (PD-1) was the first among these inhibitory receptors that were identified to be overexpressed in functionally impaired T cells. The roles of other inhibitory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) have also been demonstrated in T-cell dysfunctions that occur in chronic HCV patients. Blocking these inhibitory receptors in vitro restores the functions of HCV-specific CD8 T cells and allows enhanced proliferation, cytolytic activity and cytokine production. Therefore, the blockade of the inhibitory receptors is considered as a novel strategy for the treatment of chronic HCV infection.

• Molecules and Cells
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• 제38권3호
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• pp.251-258
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• 2015

Germline mutations in the breast cancer type 2 susceptibility gene (BRCA2) are linked to familial breast cancer and the progressive bone marrow failure syndrome Fanconi anaemia. Established Brca2 mouse knockout models show embryonic lethality, but those with a truncating mutation at the C-terminus survive to birth and develop thymic lymphoma at an early age. To overcome early lethality and investigate the function of BRCA2, we used T cell-specific conditional Brca2 knockout mice, which were previously shown to develop thymic lymphoma at a low penetrance. In the current study we showed that the number of peripheral T cells, particularly na$\ddot{i}$ve pools, drastically declined with age. This decline was primarily ascribed to improper peripheral maintenance. Furthermore, heterozygous mice with one wild-type Brca2 allele manifested reduced T cell numbers, suggesting that Brca2 haploinsufficiency might also result in T cell loss. Our study reveals molecular events occurring in Brca2-deficient T cells and suggests that both heterozygous and homozygous Brca2 mutation may lead to dysfunction in T cell populations.

• Parasites, Hosts and Diseases
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• 제59권6호
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• pp.573-583
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• 2021

Toxoplasma gondii, an intracellular protozoan parasite that infects one-third of the world's population, has been reported to hijack host cell apoptotic machinery and promote either an anti- or proapoptotic program depending on the parasite virulence and load and the host cell type. However, little is known about the regulation of human FHs 74 small intestinal epithelial cell viability in response to T. gondii infection. Here we show that T. gondii RH strain tachyzoite infection or ESP treatment of FHs 74 Int cells induced apoptosis, mitochondrial dysfunction and ER stress in host cells. Pretreatment with 4-PBA inhibited the expression or activation of key molecules involved in ER stress. In addition, both T. gondii and ESP challenge-induced mitochondrial dysfunction and cell death were dramatically suppressed in 4-PBA pretreated cells. Our study indicates that T. gondii infection induced ER stress in FHs 74 Int cells, which induced mitochondrial dysfunction followed by apoptosis. This may constitute a potential molecular mechanism responsible for the foodborne parasitic disease caused by T. gondii.

• 한국식품영양과학회지
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• 제35권10호
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• pp.1329-1335
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• 2006

AIDS로의 진행과정은 단순히 몇몇 기작에 의한 것이 아니라 여러 경로를 거쳐 발생하며 그 진행속도도 개개인에 따라 다양하게 나타나고 있다. 본 연구에서는 쥐 AIDS 모델을 이용하여 항산화호르몬으로 알려진 DHEAS의 면역조절 효과를 확인하고자 하였다. DHEAS의 투여는 LP-BM5 retrovirus 감염으로 인한 T와 B 임파구의 mitogenesis를 증가시켰으며 Th1/Th2 type cytokines의 발현에도 영향을 미쳤는데 주로 전사수준에서 작용한 것으로 생각된다/ 또한 retrovirus 감염으로 인한 간조직의 지질과산화 유발을 억제하여 조직 내의 항산화제인 vitamin E의 함량을 유지시킴으로 NF-kB의 활성화를 통한 retrovirus의 복제를 억제시켜 Th1/Th2 type cytokines의 불균형적인 발현을 저해하였을 것으로 여겨진다. 따라서 쥐 AIDS모델에 있어서 DHEAS의 면역조절 효과를 확인한 본 연구는 향후 HIV감염 이후 AIDS로의 진행 과정 시 항산화제의 역할과 기작 규명에 대한 가능성을 제시할 수 있을 것으로 생각된다.

• IMMUNE NETWORK
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• 제20권1호
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• pp.2.1-2.19
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• 2020

Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection. This stem cell-like CD8 T-cell subset has been also observed in both mouse and human tumor models. Most importantly, in both chronic viral infection and tumor models, the proliferative burst of Ag-specific CD8 T cells driven by PD-1-directed immunotherapy comes exclusively from this stem cell-like CD8 T-cell subset. Therefore, a better understanding of the mechanisms how CD8 T-cell subsets are regulated during chronic viral infection and cancer is required to improve the current immunotherapies that restore the function of exhausted CD8 T cells. In this review, we discuss the differentiation of virus-specific CD8 T cells during chronic viral infection, the characteristics and function of CD8 T-cell subsets, and the therapeutic intervention of PD-1-directed immunotherapy in cancer.

• IMMUNE NETWORK
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• 제22권1호
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• pp.6.1-6.19
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• 2022

Chimeric antigen receptor (CAR) T cells, which express a synthetic receptor engineered to target specific antigens, have demonstrated remarkable potential to treat haematological malignancies. However, their transition beyond haematological malignancy has so far been unsatisfactory. Here, we discuss recent challenges and improvements for CAR T cell therapy against solid tumors: Antigen heterogeneity which provides an effective escape mechanism against conventional mono-antigen-specific CAR T cells; and the immunosuppressive tumor microenvironment which provides physical and molecular barriers that respectively prevent T cell infiltration and drive T cell dysfunction and hypoproliferation. Further, we discuss the application of CAR T cells in infectious disease and autoimmunity.

• Clinical and Experimental Pediatrics
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• 제56권7호
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• pp.298-303
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• 2013

Purpose: The purpose of this study was to evaluate short-term thyroid dysfunction and related risk factors in pediatric patients who underwent hematopoietic stem cell transplantation (HSCT) during childhood. Methods: We studied 166 patients (100 boys and 66 girls) who underwent HSCT at the Catholic HSCT Center from January 2004 through December 2009. The mean age at HSCT was $10.0{\pm}4.8$ years. Thyroid function of the patients was tested before and during 3 months of HSCT. Results: Out of 166 patients, 165 (99.4%) underwent allotransplantation. Acute graft-versus-host disease (GVHD, grades II to IV) developed in 76 patients. Conditioning regimens before HSCT include total body irradiation (n=57), busulfan (n=80), and reduced intensity (n=29). Forty-five (27.1%) had thyroid dysfunction during 3 months after HSCT (29 euthyroid sick syndrome [ESS], 6 subclinical hyperthyroidism, 4 subclinical hypothyroidism, 3 hypothyroxinemia, 2 overt hyperthyroidism, and 1 high $T_4$ syndrome). In a univariate logistic regression analysis, age at HSCT (P=0.002) and acute GVHD (P=0.009) had statistically significant relationships with thyroid dysfunction during 3 months after HSCT. Also, in a univariate logistic regression analysis, ESS (P=0.014) showed a strong statistically significant association with mortality. Conclusion: In our study 27.1% patients experienced thyroid dysfunction during 3 months after HSCT. Increase in age and acute GVHD may be risk factors for thyroid dysfunction during 3 months after HSCT. There was a significant association between ESS and mortality.

• IMMUNE NETWORK
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• 제23권5호
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• pp.36.1-36.16
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• 2023

Thymic epithelial cells (TECs) play a critical role in thymic development and thymopoiesis. As individuals age, TECs undergo various changes that impact their functions, leading to a reduction in cell numbers and impaired thymic selection. These age-related alterations have been observed in both mice and humans. However, the precise mechanisms underlying age-related TEC dysfunction remain unclear. Furthermore, there is a lack of a comprehensive study that connects mouse and human biological processes in this area. To address this gap, we conducted an extensive transcriptome analysis of young and old TECs in mice, complemented by further analysis of publicly available human TEC single-cell RNA sequencing data. Our analysis revealed alterations in both known and unknown pathways that potentially contribute to age-related TEC dysfunction. Specifically, we observed downregulation of pathways related to cell proliferation, T cell development, metabolism, and cytokine signaling in old age TECs. Conversely, TGF-β, BMP, and Wnt signaling pathways were upregulated, which have been known to be associated with age-related TEC dysfunctions or newly discovered in this study. Importantly, we found that these age-related changes in mouse TECs were consistently present in human TECs as well. This cross-species validation further strengthens the significance of our findings. In conclusion, our comprehensive analysis provides valuable insight into the biological and immunological characteristics of aged TECs in both mice and humans. These findings contribute to a better understanding of thymic involution and age-induced immune dysfunction.

• Preventive Nutrition and Food Science
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• 제10권2호
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• pp.161-166
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• 2005

We investigated the effect of pycnogenol (PYC) supplementation on retarding the immune dysfunction of CS7BL/6 mice after murine AIDS (MAIDS) development. Dysfunction of T and B cell mitogenesis from primary cultured splenocytes has been observed with retrovirus infection and PYC supplementation partially recovered the dysfunction of T and B cells. There was an abnormal shift of cytokine pattern with retrovirns infection, which was designated by the decreased secretion of Th1 cytokines and increased secretion of Th2 cytokines. PYC supplementation increased IL-2 and $IFN-\gamma$ secretion and decreased IL-4, IL-6, and $TNF-\alpha$ secretion, but it was not sufficient enough to maintain the normal level of these cytokines. Hepatic vitamin E level was significantly decreased by retrovirns infection, in accordance with increased hepatic lipid peroxidation level, whereas PYC supplementation normalized the hepatic level of vitamin E and lipid peroxidation. This study suggests that PYC supplementation may partially help retard the incidence of symptoms during MAIDS.

• IMMUNE NETWORK
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• 제16권5호
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• pp.281-285
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• 2016

CD4⁺ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet b cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.