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61.
Fas (CD95) is a cell surface glycoprotein that mediates apoptotic cell death when cross-linked with agonistic anti-Fas monoclonal antibodies (MAbs) or the endogenous Fas ligand. In this study, we investigated the in vitro biological properties of a panel of anti-human Fas MAbs. We found that five anti-Fas MAbs of IgG1 subclass (B.E28, B.G30, B.L25, DX2, and B.G34) induced marked apoptotic cell death in Fas-expressing leukemia cells, although this killing was delayed when compared to the cytolytic effect mediated by the prototypic anti-Fas MAb of IgM subclass (clone CH-11). On the other hand, four clones (ZB4, B.G27, B.D29, and B.K14) efficiently blocked apoptotic cell death induced by the CH-11 MAb or Fas ligand. The ability of these MAbs to inhibit cell death appeared to correlate with their relative affinity for the Fas molecule. Furthermore, different clones recognized the same epitope and elicited different effects (induction or inhibition of cell killing); conversely, different clones elicited the same effect but recognized different epitopes. These results suggest that the different biological effects of anti-Fas MAbs would not be mediated in an epitope-restricted manner. The relative binding affinity might correlate to some extent with the biological properties of the MAb. 相似文献
62.
A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix 总被引:2,自引:0,他引:2
Hideki Fujii Naoyuki Nishikawa Hiroyuki Komazawa Makoto Suzuki Masayoshi Kojima Isamu Itoh Aya Obata Koichi Ayukawa Ichiro Azuma Ikuo Saiki 《Clinical & experimental metastasis》1998,16(1):94-104
A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthe-sized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, Rrev-COCH2CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (Rrev-COCH2CH2-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis. © Rapid Science 1998 相似文献
63.
The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role 总被引:8,自引:0,他引:8
Youngnak-Piboonratanakit P Tsushima F Otsuki N Igarashi H Machida U Iwai H Takahashi Y Omura K Yokozeki H Azuma M 《Immunology letters》2004,94(3):215-222
PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-gamma. The T-cell proliferative responses and IFN-gamma production that were induced by IFN-gamma-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin. 相似文献
64.
Expression of membrane-bound and soluble receptor activator of NF-kappaB ligand (RANKL) in human T cells 总被引:1,自引:0,他引:1
The receptor activator of NF-kappaB ligand (RANKL) and its receptor RANK are critical regulators for immune responses as well as bone remodeling. RANKL is a type II transmembrane protein that has two forms-a membrane-anchored protein and a secreted protein. In this report, we demonstrate for the first time the kinetical expression of two forms of RANKL in human T cells using two monoclonal antibodies (mAbs) against human RANKL, which we newly derived. Freshly isolated T cells rarely expressed mRANKL, while the activation of T cells induced a substantial but minimal level of mRANKL as well as the accumulation of considerable amounts of sRANKL. The addition of the metalloprotease inhibitor KB-R8301 efficiently suppressed the release of sRANKL from activated T cells or RANKL-transfectants, and reciprocally enhanced the mRANKL expression. The membrane form of RANKL was also expressed on the infiltrating T cells in the rheumatoid synovial fluid and in the gingival tissues of patients with periodontitis. Our results demonstrate that the expression of mRANKL on T cells is strictly limited, and the majority of RANKL protein produced by T cells may be active in the soluble form after shedding. The mAbs that were derived in this study may be useful for investigating the regulation and function of RANKL in immune responses and bone remodeling. 相似文献
65.
Keisuke Yoshihama Hideki Mutai Mariko Sekimizu Fumihiro Ito Shin Saito Shintaro Nakamura Takuya Mikoshiba Ryoto Nagai Akiko Takebayashi Fuyuki Miya Kenjiro Kosaki Hiroyuki Ozawa Tatsuo Matsunaga 《Clinical genetics》2023,103(4):466-471
Carotid body tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs. 相似文献
66.
67.
Marked Suppression of T Cells by a Benzothiophene
Derivative in Patients with Human T-Lymphotropic Virus Type
I-Associated Myelopathy/Tropical Spastic Paraparesis
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Masahiko Makino Miyuki Azuma Shin-Ichi Wakamatsu Yukio Suruga Shuji Izumo Mitchel M. Yokoyama Masanori Baba 《Clinical and Vaccine Immunology : CVI》1999,6(3):316-322
In a search for new anti-autoimmune agents that selectively
suppress activation of autoreactive T cells, one such agent,
5-methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide
(CI-959-A), was found to be effective. This compound, which is known to
suppress tumor necrosis factor alpha (TNF-α)-induced CD54 expression,
inhibited the primary proliferative response of the T cell to antigen
(Ag)-presenting cells (APCs) including allogenic dendritic cells (DCs),
autologous Epstein-Barr virus-infected B cells, and human T
lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T
cells from patients with HTLV-I-associated myelopathy/tropical spastic
paraparesis (HAM/TSP) spontaneously proliferate in vitro, and their
activation is reported to be associated with CD54 expression. The
spontaneous proliferation of T cells from patients with HAM/TSP was
entirely blocked by CI-959-A. However, in this study, the T-cell
proliferation in 15 patients with HAM/TSP was found to depend more
extensively on major histocompatibility complex (MHC) class II and CD86
than on CD54 Ags. Since most important APCs for the development of
HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on
DC generation and on the expression of surface molecules on activated T
cells is examined. CI-959-A suppressed recombinant
granulocyte-macrophage colony stimulating factor (GM-CSF)- and
recombinant interleukin-4-dependent differentiation of DCs from
monocytes and inhibited the expression of CD54 and, more extensively,
MHC class II and CD86 Ags. CI-959-A showed little toxicity toward
lymphoma or HTLV-I-infected T-cell lines or toward monocytes and
cultured DCs. These results suggest that CI-959-A might be a potent
anti-HAM/TSP agent.Human T lymphotropic virus type I
(HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
is thought to be an autoimmune disease induced by HTLV-I infection
(8, 9, 24). The T lymphocytes obtained from patients with
HAM/TSP patients produce interleukin-2 (IL-2) in vivo and proliferate
spontaneously in vitro without any additional stimuli or cytokines
(35). This spontaneous proliferation of T lymphocytes (SPL)
depends on the interaction of T cells with antigen (Ag)-presenting
cells (APCs) such as dendritic cells (DCs) (17, 25) and
HTLV-I-infected CD4+ T cells (15, 32). The DCs
localized in the blood and nonlymphoid organs are considered to be
functionally immature, in that they are optimized for the uptake and
processing of Ag but not for the initiation of primary T-cell
responses. However, after the uptake of Ag and exposure to inflammatory
agents including tumor necrosis factor alpha (TNF-α) and IL-1, the
DCs undergo a process of maturation and gain the ability to present Ag
to T cells for their priming (22, 26). In addition to DCs,
HTLV-I-infected CD4+ T cells directly stimulate autologous
CD4+ T cells in a major histocompatibility complex (MHC)
class II- and CD86 molecule-dependent fashion (32). Among
the T cells stimulated with these APCs, some might cross-react with
self Ags and closely associate with the development of HAM/TSP.We have been searching for compounds that inhibit the cellular
interaction between APCs and T cells to suppress the activation of
autoreactive and Ag-specific T cells. The molecules associated with the
APC-T cell interaction may provide an effective target for therapy for
autoimmune diseases. Binding of APCs and T cells is initiated by
contact of adhesion molecules, such as CD54 and CD11a/CD18, expressed
on both cells, and induction of sustained proliferation of T cells
requires two independent signals provided by APCs: a T-cell
receptor-mediated Ag-specific signal and a signal mediated by
costimulatory molecules (CSMs) (10, 20) including CD86 and
CD58 Ags (1, 11, 31). Blocking of their tight binding
through adhesion molecules or interaction of the CSMs with CSM ligands
effectively suppressed the abnormal expansion of disease-associated T
cells in vivo and in vitro (19, 30, 32) and sometimes
effectively induced a long-term unresponsiveness of T cells to recall
stimuli.5-Methyl-3-(1-methylethoxy)benzo[b]thiophene-2-carbox-amide
(CI-959-A) is known to inhibit CD54 expression, and its derivative is
reported to inhibit casein kinase II (4). In the present
study, we found that CI-959-A markedly suppressed SPL in patients with
HAM/TSP. Furthermore, the compound suppressed the primary T-cell
proliferative response to stimuli provided by various APCs, the
differentiation of immature DCs from monocytes and their subsequent
maturation, and the induction of expression of MHC class II, CD54, and
CD86 Ags on activated CD4+ T cells. 相似文献
68.
Changes in liver regenerative factors in a case of living-related liver transplantation 总被引:1,自引:0,他引:1
Eguchi S Okudaira S Azuma T Ohno Y Fujioka H Furui J Tanaka K Kanematsu T 《Clinical transplantation》1999,13(6):536-544
Liver regeneration in a patient with fulminant hepatic failure (FHF) who underwent living-related partial liver transplantation (LRLT) was investigated regarding hepatic growth factors. The patient was a 16-yr-old Japanese male who developed severe subacute FHF. LRLT was performed using an extended left lobe of the ABO matched patient's mother. In the recipient, the pre-transplant levels of both plasma hepatocyte growth factor (HGF) and transforming growth factor (TGF)-beta were extremely high and rapidly decreased following the liver replacement. The liver volume evaluated using a CAT scan increased 195% after 2 wk in graft liver and 110% after 2 wk in the hepatectomized donor. The explanted liver (FHF liver), the liver from donor (normal liver), and the graft liver [the 3rd post-transplant day (POD 3)] were all investigated immunohistochemically. FHF liver: No liver regeneration was observed [proliferative cell nuclear antigen (PCNA) labeling index (L.I.): 0%]. In the liver, both HGF in the hepatocytes and c-met on the membrane of the hepatocytes were positive. TGF-beta was positive in the hepatocytes and no apoptosis was detected by the TUNEL method. Donor liver (POD 0): Few PCNA stained hepatocytes were detected. No HGF was detected but c-met was clearly detected on the cell membrane of the hepatocytes. Neither TGF-beta nor apoptosis was detected. Graft liver (POD 3): The PCNA L.I. was conspicuous at 40%. HGF was positive in non-parenchymal cells and c-met was positive in the cytoplasm of the hepatocytes. TGF-beta was negative while apoptosis was positive in the zone 3 hepatocytes. In conclusion, these findings suggested that the liver of the patient with FHF did not respond to liver regenerative stimulus, in part, through involvement of inhibitor TGF-beta. On POD 3, the transplanted graft was in a vigorous regenerative status in comparison to that in the hepatectomized donor. The HGF/c-met system is thought to be involved in the mechanism of regeneration. Intrahepatic apoptosis was detected in the graft on the 3rd post-transplant day probably due to transient ischemia in the liver, which was not related to the Fas/Fas-ligand system. 相似文献
69.
70.
Microglial proliferation in cortical neural cultures exposed to feline immunodeficiency virus 总被引:6,自引:0,他引:6
Microglia are thought to play an important role in neurodegenerative changes due to infection with human or animal immunodeficiency viruses. Using feline immunodeficiency virus and cat neural cultures, we observed a dramatic increase in the accumulation of microglia from a basal rate of 5-7% day(-1) to 25-126% day(-1). Both live virus and heat-inactivated virus induced proliferation. Negligible proliferation was seen in purified microglial cultures. Conditioned medium from astrocytes or mixed neural cultures treated with feline immunodeficiency virus stimulated the proliferation of purified microglia. Disease progression may be facilitated by early non-infectious interactions of lentiviruses with neural tissue that promote the activation and proliferation of microglia. 相似文献