• Archives of Pharmacal Research
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• 제22권5호
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• pp.437-447
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• 1999

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM) results from the destruction of insulin-producing pancreatic $\beta$ cells by a progressive $\beta$ cell-specific autoimmune process. The pathogenesis of autoimmune IDDM has been extensively studied for the past two decades using animal models such as the non-obese diabetic (NOD) mouse and the Bio-Breeding (BB) rat. However, the initial events that trigger the immune responses leading to the selective destruction of the $\beta$ cells are poorly understood. It is thought that $\beta$ cell auto-antigens are involved in the triggering of $\beta$ cell-specific autoimmunity. Among a dozen putative $\beta$ cell autoantigens, glutamic acid decarboxylase (GAD) has bee proposed as perhaps the strongest candidate in both humans and the NOD mouse. In the NOD mouse, GAD, as compared with other $\beta$ cell autoantigens, provokes the earliest T cell proliferative response. The suppression of GAD expression in the $\beta$ cells results in the prevention of autoimmune diabetes in NOD mice. In addition, the major populations of cells infiltrating the iselts during the early stage of insulitis in BB rats and NOD mice are macrophages and dendritic cells. The inactivation of macrophages in NOD mice results in the prevention of T cell mediated autoimmune diabetes. Macrophages are primary contributors to the creation of the immune environment conducive to the development and activation of $\beta$cell-specific Th1-type CD4+ T cells and CD8+ cytotoxic T cells that cause autoimmune diabetes in NOD mice. CD4+ and CD8+ T cells are both believed to be important for the destruction of $\beta$ cells. These cells, as final effectors, can kill the insulin-producing $\beta$ cells by the induction of apoptosis. In addition, CD8+ cytotoxic T cells release granzyme and cytolysin (perforin), which are also toxic to $\beta$ cells. In this way, macrophages, CD4+ T cells and CD8+ T cells act synergistically to kill the $\beta$ cells in conjunction with $\beta$ cell autoantigens and MHC class I and II antigens, resulting in the onset of autoimmune type I diabetes.

• Molecules and Cells
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• 제39권7호
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• pp.557-565
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• 2016

The paired immunoglobulin-like type 2 receptor (PILR) family consists of two functionally opposite members, inhibitory $PILR{\alpha}$ and activating $PILR{\beta}$ receptors. PILRs are widely expressed in various immune cells and interact with their ligands, especially CD99 expressed on activated T cells, to participate in immune responses. Here we investigated whether PILR-derived agonists inhibit ${\beta}1$ integrin activity as ligands for CD99. PILR-derived peptides as well as PILR-Fc fusion proteins prevented cell adhesion to fibronectin through the regulation of ${\beta}1$ integrin activity. Especially, PILRpep3, a representative 3-mer peptide covering the conserved motifs of the PILR extracellular domain, prevented the clustering and activation of ${\beta}1$ integrin by dephosphorylating FAK and vinculin, which are major components of focal adhesion. In addition, PILRpep3 inhibited transendothelial migration of monocytes as well as endothelial cell tube formation. Furthermore, upon intraperitoneal injection of PILRpep3 into mice with collagen-induced arthritis, the inflammatory response of rheumatoid arthritis was strongly suppressed. Taken together, these results suggest that PILR-derived agonist ligands may prevent the inflammatory reactions of rheumatoid arthritis by activating CD99.

• IMMUNE NETWORK
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• 제23권4호
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• pp.33.1-33.13
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• 2023

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been acknowledged as an effective mean of preventing infection and hospitalization. However, the emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) has led to substantial increase in infections among children and adolescents. Vaccine-induced immunity and longevity have not been well defined in this population. Therefore, we aimed to analyze humoral and cellular immune responses against ancestral and SARS-CoV-2 variants after two shots of the BNT162b2 vaccine in healthy adolescents. Although vaccination induced a robust increase of spike-specific binding Abs and neutralizing Abs against the ancestral and SARS-CoV-2 variants, the neutralizing activity against the Omicron variant was significantly low. On the contrary, vaccine-induced memory CD4⁺ T cells exhibited substantial responses against both ancestral and Omicron spike proteins. Notably, CD4⁺ T cell responses against both ancestral and Omicron strains were preserved at 3 months after two shots of the BNT162b2 vaccine without waning. Polyfunctionality of vaccine-induced memory T cells was also preserved in response to Omicron spike protein. The present findings characterize the protective immunity of vaccination for adolescents in the era of continuous emergence of variants/subvariants.

• 생명과학회지
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• 제34권6호
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• pp.418-425
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• 2024

고형암은 여러 세포 유형의 이질적인 집단으로 구성되며, 암줄기세포는 자가 재생과 분화의 특성을 가지고 있다. 암줄기세포에서는 자가재생을 조절하는 줄기세포 신호전달체계가 과도하게 활성화되어 있어 암줄기세포는 암세포의 증식과 암 진행에 중요하다. 암줄기세포의 정의는 급성골수성백혈병에 의해 처음 제안되었으며, 다양한 연구를 통해 세포 표면 표지 발현에 따라 암 줄기세포를 분류할 수 있게 되었다. 또한, 암줄기세포는 종양 미세환경에서 잠재력을 보존하고 있고, 다양한 종양 미세환경 세포 유형은 정지 상태의 암줄기 세포를 유지하고 암 성장의 조절자 역할을 한다. 현재 사용되는 암 치료 방법은 증식성 세포를 표적으로 하기 때문에 치료에, 저항성을 가지는 휴지기 상태의 암 줄기세포는 재발이나 전이의 위험을 증가시키며, 종양 미세환경의 다양한 신호전달체계는 혈관계와 세포 외 기질을 리모델링함으로써 종양 지지 환경으로의 변화를 유도한다. 따라서, 암을 효과적으로 치료하려면 암줄기세포와 종양 미세환경을 표적 치료해야 하며, 종양 미세환경이 어떻게 면역 반응의 재프로그램을 유도하여 암의 성장, 면역 저항성 및 전이를 촉진하는지 이해하는 것이 중요하다. 따라서 본 총설을 통해 종양 미세환경에서 면역억제를 강화할 수 있는 세포 및 분자 메커니즘에 대한 현재 및 새로운 개념을 요약하고자 한다.

• Journal of Animal Science and Technology
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• 제49권5호
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• pp.599-610
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• 2007

근육내 파두유를 주입한 육계병아리에서 사료 중 크릴 밀 수준이 세포성 면역반응에 미치는 영향을 조사하였다. 갓 부화한 육계병아리(Ross) 수컷에 크릴 밀 0.0(기초사료), 0.5, 1.0 및 2.0% 사료를 급여하고 3주간 사육하였다. 20일령에 10㎕의 파두유를 정강이 근육내에 주입하였고, 24시간 뒤(21일령)에 혈중 TNF-α 활성과 오보트렌스훼린 수준 및 PBMC와 비장세포의 증식도를 올리브유를 주입한 대조구와 비교하였다. 크릴 밀 사료는 육계병아리의 생산성과 혈장 오보트렌스훼린 수준에 유의한 영향을 미치지 않았으나, 크릴 밀 0.0% 사료에 비해서 유의하게(p<0.0001) 혈장 TNF-α 활성을 감소시키고 PBMC 증식도를 높였다. 비장 세포증식도는 크릴 밀 1.0% 사료에서 유의하게(p=0.01) 높았다. 파두유 주입은 혈중 TNF-α 활성(p<0.0001), 오보트랜스훼린 수준 및 PBMC증식도(p<0.0001)를 높였다. 파두유 주입 시에 PBMC 증식도는 사료중 크릴 밀 수준에 따라 점차 감소(p<0.05) 하였고 비장세포 증식도는 크릴 밀 1.0 및 2.0% 사료에서 유의하게(p< 0.05) 감소하였다. 본 연구는 사료중 크릴밀이 파두유 주입으로 활성화한 선천 면역과 세포성 면역을 변화시킨다는 것을 나타내었다. (색인:파두유(croton oil), tumor necrosis factor -α(TNF-α), PBMC와 비장세포의 증식, 크릴 밀, 육계 병아리)

• Journal of Radiation Protection and Research
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• 제43권2호
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• pp.66-74
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• 2018

Background: Tumor response to anticancer therapies can much be influenced by microenvironmental factors. In this study, we determined the effect of these microenvironmental factors on DNA methylation using A549 human lung adenocarcinoma cell line. Materials and Methods: We subjected A549 cells to various conditions mimicking tumor microenvironment including hypoxia, acidosis (sodium lactate), oxidative stress ($H_2O_2$), bystander effect (supernatant from doxorubicin (Dox)-treated or irradiated cells), and immune cell infiltration (supernatant from THP-1 or Jurkat T cells). Genomic DNA was isolated from these cells and analyzed for DNA methylation. Clonogenic cell survival, gene expression, and metabolism were analyzed in cells treated with some of these conditions. Results and Discussion: We found that DNA methylation level was significantly decreased in A549 cells treated with conditioned media from Dox-treated cells or Jurkat T cells, or sodium lactate, indicating an active transcription. To determine whether the decreased DNA methylation affects radiation sensitivity, we exposed cells to these conditions followed by 6 Gy irradiation and found that cell survival was significantly increased by sodium lactate while it was decreased by conditioned media from Dox-treated cells. We further observed that cells treated with conditioned media from Dox-treated cells exhibited significant changes in expression of genes including BAX and FAS (involved in apoptosis), NADPH dehydrogenase (mitochondria), EGFR (cellular survival) and RAD51 (DNA damage repair) while sodium lactate increased cellular metabolism rather than changing the gene expression. Conclusion: Our results suggest that various tumor microenvironmental factors can differentially influence DNA methylation and hence radiosensitivity and gene expression in A549 cancer cells.

• 대한미생물학회지
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• 제21권3호
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• pp.311-329
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• 1986

The experimental exposure of animals to sources of ultraviolet radiation (UVR) which emit their energy primarily in the UVB region (280-320nm) is known to result in a number of well-described changes in the recipient's immune competence. Two such changes include a depressed capacity to effectively respond immunologically to transplants of syngeneic UVR tumors and a markedly reduced responsiveness to known inducers of delayedtype (DTH) and contact hypersensitivity (CH) reactions. The results of experiments that were designed to elucidate the mechanisms responsible for UVR-induced immunomodulation have implicated: 1) an altered pattern of lymphocyte recirculation, 2) suppressor T cells(Ts), 3) deviations in systemic antigen presenting cell (APC) potential. 4) changes in the production of interleukin-1-like molecules, and 5) the functional inactivation of epidermal Langerhans cells in this process. The exposure of skin to UVR, therefore, causes a number of both local and systemic alterations to the normal host immune system. In spite of this seeming complexity and diversity of responses, our recent studies have established that each of the UVR-mediated changes is probably of equal importance to creating the UVR-induced immunocompromised state. Normal animals were exposed to low dose UVR radiation on their dorsal surfaces under conditions where a $3.0\;cm^2$ area of skin was physically protected from the light energy. Contact sensitization of these animals with DNFB, to either the irradiated or protected back skin, resulted in markedly reduced CH responses. This was observed in spite of a normal responsiveness following the skin sensitization to ventral surfaces of the UVR-exposed animals. Systemic treatment of the low dose UVR recipients with the drug indomethacin (1-3 micrograms/day) during the UVR exposures resulted in a complete reversal of the depressions observed following DNFB sensitization to "protected" dorsal skin while the altered responsiveness found in the group exposed to the skin reactive chemical through directly UVR-exposed sites was maintained. These studies implicate the importance of EC as effective APC in the skin and also suggest that some of the systemic influences caused by UVR exposure involve the production of prostaglandins. This concept was further supported by finding that indomethacin treatment was also capable of totally reversing the systemic depressions in CH responsiveness caused by high dose UVR exposure (30K joules/$m^2$) of mice. Attempts to analyze the cellular mechanisms responsible established that the spleens of all animals which demonstrated altered CH responses, regardless of whether sensitization was through a normal or an irradiated skin site, contained suppressor cells. Interestingly, we also found normal levels of T effector cells in the peripheral lymph nodes of the UVR-exposed mice that were contact sensitized through normal skin. No effector cells were found when skin sensitization took place through irradiated skin sites. In spite of such an apparent paradox, insight into the probable mechanisms responsible for these observations was provided by establishing that UVR exposure of skin results in a striking and dose-dependent blockade of the efferent lymphatic vessels in all peripheral lymph nodes. Therefore, the afferent phases of immune responses can apparently take place normally in UVR exposed animals when antigen is applied to normal skin. The final effector responses, however, appear to be inhibited in the UVR-exposed animals by an apparent block of effector cell mobility. This contrasts with findings in the normal animals. Following contact sensitization, normal animals were also found to simultaneously contain both antigen specific suppressor T cells and lymph node effector cells. However, these normal animals were fully capable of mobilizing their effector cells into the systemic circulation, thereby allowing a localization of these cells to peripheral sites of antigen challenge. Our results suggest that UVR is probably not a significant inducer of suppressor T-cell activity to topically applied antigens. Rather, UVR exposure appears to modify the normal relationship which exists between effector and regulatory immune responses in vivo. It does so by either causing a direct reduction in the skin's APC function, a situation which results in an absence of effector cell generation to antigens applied to UVR-exposed skin sites, inhibiting the capacity of effector cells to gain access to skin sites of antigen challenge or by sequestering the lymphocytes with effector cell potential into the draining peripheral lymph nodes. Each of these situations result in a similar effect on the UVR-exposed host, that being a reduced capacity to elicit a CH response. We hypothesize that altered DTH responses, altered alloresponses, and altered graft-versus-host responses, all of which have been observed in UVR exposed animals, may result from similar mechanisms.

• Molecules and Cells
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• 제39권5호
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• pp.426-438
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• 2016

Plant disease resistance occurs as a hypersensitive response (HR) at the site of attempted pathogen invasion. This specific event is initiated in response to recognition of pathogen-associated molecular pattern (PAMP) and subsequent PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI). Both PTI and ETI mechanisms are tightly connected with reactive oxygen species (ROS) production and disease resistance that involves distinct biphasic ROS production as one of its pivotal plant immune responses. This unique oxidative burst is strongly dependent on the resistant cultivars because a monophasic ROS burst is a hallmark of the susceptible cultivars. However, the cause of the differential ROS burst remains unknown. In the study here, we revealed the plausible underlying mechanism of the differential ROS burst through functional understanding of the Magnaporthe oryzae (M. oryzae) AVR effector, AVR-Pii. We performed yeast two-hybrid (Y2H) screening using AVR-Pii as bait and isolated rice NADP-malic enzyme2 (Os-NADP-ME2) as the rice target protein. To our surprise, deletion of the rice Os-NADP-ME2 gene in a resistant rice cultivar disrupted innate immunity against the rice blast fungus. Malic enzyme activity and inhibition studies demonstrated that AVR-Pii proteins specifically inhibit in vitro NADP-ME activity. Overall, we demonstrate that rice blast fungus, M. oryzae attenuates the host ROS burst via AVR-Pii-mediated inhibition of Os-NADP-ME2, which is indispensable in ROS metabolism for the innate immunity of rice. This characterization of the regulation of the host oxidative burst will help to elucidate how the products of AVR genes function associated with virulence of the pathogen.

• 생명과학회지
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• 제19권2호
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• pp.284-288
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• 2009

선천성 면역은 숙주의 물리적 방어벽을 뚫고 침입하는 감염성 질병 원인균에 대항하는 첫 번째 방어로서 아주 중요한 역할을 한다. Mannose-binding lectin (MBL 또는 mannan-binding protein, MBP)은 혈청 내에 존재하는 면역성 단백질로서 감염 후 즉시 유발되는 acute phase response의 특정 단백질이다. MBL 단백질은 세균, 바이러스, 곰팡이, 기생충 등의 탄수화합물 구조에 결합하여 식균 작용을 돕거나 보체경로를 활성화 시킨다. MBL 단백질은 C-말단이 탄수화물을 인식하는 도메인이며, 연결 목 부위와 콜라겐 부위로 구성되어 있다. 혈청 내의 MBL 농도가 낮으면 높은 빈도로 면역결핍현상이 관찰된다고 알려져 있다. MBL 단백질의 기능과 유전에 대해 많은 연구가 되어져 왔으나 아직 MBL 단백질 복합체 등에 대한 연구는 많이 이루어져 있지 않다. 따라서 MBL 연구에 필수적인 MBL cDNA 제조와 재조합 단백질의 합성, 그리고 재조합 단백질을 항원으로 사용하여 polyclonal antibody를 생산한 연구 결과를 보고하는 바이다. 본 연구결과로 획득한 MBL cDNA, 재조합 단백질과 anti-MBL 항체는 앞으로의 MBL 연구에 절대적으로 필요한 도구가 될 것으로 생각된다.

• 대한약리학회지
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• 제31권3호
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• pp.323-331
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• 1995

사구체내 단핵구의 침윤은 면역학적뿐 아니라 비면역학적 사구체 질환 발생 초기에 특징적으로 관찰된다. 단핵구에서 합성되는 대표적인 사이토 카인인 tumor necrosis factor $(TNF){\alpha}$의 합성이 각종 사구체 질환과 관련되어 증가할 뿐 아니라 외부에서 투여한 $TNF{\alpha}$는 사구체 질환의 발생과 진행에 수반된 유사한 증세를 초래한다. 따라서 본 연구에서는 사구체 질환의 표적세포인 혈관간 세포를 이용하여 $TNF{\alpha}$에 의한 세포독성 기전을 검색하고자 하였다. 표준화된 체걸름법을 이용하여 사구체를 분리한후 collagenase로 처리하여 배양하므로써 혈관간 세포의 특징을 지닌 일차 배양 혈관간 세포계를 수립하였다. 세포독성의 지표로서 지질과산화물을 측정했을때, $TNF{\alpha}$는 용량의존적으로 배양 혈관간 세포의 지질과산화를 증가시켰다. 배양혈관간 세포를 $45^{\circ}C$에서 30분간 처리했을 때 heat shock protein 70의 합성이 증가함을 western 분석으로 확인하였을 뿐 아니라, $TNF{\alpha}$에 의한 지질과산화 증가를 효과적으로 억제함을 관찰하였다. 이상의 결과는 $TNF{\alpha}$에 의한 지질과산화 증가가 사구체 질환의 발생이나 진행에 관하여할 수 있음과 고온 전처리에 의해서 heat shock 반응을 초래하므로써 $TNF{\alpha}$에 의한 사구체 손상을 보호할 수 있음을 시사하였다.