• Archives of Pharmacal Research
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• v.22 no.5
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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.

• Journal of Chest Surgery
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• v.53 no.1
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• pp.22-27
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• 2020

Background: Previous studies have shown that lung cancer stem cells express CD133 and that certain cancer stem cells express cancer germline antigens (CGAs). The transcriptional regulation of CD133 is complicated and poorly understood. We investigated CD133 and CGA expression in a non-small cell lung cancer cell line. Methods: The expression levels of CD133 and CGAs (MAGE-6, GAGE, SSX, and TRAG-3) were measured in an NCI-H292 lung cancer cell line. The methylation status of the CD133 gene promoter region was analyzed. The expression levels and promoter methylation statuses of CD133 and CGAs were confirmed by treatment with the demethylating agent 5-aza-2'-deoxycytidine (ADC). Results: After treatment with ADC, CD133 expression was no longer detected. MAGE-6 and TRAG-3 were detected before ADC treatment, while GAGE and SSX were not detected. ADC treatment upregulated MAGE-6 and TRAG-3 expression, while GAGE expression was still undetected after treatment, and only weak SSX expression was observed. GAGE expression was not correlated with expression of CD133, while the levels of expression of MAGE-6, TRAG-3, and SSX were inversely correlated with CD133 expression. Conclusion: These results showed that CD133 expression can be regulated by methylation. Thus, the demethylation of the CD133 promoter may compromise the treatment of lung cancer by inactivating cancer stem cells and/or activating CGAs.

• Biomolecules & Therapeutics
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• v.15 no.4
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• pp.218-223
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• 2007

T cell proliferation is a pivotal to an effective immune response. Cyclin-dependent kinase (cdk) inhibitor, $p27^{kip1}$ is degraded to initiate T cell expansion. In this study, we show that although the expression of $p27^{kip1}$ protein was down-regulated, that of $p21^{cip1}$, another cdk inhibitor, was up-regulated in $CD8^+$ T cells following in vitro stimulation. Ex vivo gB antigen-stimulation following HSV immunization increased $p21^{cip1}$ positive cells that co-expressed IFN-$\gamma$. Moreover, $p21^{cip1}$ was co-expressed with IFN-${\gamma}$ in E7 antigen-stimulated $CD8^+$ T cells, whereas $p27^{kip1}$ was not. Our findings imply a role of $p21^{cip1}$ proteins in antigen-induced effector $CD8^+$ T cells differentiation in vivo.

• IMMUNE NETWORK
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• v.8 no.2
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• pp.46-52
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• 2008

Background: Oral tolerance is defined by the inhibition of immune responsiveness to a protein previously exposed via the oral route. Protein antigens exposed via the oral route can be absorbed through the mucosal surfaces of the gastrointestinal tract and can make physical contact with immune cells residing in the intestinal lamina propria (LP). However, the mechanisms of oral tolerance and immune regulation in the intestines currently remain to be clearly elucidated. Methods: In order to determine the effect of oral protein antigen intake (ovalbumin, OVA) on the intestinal LP, we assessed the expression profile of the T cell receptor and the co-receptors on the cells from the intestines of the tolerant and immune mouse groups. Results: We determined that the proportion of OVA-specific B cells and ${\gamma}{\delta}$ T cells had decreased, but the CD8${\alpha}{\beta}$ and D8${\alpha}{\alpha}$ T cells were increased in the LP from the tolerant group. The proportion of CD8＋ T cells in the spleen did not evidence any significant differences between treatment groups. Conclusion: These results indicate that CD8＋ T cells in the intestinal LP may perform a regulatory role following antigen challenge via the oral route.

• Journal of Veterinary Clinics
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• v.26 no.6
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• pp.528-533
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• 2009

In the current study, the mesenchymal stem cells (MSCs) isolated and propagated from the human umbilical cord blood (UCB) were tested for their capabilities of differentiation into chondrocytes in vitro. The mesenchymal progenitor cells (MPCs) collected from UCB were cultured in a low glucose DMEM medium with 10% FBS, L-glutamine and antibiotics. The human MSC colonies were positively stained by PAS reaction. When the immunophenotypes of surface antigens on the MSCs were analyzed by fluorescence-activated cell sorter (FACS) analysis, these cells expressed positively MSC-related antigens of CD 29, CD44, CD 90 and CD105, whereas they did not express antigens of CD14, CD31, CD34, CD45, CD133 and HLA-DR. Following induction these MSCs into chondrocytes in the chondrogenic differentiation medium for 3 weeks or more, the cells were stained positively with safranin O. We clearly confirmed that human MSCs were successfully differentiated into chondrocytes by RT-PCR and immunofluorescent stain of type-II collagen protein. These data also indicate that the isolation, proliferation and differentiation of the hUCB-derived MSCs in vitro can be used for elucidating the mechanisms involved in chondrogenesis. Moreover this differentiation technique can be applied to developing cell-based tissue regeneration or repair damaged tissues.

• Clinical and Experimental Pediatrics
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• v.53 no.11
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• pp.957-964
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• 2010

Purpose: Our study attempted to determine the prognostic significance of minimal residual disease (MRD) detected by a simplified flow cytometric assay during induction chemotherapy in children with B-cell acute lymphoblastic leukemia (B-ALL). Methods: A total of 98 patients were newly diagnosed with precursor B-ALL from June 2004 to December 2008 at the Asan Medical Center (Seoul, Korea). Of those, 37 were eligible for flow cytometric MRD study analysis on day 14 of their induction treatment. The flow cytometric MRD assay was based on the expression intensity of CD19/CD10/CD34 or aberrant expression of myeloid antigens by bone marrow nucleated cells. Results: Thirty-five patients (94.6%) had CD19-positive leukemic cells that also expressed CD10 and/or CD34, and 18 (48.6%) had leukemic cells with aberrant expression of myeloid antigens. Seven patients with ${\geq}1%$ leukemic cells on day 14 had a significantly lower relapse-free survival (RFS) compared to the 30 patients with lower levels (42.9 % [18.7%] vs. 92.0% [5.4%], $P$=0.004). Stratification into 3 MRD groups (${\geq}1%$, 0.1-1%, and <0.1%) also showed a statistically significant difference in RFS (42.9% [18.7%] vs. 86.9% [8.7%] vs. 100%, $P$=0.013). However, the MRD status had no significant influence on overall survival. Multivariate analysis demonstrated that the MRD level on day 14 was an independent prognostic factor with borderline significance. Conclusion: An MRD assay using simplified flow cytometry during induction chemotherapy may help to identify patients with B-ALL who have an excellent outcome and patients who are at higher risk for relapse.

• Korean Journal of Veterinary Research
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• v.34 no.2
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• pp.287-299
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• 1994

Plasma protein which has been known as one of nonspecific immunostimulators was added to feedstuff to examine its effect on the enhancement of cellular immune response in porcine immune system. A total of 40 piglets, 20 male and 20 female each, were fed for 30 days with or without plasma protein. The peripheral blood were collected and analyzed for the investigation of leukocyte subpopulations and their activities by using a panel of monoclonal antibodies specific to porcine leukocyte differentiation antigens and flow cytometry. The results obtained as follows. 1. Subpopulations expressing major histocompatibility complex(MHC) class I antigen were $96.2{\pm}3.1%$ and $86.6{\pm}3.8%$ in piglets fed with plasma protein and in piglets fed without plasma protein, respectively. 2. Proportion of leukocyte subpopulation expressing MHC class II antigens were significantly higher in the piglets fed with plasma protein than ones without plasma protein. The proportion was $27.6{\pm}3.6%$ and $16.6{\pm}2.2%$ in MHC class II DQ antigen, and $28.1{\pm}2.0%$ and $20.0{\pm}0.3%$ in MHC class II DR antigen, respectively. 3. A significant increase in the proportion of cells expressing poCD2 was not found in piglets fed plasma protein. 4. Proportion of subpopulation expressed porcine(Po) CD4 antigens which specific to helper T lymphocytes were not increased (18.3-19.1% vs. 25.6-28.8%), rather slightly decreased, in plasma protein-treated group. 5. The most important increase of proportion in plasma protein-treated group was the leukocyte subpopulation specific to $poCD8^+$ T cytotoxic/suppressor lymphocytes. The expression level was significantly higher up to 45.9-47.1% in plasma protein-treated group in comparing with 29.7-33.0% in non-plasma protein-treated group. 6. Lymphoblastogenetic responses using different concentrations of Con A mitogen and plasma protein has found that the responses of lymphocyte from piglets fed plasma protein was significantly activated (p<0.01). The activities measured by 3[H]-thymidine incorporation showed 3-6 times stronger in plasma protein-treated group than those in non-plasma protein-treated group. The study has concluded that plasma protein, which has known as a nonspecific immunostimulator, may have an immunoenhancing activities in porcine lymphoid system by increase the activated cell proportions and their blastogenetic properties which is critical to host immune responses.

• Biomedical Science Letters
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• v.13 no.4
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• pp.325-332
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• 2007

Cell-mediated immune response (CMI) is a major immune protective mechanism against tuberculosis (TB) infection. Among several components involved in CMI, recent studies suggest that CD8+ T cells are important in controlling TB infection. In our previous report, we defined four Mycobacterium tuberculosis (MTB) derived epiotpe peptides specific for HLA-A*0201-restricted CD8+ T cells. These four peptides are $PstAl_{75-83}$, $ThyA_{30-38}$, $RpoB_{127-135}$ and $85B_{15-23}$. In this study, these epitope peptides specific CD8+ T cell responses in tuberculous pleurisy were investigated using ex vivo $IFN-\gamma$ elispot assay and intracellular $IFN-\gamma$ staining method. As a result, we observed these epitope peptide specific CD8+ T cell responses are induced in all three patients with tuberculous pleurisy suggesting that CD8+ T cells are involved in protective immune mechanism against MTB infection in tuberculous pleurisy. However, the CMI to mitogens and MTB antigens from pleural fluids of patients with tuberculous pleurisy does not seem to correlate with that from peripheral blood, although the sample size is too small to make any conclusion. In sum, the MHC I restricted CD8+ T cell responses seem to be induced efficiently in the pleural fluids, at the site of TB infection, in which the CMI is actively induced. In addition, these experiments suggest that MHC I restricted CD8+ T cell mediated immune responses are also involved in protective mechanism against MTB infection in extra-pulmonary TB.

• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.493-509
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• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Journal of the korean academy of Pediatric Dentistry
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• v.35 no.4
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• pp.597-606
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• 2008

Resorption of alveolar bone in periodontitis is due to excessive differentiation and activation of osteoclasts. Bacterial antigens causing periodontitis activates CD4 T cells, which leads to expressing RANK ligand (RANKL) on CD4 T cells. RANKL binds RANK on preosteoclasts or osteoclasts, and enhances the differentiation preosteoclasts into osteoclasts and the activation of mature osteoclasts. CD137, one of TNF receptor (TNFR) family, expressed on activated T cells binds with CD137 ligand (CD137L) on antigen presenting cells. Cross-linking of CD137 by CD137L acts as T cell co-stimulatory signals and, therefore, enhances the activation of T cell. In this study, I elucidated the biological responses of CD137L on (pre)osteoclasts and RANKL on T cells in the context of in vivo interaction between T cells and osteoclasts. RAW264.7, murine monocytic cells, constitutively express CD137L. Ligation of CD137L with anti-CD137L mAb inhibited RANKL-induced osteoclast formation in a dosedependent manner. Bone marrow cells are expressed CD137L by the treatment with M-CSF. Cross-linking of CD137L abolished M-CSF/ RANKL-evoked the formation of multi-nucleated osteoclasts. Both mouse CD4 and CD8 T cells are expressed RANKL following their activation. Ligation of RANKL with OPG, the decoy receptor for RANKL, inhibited both CD4 and CD8 T cell proliferation. These effects were attributed to RANKL-induced apoptosis. These data indicate that CD137L and RANKL on osteoclasts and T cells, respectively provide them with inhibitory signal.