• Animal cells and systems
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• 제8권2호
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• pp.117-123
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• 2004

The purpose of this study was to analyze inhibitory effects of anti-4-1BB monoclonal antibody on melanoma metastasis The 4-1BB (CD137) T cell molecule is a member of the TNF receptor family and its activation by either 4-1BB ligand or antibody induces T cell activation and growth. In the present study, administration of anti-4-1BB mAb induced inhibition of melanoma metastasis. Agonistic anti-4-1BB mAb induced not only CD$8^+$4-1BBT cells but also CD$8^+$IFN-${\gamma}$$^{+}$ T cell population. In the presence of anti-CD3 antibody, lymphocytes produced high levels of IFN-${\gamma}$ and low levels of IL-4 in anti-4-1BB mAb treated group. Exposure of melanoma cells to IFN-${\gamma}$ induced expression of MHC-I molecules. Thus, the increase in number of CD$8^+$T cells and enhanced MHC-I expression on B16F10 cells by augmented IFN-${\gamma}$ production in response to anti-4-1BB mAb may result in suppression of tumor growth and metastasis.s.

• BMB Reports
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• 제47권3호
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• pp.122-129
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• 2014

Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In-depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-${\gamma}$. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions.

• Journal of Periodontal and Implant Science
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• 제32권3호
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• pp.457-473
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• 2002

이 연구는 배양된 치주인대세포에 TGF(Transforming growth factor)-${\beta}_1$과 PDGF(Plateletderived growth factor)-BB를 농도별로 혼합 주입해서 세포의 증식능, 단백질 및 교원질 합성능을 측정해 봄으로서 TGF-${\beta}_1$ 이 치주인대세포의 중식과 활성에 대한 PDGF-BB의 효과를 상승시킬 수 있은지 알아보고자 본 실험을 실시하였다. 교정치료를 위해 내원한 환자로 부터 건강한 제일소구치를 발거하여 치주인대세포률 분리, 배양하여 TGF-${\beta}_1$과 PDGF-BB를 동시에 주입한 군과 TGF-${\beta}_1$를 4, 24시간 전처리 배양한 군과 나누어 실험하였다. TGF-${\beta}_1$, PDGF-BB를 주입하지 않은군을 대조군으로 하여 DNA 합성능, 총단백질과 교원질 합성능을 측정하여 다음과 같은 결과를 얻었다. 치주인대세포에 TGF-${\beta}_1$과 PDGF-BB을 동시 주입하였을 때 DNA 합성능의 효과는 대조군에 비해 모든 군에서 증가된 양상을 보였으며 1ng/ml PDGF-BB 투여군에 비해 10ng/ml PDGF-BB 투여군에서 증가 양상이 높았고 PDGF-BB 단독 투여군보다 TGF-${\beta}_1$병용 투여군에서 DNA 합성능이 증가된 양상을 나타내었으며 5ng/ml TGF-${\beta}_1$과 10ng/ml PDGF-BB 투여군에서 가장 높은 증가 양상을 보였다. TGF-${\beta}_1$ 4시간과 24시간 전처리 배양군 양군 공히 lng/ml PDGF-BB 투여군을 제외한 모든 군에서 대조군에 비해 증가된 양상을 보였으며 lng/ml PDGF-BB 투여군에 비해 10ng/ml PDGF-BB 투여군에서 증가 양상이 더 높았고 PDGF-BB 단독 투여군보다 TGF-${\beta}_1$ 전 처리군에서 DNA 합성능이 증가된 양상을 나타내 였으며 5ng/ml TGF-${\beta}_1$ 전 처리 후 10ng/ml PDGF-BB 투여군에서 가장 높은 증가 양상을 보였다. 치주인대세포에 TGF-${\beta}_1$과 PDGF-BB을 동시 주입하였을 때 총단백질합성량은 대조군에 비해 모든 군에서 증가된 양상을 보였으며 lng/ml PDGF-BB 투여군에 비해 10ng/ml PDGF-BB 투여군에서 증가 양상이 더 높게 나타났다. PDGF-BB 단독 투여군보다 TGF-${\beta}_1$ 병용 투여군에서 총단백칠 합성양이 증가된 양상을 나타내었다. TGF-${\beta}_1$ 4과 24시간 전처리 배양군의 총단백질 합성양은 대조군에 비해 모든 군에서 증가된 양상을 보였으며 1ng/ml PDGF-BB 투여군에 비해 10ng/ml PDGF-BB 투여군에서 증가 양상이 더 높았고 TGF-${\beta}_1$ 전처리 배양군이 PDGF-BB 단독 투여군보다 총단백질 합성양이 증가된 양상을 나타내었다. TGF-111과 PDGF-BB를 동시 투여하였을 때 대조군에 비해 모든 군에서 교원질 합성능이 증가하는 경향을 나타내었으며, 비교원성단백질의 합성능은 1, 10ng/ml PDGF-BB 단독투여군을 제외하고 대조군에 비해 증가하는 경향을 보였다. 총단백질에 대한 교원질 합성의 상대적 비율 PDGF-BB 단독 투여군보다 TGF-${\beta}_1$ 병용 투여군에서 감소하는 정향을 나타내었다. TGF-${\beta}_1$ 4과 24시간 전처리 배양군의 교원질과 비교원성 단백질 합성능은 대조군에 비해 모든 군에서 교원질과 비교원성 단백질 합성능이 증가하는 경향을 나타내었으며 PDGF-BB 단독 투여군보다 TGF-${\beta}_1$ 병용 투여군에서 총단백질 합성양이 증가된 양상을 나타내었으며 그 정도는 TGF-${\beta}_1$의 농도 의존적인 양상을 보였다. 총단백질에 대한 교원질 합성의 상대적비율은 TGF-${\beta}_1$ 4,24시간전처리 배양군 모두에서 대조군에 비해 감소하는 경향을 나타내었다. 이상의 결과를 종합해 볼 때 치주인대세포에서 TGF-${\beta}_1$은 PDGF-BB의 기능을 조절하는 능력을 가지고 있으며 두 성장인자 주입시 동시주입시보다 TGF-${\beta}_1$을 전처리 해 줌으로써 PDGF-BB의 반응을 더욱 촉진시킬 수 있음을 알 수 있었다.

• Molecules and Cells
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• 제24권1호
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• pp.132-138
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• 2007

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T-cells, and 4-1BB signaling due to interaction with 4-1BB ligand or ligation with anti-4-1BB monoclonal antibody (mAb) costimulates T cells. It has been shown that administration of anti-4-1BB mAb induces anti-tumor immunity in mice, but the nature of the cellular subsets responsible for this immunity is uncertain. In this study we found that anti-4-1BB mAb administration to B16F10 melanoma-bearing mice induced marked expansion of $CD11c^+CD8^+$ T-cells in parallel with suppression of pulmonary tumors. The mAb-treated mice produced higher levels of $IFN-{\gamma}$ in their tumor tissues, spleen and lymph nodes than mice exposed to control antibody. When the $CD11c^+CD8^+$ T-cells were purified and re-stimulated in vitro, they produced high levels of the Th1 cytokines, $IFN-{\gamma}$ and IL-2, but low levels of the Th2 cytokines, IL-4 and IL-10. Furthermore, they expressed high levels of 4-1BB and CD107a, a marker of activated cytotoxic T-lymphocytes. Our results suggest that $CD11c^+CD8^+$ T-cells play a role in the anti-tumor immunity induced by anti-4-1BB mAb.

• Clinical and Experimental Pediatrics
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• 제54권9호
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• pp.373-379
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• 2011

Purpose: 4-1BB (CD 137) is a costimulatory molecule expressed on activated T-cells. Repression by 4-1BB is thought to attenuate Th2-mediated allergic reactions. The aim of this study was to investigate the effect of 4-1BB on allergic airway inflammation in a murine asthma model. Methods: BALB/c mice were sensitized to and challenged with ovalbumin (OVA). Hu.4-1BB-Fc was administered 1 day before the first OVA sensitization or 1 day after the second OVA sensitization. Following antigen challenge, airway responsiveness to methacholine was assessed and bronchoalveolar lavage (BAL) fluid was analyzed. Total immunoglobulin (Ig) E, OVA-specific IgE, $IgG_1$, and $IgG_{2a}$ levels in sera were measured by enzyme-linked immunosorbent assay. Lung pathology was also evaluated. Results: In mice treated with Hu.4-1BB-Fc before the first OVA sensitization, there was a marked decrease in airway hyperresponsiveness, total cell count, and eosinophil count in the BAL fluid. In addition, Hu.4-1BB-Fc treatment decreased serum OVA-specific $IgG_1$ levels and increased serum $IgG_{2a}$ level significantly compared with the corresponding levels in mice sensitized to and challenged with OVA. Hu.4-1BB-Fc-treated mice also showed suppressed peribronchial and perivascular inflammatory cell infiltration. In contrast, treatment with Hu.4-1BB-Fc 1 day after sensitization had no effect on airway hyperresponsiveness and showed less suppression of inflammation in lung tissue. Conclusion: Administration of Hu.4-1BB-Fc can attenuate airway inflammation and hyperreactivity in a mouse model of allergic airway inflammation. In addition, administration before sensitization may be more effective. These findings suggest that 4-1BB may be a useful therapeutic molecule against asthma.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1995년도 춘계학술대회
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• pp.82-82
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• 1995

4-lBB molecule is expressed on the surface of activated CD4$\^$+/ and CD8$\^$+/ T cells. We generated a panel of anti-4-1 B5 murine mAbs using a fusion protein consisting of the extracellular domain of human 4-1 BB fused to Glutathione S-transferase. The binding activity against cell surface 4-1 BB molecule was assessed by flow cytometry analysis. These studies showed that several anti-4-1 BB mAbs bound to 10-30% of CD4$\^$+/ and CD8$\^$+/T cells in PHA or Con A stimulated PBLs, although these mAbs interacted with only, l-2% of CD4$\^$+/ and CD8$\^$+/ T cells in normal PBLs, indicating the specificity of mAbs to the 4-l BB molecule on activated CD4$\^$+/ and CD8$\^$+/ T cells. Next, we examined the effect of an anti-4-l BB mAb (4B4-1-1) on allogeneic mixed lymphocyte reactions (MLRs). The data indicated that the antibody significantly inhibited the proliferative response at higher concentrations. When tested with several T cell mitogens, the antibody had no stimulatory or inhibitory effects on the mitogen-mediated T cell proliferation. These data suggest that 4-1 BB molecule may play a role in the regulation of antigen-mediated immune response.

• IMMUNE NETWORK
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• 제2권3호
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• pp.133-136
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• 2002

Background: The costimulatory molecule 4-1BB, a member of nerve growth factor receptor/tumor necrosis factor (NGFR/TNFR) super family, is involved in cell survival and death. Methods: In this study, female C57BL/6 ($H-2^b$) mice were used as a recipient, and DBA/2 ($H-2^d$) as a donor to assess a mixed lymphocyte reaction (MLR) and CTL response in vitro, and skin graft survival. IL-2, IFN level was measured by ELISA. Results: Mixed lymphocyte reaction (MLR) analysis showed that 4-1BB-deficient responder cells showed enhanced cellular proliferation over littermate controls. In contrast, IL-2 production was diminished only in 4-1BB knockout cultures. The IFN expression, on the other hand, was comparable between the groups. When female C57BL/6 ($H-2^b$) mice were grafted with the trunk skin of DBA/2 ($H-2^d$) mice, the in vivo tissue destruction of 4-1BB-deficient mice was not distinct from the normal littermates. Conclusion: These data suggest that 4-1BB is critical for the induction of alloreactive responses in vitro but 4-1BB alone could not change the course of skin rejection in vivo.

• 대한수의학회지
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• 제29권4호
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• pp.457-460
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• 1989

This work was carried out to get some informations about blood types and their researches, involved blood stock and genetic identification. Horses examined were total 55 heads of sire, mare and their progeny in Korean Horse Affairs Association. 1. Albumin phenotypes of 26 mare were examined. The appearance of phenotype AA, BB, AB, was 1, 18, 7 respectively. The gene frequency of albumin A was 0.17 and albumin B was 0.76. 2. The appearance of phenotype AA, BB, AB in 29 progeny was 1, 16, 12 respectively. The gene frequency of albumin A was 0.24 and albumin B was 0.76. The gene frequency of gene A was higher than their parents. 3. Identification of the relationship between parents and their progeny was also examined. 4 of type AB between AA & BB, 4 of type BB between BB & BB, 13 of type AB between BB & AB were borned. In third case, all of progeny was type AB. This results suggest positive relationship between them.

• 한국임상수의학회지
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• 제9권2호
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• pp.433-449
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• 1992

Total CPK activities and CPK isoenzymes fractions of the sera and tissues were examined to obtain the physiological basic data of ruminant available in veterinary clinical practice. For the sera total CPK activities and CPK isoenzymes fractions, total 39 clinically healthy Korean native goats (3 to 10 months old, IS of female and 18 of male) and 6 of Korean native goats (1 to 2 years old, 3 of female and 3 of male) were used. Seventeen Korean native cattle (3 to 6 years old, 10 of female and 7 of male) and 27 Holstein-Friesian cattle (2 to 8 months old, 7 of female and 3 to 12 years old, 20 of female) were also examined for the sera total CPK activities and CPK isoenzymes fractions. For the total CPK activities and CPK isoenzyme fractions, 3 of female Korean native goats (7 months old), 3 of female Korean native cattle (2 years old) and 3 of dairy cattle (2 years old, 2 of female and 1 of male) were used. The tissues examined were the cerebrum (2 of Korean native cattle), spinal cord (1 of Korean native cattle), heart, lung, diaphragm, reticulum, liver, spleen, kidney, jejunum. colon and femoral muscle. The results obtained were as follows : 1. In Korean native goats less than 1-year-old. serum total CPK activities were 67.8${\pm}$17.7(39.0~96.5) IU/$\ell$ in female and 63.4${\pm}$19.0(28.7~94.4) IU/$\ell$ in male. Further they were 67.0${\pm}$5.3(59.5~70.7) IU/$\ell$ and 54.5${\pm}$11.1(39.1~69.4) IU/$\ell$ in female and male Korean native goats over 1-year-old, respectively. Serum total CPK activities of female were slightly higher than those of male. Significance between age and sex was not found. 2. Serum total CPK activities were 56.8${\pm}$19.7(27.6~90.5) IU/$\ell$ and 65.6${\pm}$10.8(52.8~78.0) IU/$\ell$ in female and male Korean native adult cattle, respectively, Serum total CPK activities of male were slightly higher than those of female, but they were not significant 3. Serum total CPK activities we,e 72.5${\pm}$8.2(57.2~83.2) IU/$\ell$ and 60.8${\pm}$12.5(42.7~80.6) IU/$\ell$ in calves and adult of dairy acttle, respectively. Serum total CPK activities of calves were significantly higher than those of adult(p<0.05). 4. In Korean native goats less than 1-year-old, serum CPK isoenzymes fractions were high with decreasing order of MM>MB>BB and MM>BB>MB in female and male, respectively. Further they were high with decreasing order of MM>MB>BB and MM>B8>MB in female and male Korean native goats over 1-year-old, respectively. The main fractions of CPK isoenzymes were MM in sera of Korean native goats. 5. Serum CPK Isoenzyme fractions were high with decreasing order of MM>MB>BB In both female and male of Korean native cattle. The main fraction among them was MM. 6. Serum CPK isoenzymes fractions were high with decreasing order of MM>BB>MB in both calves and adult of dairy cattle. The main fraction among them was MM. 7. Total CPK activities were high with decreasing order of the femoral muscle>kidney>reticulum>diaphragm>liver>spleen>heart>colon>lung>jejunum in Korean native goats. 8. Total CPK activities were high with decreasing order of the spinal cord >cerebrum>femoral muscle>reticulum>kidney>liver>spleen>diaphragm>lung>colon>heart>jejunum in Korean native cattle. 9. Total CPK activities were high with decreasing order. of the femoral muscle >liver>retoculum>kidney>heart>colon>lung>spleen>jejunum>diaphrasm in dairy cattle. 10. The pattern of the cardiac CPK isoenzymes fractions was identical in Korean native goats, Korean native cattle and dairy cattle. They were high in the order of MM>MB without BB fractions and the main fraction was MM. 11. The pattern of the pulmonary CPK isoenzymes fractions was the same Korean native goats, Korean native cattle and dairy cattle. They were high with decreasing order of MM>MB>BB and the main fraction among them was MM. 12. The pattern of CPK isoenzymes fractions of the diaphragm was Identical in Korean native goats and Korean native cattle. They were high with decreasing order of MM >BB >MB except dairy cattle (MM>MB>BB) but the main fraction among them was MM. 13. The pattern of the reticular CPK isoenzymes fractions was identical in Korean native cattle and dairy cattle. They were high with decreasing order of BB >MM >MB except Korean native goats(BB>MB>MM) but the main, fraction among them was BB 14. The pattern of the hepatic CPK isoenzymrs fractions was identical in Korean native cattle and dairy cattle. They were high with decreasing order of MB >BB >MM except Korean native goats(MB>MM>BB)but the main fraction was MB. 15. The splenic CPK isoenzymes fractions showed different pattern. They were high with decreasing order of MB>BB>MM, MM>BB>MB and BB>MB>MM in Korean native goats, Korean native cattle and dairy cattle, respectively. The main fraction among them was different from each other. 16. The pattern of the renal CPK isoenzymes fractions was identical in Korean native cattle and dairy cattle. They were high with decreasing order of MM >MB>BB except Korean native goats(BB>MB>MM). 17. The CPK isoenzymes fractions of the Jejunums showed different pattern. They were high with decreasing order MM>MB>BB, MM>BB>MB and BB>MM>MB in Korean native goats, Korean native cattle and dairy cattle, respectively. The main fractions were MM In Korean native goats and Korean native cattle, and BB in dairy cattle. 18. The colonic CPK isoenzymes fractions showed different pattern. They were high with decreasing order of MM>MB>BB, MM>BB>MB and BB>rrfB>MM in Korean native goats, Korean native cattle and dairy cattle, respectively. The main fractions were MM in Korean native goats and Korean . native cattle, and BB in dairy cattle. 19. The cerebral CPK isoenzymes fractions were high with decreasing order of BB >MM without MB detected in Korean native cattle and those of spinal cord were high with decreasing order of BB >MM >MB. The main fractions in both cerebrum and spinal cord were BB.

• Journal of Periodontal and Implant Science
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• 제26권4호
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• pp.873-887
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• 1996

Platelet-derived growth factor(PDGF) is one of the polypeptide growth fators. PDGF has been reported as a biological mediator which regulates activities of wound healing process including the cell proliferation, migration and metabolism. Recent studies indicated that demineralized root surface as the primary site for growth factor application has advantages over other application method, especially due to binding capacity of growth factor for exposed matrix component of deminera1ized dentin surface. The purpose of this study is to evaluate optimal application time of PDGF-BB on proliferation of human gingival fibroblasts using deminera1ized dentin surface as primary application site. Human gingival fibroblasts and dentin slabs were prepared from the first premolar tooth extracted for the orthodontic treatment, cells were cultured in DMEM/I0% FBS at the $37^{\circ}C$, 5% CO2 incubator. All of the dentin slabs were preconditioned with Tetracycline HCI(100mg/ml) solution and rinsed in PBS. In the cell proliferation experiment, experimental group was immersed in DMEM containing 10% FBS, 50ng/rnl PDGF-BB during different time(30sec, 1, 2, 4, 8 minutes) and dried. Cells at concentration of $1{\times}10^5$cells/ml were seeded in each culture well which contained dentin slabs and incubated for 6 hours. Then, all of the dentin slabs were moved into new 24 well culture dish and incubated for 24, 48, 72 hours. The cell counting was done by hemocytometer with inverted phase contrast microscope after trypsinization. The results were as follows : The application of PDGF-BB for 1, 2 min slightly increased the number of gingival fibroblasts, and the application of PDGF-BB for 4, 8 min prominently increased the number of gingival fibroblasts. The application of PDGF-BB for 4 min showed maximum proliferation rate of gingival fibroblasts at 24, 48, 72 hours, and the application of PDGF-BB for 8 min showed less proliferation rate of gingival fibroblasts compared to the application of PDGF-BB for 4 min at 24, 48, 72 hours. In conclusion, the application of PDGF-BB for 4 min appeared to be optimal to obtain maximum proliferation of gingival fibroblasts using demineralized dentin surface as primary applicaton site of PDGF-BB.