Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen-induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro

Oh, Bo Ram,Suh, Dong-hyeon,Bae, Daekwon,Ha, Nina,Choi, Young Il,Yoo, Hyun Jung,Park, Jin Kyun,Lee, Eun Young,Lee, Eun Bong,Song, Yeong Wook BioMed Central 2017 Arthritis research & therapy Vol.19 No.-

<P><B>Background</B></P><P>Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA).</P><P><B>Methods</B></P><P>CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry.</P><P><B>Results</B></P><P>In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3<SUP>+</SUP> T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation.</P><P><B>Conclusion</B></P><P>CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.</P>

Poster Session : PS 0694 ; Rheumatology ; Appearance of Psoriasis after TNF-a Blocker and Use of Ustekinumab or Tocilizumab for Refractory Monoarthritis

( Jin Young Moon ),( Dong Jin Go ),( Jae Hyun Lee ),( Jin Kyun Park ),( Eun Bong Lee ),( Yeong Wook Song ),( Jai Il Youn ),( Eun Young Lee ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Nowadays, tumor necrosis factor-a (TNF-a) blockers are used for the treatment of RA, infi ammatory bowel diseases (IBD), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis. Paradoxically, there are some reports of appearance of psoriasis after TNF-a blockers. We report a patient who have seronegative mono-rheumatoid arthritis (mono-RA) on knee joint that experienced psoriasis after TNF-a blocker therapy (adalimumab and etanercept). For the patient, oral medication is not available due to intolerance; thus, we tried ustekinumab which is an anti-IL-12/23 monoclonal antibody that has been used to treat psoriasis. After ustekinumab injection, psoriatic skin lesions and joint symptoms were much improved in the patient. But in the following period, joint pain and swelling aggravated and synovial fi uid cytokine levels such as IL-6 and IL-17 were elevated. Treatment was changed to tocilizumab, humanized monoclonal antibody against IL-6 receptor. After injection, knee joint swelling rapidly subsided without worsening of psoriatic skin lesion.

Case Reports : Appearance of Psoriasis after Tumor Necrosis Factor-α Blocker and Use of Ustekinumab or Tocilizumab for Refractory Monoarthritis

( Jinyoung Moon ),( Nakwon Kwak ),( Jin Lim ),( Dong Jin Go ),( Jae Hyun Lee ),( Jin Kyun Park ),( Eun Bong Lee ),( Yeong Wook Song ),( Jai Il Youn ),( Eun Young Lee ) 대한류마티스학회 2015 대한류마티스학회지 Vol.22 No.4

Nowadays, tumor necrosis factor-α (TNF-α) blockers are used for treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Paradoxically, there are some reports on the appearance of psoriasis after administration of TNF-α blockers. Here, we report on a patient with monoarthritis in a knee joint who experienced psoriasis after TNF-α blocker therapy (adalimumab and etanercept). Oral medication was not a treatment option due to patient intolerance; thus, we tried ustekinumab, an anti-interleukin (IL)-12/23 monoclonal antibody used for treatment of psoriasis. Following ustekinumab injection, psoriatic skin lesions and joint symptoms were much improved. However, in the following period, joint pain and swelling became aggravated and synovial fluid cytokine levels including IL-6 and IL-17 were elevated. The treatment was changed to tocilizumab, a humanized monoclonal antibody against IL-6 receptor. After injection, knee joint swelling rapidly subsided without worsening of psoriatic skin lesions. (J Rheum Dis 2015;22:263-268)

백혈병 마우스 모델의 동종골수이식에서 활성화된 자연살해세포들의 보충이 이식편대백혈병효과와 이식편대숙주반응에 미치는 영향

엄현석,한치화,박수정,김소연,정낙균,정대철,진종률,최일봉,양형모,서영훈,송현근,최인표,민우성,김춘추 대한조혈모세포이식학회 2001 대한조혈모세포이식학회지 Vol.6 No.1

배경: 백혈병에서 동종골수이식 (allogeneic bone marrow transplantation)의 성공적 치료 효과를 얻기 위해서는 이식편대숙주반응 (graft-versus-host disease, GVHD) 발생의 극복과 재발의 방지가 중요한 과제이다. 골수를 역류원심성 세포분리 (counterflow centrifugal elutriation, CCE) 방법으로 분리하여 얻은 rotor off (R/O) 세포분획은 T 세포의 수는 적지만 조혈모세포들을 다량 포함하고 있어 동종골수이식에서 주조직적합복합체 (major histocompatibility complex, MHC) 차이를 극복할 수 있고, 이식편의 생착 성공과 GVHD 발생 예방에 효과적이다. 그러나 골수로부터 T 세포를 제거하면 백혈병세포를 공격하는 이식편대백혈병 (graft-versus-leukemia, GVL) 효과가 감소되기 때문에 백혈병 재발의 빈도가 높다. 자연살해세포 (natural killer cell, NK cell)의 보충 첨가는 동종골수이식 후 GVHD 발생을 줄이면서 충분한 GVL 효과를 얻을 수가 있다. 따라서 저자는 분리 후 IL-2로 활성화시킨 NK 세포들을 골수 R/O 세포분획과 함께 백혈병 마우스 모델에 동종이식함으로써 GVHD와 GVL에 미치는 효과를 관찰하였다. 방법: Balb/c (H-2^(d)) 마우스에서 유래된 A20 (murine B-lymphoma/leukemia cell line, H-2^(d)) 백혈병 세포를 이식 2 일 전에 Balb/c 마우스에 주입하고, 치사량의 전신 방사선을 조사한 직후에 Balb/c 또는 C57BL/6 (H-2^(b)) 마우스의 골수 R/O 세포분획을 꼬리정맥을 통하여 주입하였다. 이들은 모두 이식 후 6-8 주 이내에 사망하였다. 동종이식의 대조군 (n=9)에는 1 × 10^(7)의 R/O 세포분획만을 주입하였고, 실험군 (n=9)에는 C57BL/6 마우스의 비장세포들로부터 단클론항체들을 이용한 negative selection방법으로 분리한 후 IL-2로 활성화된 5 × 10^(5)의 NK 세포분획을 1 × 10^(7)의 R/O 세포분획과 함께 주입하였다. GVL 효과의 판정은 이식 후 14 일과 28 일 째 되는 날 마우스에서 골수, 비장, 간 등을 얻어 백혈병 세포들의 침윤을 조직학적으로 관찰하였으며, GVHD의 정도는 육안적 관찰법으로 평가하였다. 결과: R/O 세포분획만을 이식한 대조군의 골수, 비장, 그리고 간 조직에서는 A20 백혈병 세포의 침윤이 각각 89% (8/9), 78% (7/9)와 22% (2/9)에서 관찰되었고, R/O 세포분획과 NK 세포분획을 함께 이식한 실험군에서는 비장과 간을 제외한 골수에서만 89% (8/9)에서 A20 백혈병 세포의 침윤이 관찰되어 두 군 사이에 장기별 분포의 차이를 볼 수 있었다 (P= 0.0001). 한편 GVHD는 두 군 모두에서 경하게 나타나서 유의한 차이는 없었다. 또한 생착 부전으로 사망한 마우스는 없었다. 결론: CCE를 이용하여 T 세포를 제거한 동종골수이식에서 NK 세포의 보충은 GVHD의 악화는 일으키지 않으면서, 백혈병의 진행을 억제하는 GVL 효과를 얻을 수 있었다. Background: Allogeneic bone marrow transplantation (BMT) with T cell-depleted marrow accompanies engraftment failure and relapse of leukemia by a loss of the graft-versus-leukemia (GVL) effect frequently, while it can prevent GVHD. Supplement of NK cells could prevent GVHD and enhance GVL effect in several murine allogeneis BMT models Roter off (R/O) cell fraction obtained by counterflow centriation elutriatio (CCO) contains small number of T cells and many hematopoietic stem cells. The aim of this study was to determine the effect of R/O cell fraction supplemented with IL-2 activated NK cells on GVL and GVHD within the leukemic mouse BMT model. Methods: Inoculation of A20 (H-2d, murine B-lymphoma/leukemia, Balb/c origin) cells into Balb/c mice via the tail vein 2 days prior to lethal total body irradiation (TBI) and infusion of the Balb/c BM or C57BL/6 (H-2b) R/O fraction were performed. It resulted in 100% mortality within 6 to 8 weeks. The irradiated mice in the control group were injected with 1 × 107 R/O cell fraction alone (n=9) and in the experimental group mice were injected with 1 × 107 R/O cell fraction plus 5 × 105 negatively selected IL-2 activated NK cell fractions of the spleens via the tail vein (n=9). On day 14 and 28 after BMT, the bone marrows, spleens, and livers of mice were harvested for histopathologic analysis of the infiltrations of leukemic cells. We then evaluated the GVHD within the mice. Results: A histopathologic study of the recipients receiving R/O fraction alone showed infiltration of leukemic cells, 89% (8/9) in bone marrows, 78% (7/8) in spleens, and 22% (2/9) in livers. The experimental group of mice showed only the infiltration of leukemic cells 89% (8/9) in bone marrows, not in spleens and livers. There were the organ differences of the leukemic cells infiltrations between the two groups (P=0.0001). There were no obvious differences in the GVHD scores between these two groups, and severe GVHD was not observed. There was no engraftment failure among groups. Conclusion: Thus, our findings suggest that R/O cell fraction obtained by CCE and supplemented with NK cells can promote GVL effect without mediating clinically overt GVHD in allogeneic BMT of mouse leukemia.

구성주의 번역이론을 위한 인식론적·인지과학적 토대

봉일원,박여성 東國大學校 1994 東國論叢 Vol.33 No.-

化學發癌 物質의 發癌 能力에 關한 反應性 指數의 理論的 硏究

李一峯,宋寧大,林周相,崔茂悅,朴柄珏 嶺南大學校 基礎科學硏究所 1990 基礎科學硏究 Vol.10 No.-

There are many theoretical indices for chemical carcinogenicity. Among the various indices, the LUMO electron density and approximate superdelocalizability have taken to compared and discussed for the carcinogenicity of PAHs, aromatic amines and Azo-compounds. The sum of LUMO electron density of the trans-butadiene type 1, 2, 4 positions in a molecule has been known to be in more agreement with the observed values than those of approximate superdelocalizability. It is suggested that any trans-butadiene type 1, 2, 4 positions play an importmant role in the elucidation of mechanism of chemical carcinogenesis.

中國 特色의 社會保障체제 改革에 관한 考察

강일규,송봉규 한국직업능력개발원 2001 직업능력개발연구 Vol.4 No.2

This study examines changes in social security and welfare system since the implementation of the reform and open-up policy in China. The Chinese government has pushed reforms in social security and welfare aspects. Its efforts has brought considerable successes. First of all, one of them is the strong consciousness in social security reform. The Chinese society reached consensus on that there has been deficiency and defect in traditional social security system provided by the government, state-owned enterprises and rural communities. And they also realized that the reforms in social security should be taken urgently. China has been successfully upheld policy for reforms in social security systems with Chinese characteristics. Is doesn't reach its goal yet. But It has sustained reforms maintaining Chinese cultural and traditional characteristics. In the past, equity was the top priority in Chinese social security. Now new reform policy aims at efficiency as well as equity. Adapting efficiency principle is considered as a kind of measure to keep up with the open market economy and social developments. China has been made efforts to legislate reform initiatives for systematic control in social security. Those efforts give the expectations of profound reforms in social security in the future. But there are important principles that Chinese government should consider in implementing reforms. Those are the basic functions of the social security system. First, it is the security. Society should provide benefits that cover those who are in strained circumstances. Second, it is the universality. Society offer social benefits every individual in need regardless of region, occupation and other differences. Third, it is the equity. Social security is a mechanism of equal allocation. So society should give its members equal opportunities and rights to access social security system. When these principles are maintained, social security reform could success.

中國과 臺灣의 統一政策比較

정재일,송봉규 尙志大學校 1998 論文集 Vol.20 No.-

This paper is purposed to comparative studying on the unification policy between Taiwan and PRC(People Republic of China). On the unification policy. Taiwan suggests 'Two Regions in One Country', but PRC suggests 'Two Systems in One Country'. What are the meanings of two regions and two systems? What are the differances between 'two regions' and 'two systems'?

중국의 실업문제와 정부의 역할

강일규,송봉규 한국직업능력개발원 2001 직업능력개발연구 Vol.4 No.1

This study is intended to give a view of Chinese government's efforts in unemployment issue. The government in China has been continued significant role in the economic reforms by adopting"market economy with socialist characteristics". Unemployment in China has been rising and become serious burden to its government. We study what has brought widespread unemployment and its characteristics. We also observe social problems caused by widespread unemployment and Chinese government's efforts to cope with the mass unemployment. After Deng Xio Ping implemented reform and opening policy in 1978, China has been rapidly changed. This reform and opening policy has been the driving force for economic growth. And the economic growth made China one of the fast developing nations in the world. But Chinese economic reforms also brought some dark sides of the market mechanism. One of them is the unemployment issue. China faces mass unemployment owing to the surplus labor forced by layoffs at the state-owned enterprises, economic restructuring and rapid urbanization across the nation. The mass unemployment is contributing to a very real and serious social crisis. The government made plans to fight against unemployment, which threats economic and social securities, Including : (1) the Policy for job creating and reemployment and (2) the unemployment insurance and (3) the social insurance for the elderly and (4) emphasizing the vocational education and training and (5) Providing start-up businesses with good education and (6) exporting its labor forces aborad. In addition, we argue that it is necessary to continue the study about market economy-oriented Chinese government's efforts for unemployment in preparation for unification with socialist North Korea.

기니픽에서 Kanamycin 이독성

박찬일,송영복,정봉진,박용호 충남대학교 의과대학 지역사회의학연구소 1999 충남의대잡지 Vol.26 No.2

To evaluate experimental kanamycin - induced ototoxicity, changes of hearing loss were observed after administration of kanamycin in guinea pig, using auditory brainstem rcsponse(ABR) audiometry. Kanamycin(KM), 50mg/kg/day(group I), 100mg/kg/day(group Ⅱ), 200mg/kg/day(group Ⅲ) and 400mg/kg/day(group IV), was injected intramuscularly in each group and ABR thresholds were measured every other days through 50 days after the initial administration of KM. The injection of KM was discontinued at the day when the ABR threshold was increased more than 40 dB in each guinea pig. After the discontinuation of KM injection, ABR thresholds recovered progrssively to the base line level before the day 50 in group I and Il. But the ABR threshold changes were progressed after discontinuation of KM injection and finally they showed no responses in group III and IV. The results suggested that high dose KM administration could result progressive and irreversible hearing loss after the discontinuation of KM administration.