BACKGROUND: In the course of graft-versus-host disease (GVHD) or diseases that histologically mimic GVHD (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome), it is known that epidermal Langerhans cells (LCs) are depleted from the epidermis. However, the mechanism and significance of LC depletion is not well known. OBJECTIVES: To investigate the numerical, morphological and phenotypic changes in LCs and apoptosis of LCs in the course of GVHD using a non-irradiated mouse GVHD model. METHODS: BALB/c nu/nu mice and C57BL/6 mice were used as recipients and donors, respectively. Recipient mice were injected with T-cell-enriched donor spleen cells. Skin samples were harvested at various times after the inoculation. The numerical and morphological changes were examined by an immunofluorescence study of epidermal sheets. Apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling method and flow cytometric analysis using annexin V. Phenotypic change was studied by flow cytometric analysis of epidermal cell suspensions. The mixed epidermal cell lymphocyte reaction (MELR) was performed to examine functional changes in the epidermal cells. RESULTS: Five days after inoculation, a graft-versus-host reaction occurred. Epidermal LCs began to decrease from the sixth day. On the fifth day, the LCs became larger and had prominent dendrites. Immediately before the LCs began to decrease, many LCs became round in shape, with scanty dendrites. LC apoptosis was not observed in the epidermis either on the fifth or seventh day. Phenotypically, the expression of CD40, CD80, CD86 and major histocompatibility complex class II antigen on the LCs was upregulated on the fifth and seventh day. Epidermal cells from GVHD mice showed an increased allostimulatory capacity in the secondary MELR. CONCLUSIONS: These results suggest that at early GVHD onset, most LCs may not undergo apoptosis in the epidermis but are phenotypically activated, resulting in further activation of alloreactive T cells and aggravation of the disease.

Animals↗

PubMed2000

[Huge aneurysm of aortic coronary cusp and Valsalva sinus secondary to Behçet's disease].

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Aortic Aneurysm↗

PubMed1998

Down-regulation of CXCR2 expression on human polymorphonuclear leukocytes by TNF-alpha.

TNF-alpha is implicated in the initiation of cytokine cascades in various inflammatory settings. To assess the interactions of multiple cytokines at the level of inflammatory effector cells, we examined the effects of TNF-alpha on the expression of two IL-8Rs (CXCR1 and CXCR2) on polymorphonuclear leukocytes (PMNs). TNF-alpha decreased the surface expression of CXCR2 in a dose- and time-dependent manner. In contrast, CXCR1 expression was not affected by TNF-alpha. The release of CXCR2 into the supernatant of TNF-alpha-treated PMNs was detected by immunoblotting and immuno-slot-blot analyses, suggesting that the down-regulation of CXCR2 was caused mainly by shedding from the cell surface. The CXCR2 down-regulation was inhibited by PMSF and aprotinin, supporting the hypothesis that the shedding was mediated by serine protease(s). The intracellular Ca2+ mobilization and chemotaxis in response to IL-8 were suppressed by the pretreatment of PMNs with TNF-alpha, indicating that the decrease in CXCR2 was reflected in the decreased functional responses to IL-8. In contrast, the O2- release, which is mediated by CXCR1, was not suppressed by TNF-alpha. The treatment of whole blood with TNF-alpha also caused a significant reduction in CXCR2 and markedly suppressed intracellular Ca2+ mobilization and chemotaxis in response to IL-8, while enhancing the O2- release. These findings suggest that TNF-alpha down-regulates CXCR2 expression on PMNs and modulates IL-8-induced biologic responses, leading to the intravascular retention of PMNs with an enhanced production of reactive oxygen metabolites.

Antigens, CD↗

PubMed1998

Heterogeneity of dendritic cells in human superficial lymph node: in vitro maturation of immature dendritic cells into mature or activated interdigitating reticulum cells.

A two-color immunofluorescent analysis indicated that dendritic cells (DCs) in the human axillar lymph nodes (ie, lymph nodal DCs (LnDCs)) can be classified into three subsets. The first subset consists of CD1a+/CD86(- or dim)/CD83(- or dim) nondendriform DCs found mainly in lymph sinuses, the second is of CD1a-/CD86+/CD83+ dendriform DCs scattered in normal T zones, and the third is of large CD1a(bright)/CD86+/CD83+ dendriform DCs occasionally found in hyperplastic T zones. A three-color flow cytometric analysis, immunoperoxidase staining, and electron microscopic observation indicated that the majority of LnDCs corresponded to the first subset, which showed distinctive characteristics of DCs but did not fulfill the ultrastructural criteria for interdigitating reticulum cells (IDCs) and did not contain Birbeck granules. When LnDCs were cultured for 7 days, they became large CD1a(dim)/CD86+/CD83+ dendriform cells, which formed large complexes with many T cells and exhibited distinctive ultrastructural features of interdigitating reticulum cells. LnDCs cultured in the presence of granulocyte/macrophage colony-stimulating factor became markedly larger CD1a(bright)/CD86+/CD83+ dendriform cells forming large complexes with numerous T cells. These findings suggest that cells of the first subset represent immature LnDCs just migrating from epidermis, those of the second subset represent interdigitating reticulum cells, and those of the third subset represent interdigitating reticulum cells probably stimulated with certain immunostimulatory cytokines such as granulocyte/macrophage colony-stimulating factor. It is also suggested that either the second or the third subsets of LnDCs are derived from the first subset.

Antigens, CD↗

PubMed1998

The expression of co-stimulatory molecules and their relationship to the prognosis of human acute myeloid leukaemia: poor prognosis of B7-2-positive leukaemia.

We examined the expression of co-stimulatory molecules on leukaemic cells of 52 adult patients with acute myeloid leukaemia (AML) (34 men and 18 women) and analysed the relationship between these expressions and the patient's prognosis. B7-1 was not expressed in any of the 23 patients investigated, whereas B7-2 was expressed in 26/52 patients (50.0%). B7-2 was expressed in all AML patients with monocytic morphology (M4 or M5) and in 16/42 cases without monocytic morphology. CD54 was expressed in 28/ 37 patients examined (75.7%), and CD58 was expressed in all of the AML patients except one (M 7). The overall survival of the 26 B7-2-positive leukaemia patients (1-24 months, median survival 11.5 months) was significantly shorter than that of the 26 B7-2-negative leukaemia patients (1-71+ months, median 35.1 months) (P=0.0080). In addition, the B7-2-positive patients exhibited significantly shorter disease-free survival periods compared to the B7-2-negative patients (P=0.021). There was no significant difference in age, sex, haematological data and complete remission rate between the B7-2-positive and B7-2-negative patients. Our results indicated that B7-2 is one of the most crucial factors in the prognosis of adult acute leukaemia and can be expected to have an important role in tumour immunity.

Acute Disease↗

PubMed1998

Combined anterior thigh flaps and vascularised fibular graft for reconstruction of massive composite oromandibular defects.

Six massive, composite oromandibular defects were reconstructed using combined anterior (anterolateral and anteromedial) thigh flaps and vascularised fibular graft in bridge or chimeric fashion. Except for minor dehiscence in one case and infection in another, all flaps survived without complication. Anterior thigh flaps provide large-calibre, long vascular pedicles while derivative branches from the lateral circumflex femoral system facilitate simultaneous transplantation of multiple components. Because the pedicle of the vascularised fibular graft is of insufficient length, the lateral circumflex femoral vessels provide a remote vascular source as a flow-through vascular conduit. A combined flap using the lateral circumflex femoral system is considered to be most suitable for reconstruction of through-and-through defects of the head and neck. The authors describe the advantages of this method and the detailed anatomy of the cutaneous perforators of the anterior thigh flaps.

Adult↗

PubMed1998

Perforator-based flap for coverage of lumbosacral defects.

Lumbosacral defects on 20 patients were covered with a perforator-based flap. Cutaneous perforators derived from the 9th and 10th intercostal arteries, the 4th lumbar artery, and multiple gluteal perforators that penetrate the gluteus maximus muscle were used as vascular pedicles. Minor complications occurred in five cases. Using this method, minimal morbidity of the donor site is expected because the gluteus maximus need not be sacrificed. Accordingly, perforator-based flaps are especially indicated for ambulatory patients, but for paraplegic patients as well. Even in the event of recurrence, another perforator-based or musculocutaneous flap can be elevated from the ipsilateral side because of the presence of multiple perforators in the lumbosacral and gluteal regions.

Adult↗

PubMed1998

[Successful treatment with donor leukocyte transfusion followed by interferon-alpha in a patient with relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation].

A 44-year-old man with CML in chronic phase was admitted for BMT from an HLA-identical sibling. Ph positive cells were undetectable at 3 and 7 months after BMT but became detectable by cytogenetic analysis of bone marrow aspirates at 12 months after BMT. He was treated with IFN-alpha (6 million units/day, 3 times a week) without apparent effect. Donor leukocyte transfusion (DLT) was performed four times between 20 months and 23 months after BMT, transfusing 3.4 x 10(8) mononuclear cells/kg. However, leukocytosis appeared and the NAP score declined at 25 months after BMT. FISH analysis revealed an increase in bcr-abl positive cells. IFN-alpha was restarted using the same schedule at 26 months after BMT. Three months after restarting IFN-alpha, the leukocyte count fell to the normal range, NAP score increased to a normal level, and bcr-abl positive cells decreased markedly. He has remained in hematological and cytogenetic remission for 20 months, and bcr-abl chimeric mRNA remained undetectable by PCR. These results suggest that CML which does not respond to DLT may be cured by subsequent IFN-alpha therapy, possibly by inducing anti-leukemia immune responses.

Adult↗

PubMed1998

[A clinical study on the cases of ischemic colitis: comparison of clinical images based on time from onset of the disease to detection of bloody stool].

A study was performed on 28 cases of ischemic colitis. The patients were divided into three groups: Group A (9 cases with bloody stool detected within 2 hours after the onset of abdominal pain), Group B (7 cases with bloody stool detected in 2 to 6 hours), and Group C (12 cases with bloody stool detected after more than 6 hours). These cases were comparatively studied. Variables used were as follows: (1) age, (2) sex, (3) constipation, (4) vomiting, (5) peak value of WBC count (/microliter) after admission, (6) peak value of log CRP (microgram/dl), (7) presence of ulcerative lesion in endoscopic findings in acute stage. Using Group A B and C as classification variables, canonical discriminant analysis was performed. As a result, clear linearity was recognized in Group A-->B-->C, and the values (5), (6) and (7) were extracted as the corresponding variables. For these variables, significant difference was also noted in multivariate analysis of covariance. These results suggest that it is possible to predict the severity of the disease to some extent as represented by objective markers of inflammation by finding the time from onset of abdominal pain to detection of bloody stool.

Adolescent↗

PubMed1997

Random migration of polymorphonuclear leukocytes induced by GM-CSF involving a signal transduction pathway different from that of fMLP.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced random migration of human polymorphonuclear leukocytes (PMNs) but not chemotaxis. Chemoattractants such as N-formyl-methionyl-leucyl-phenylalanine (fMLP), leukotriene B4 (LTB4), and interleukin-8 (IL-8) induced both random migration and chemotaxis. Other inflammatory cytokines, including granulocyte colony-stimulating factor (G-CSF), interleukin 1alpha (IL-1alpha), and tumor necrosis factor alpha (TNF-alpha), did not induce either movement. One-minute exposure of PMNs to GM-CSF was sufficient for the induction of random migration, whereas fMLP-induced random migration required continued presence of fMLP. Inhibitors of phosphatidylinositol 3-kinase (PI3-K), protein kinase C (PKC), and protein tyrosine kinase (PTK) had no effect on random migration induced by GM-CSF, whereas fMLP-induced movements were partially inhibited by PTK inhibitors but not by inhibitors of PI3-K inhibitors nor PKC inhibitors. Myosin light chain kinase inhibitors inhibited movements of PMNs induced by both GM-CSF and fMLP. These findings also imply that some aspects of the signal transduction pathway of GM-CSF leading to random migration is different from that of fMLP. Our findings suggest that cell movements are controlled through diverse signal transduction systems.

Androstadienes↗

PubMed1997

Leukotriene B4-activated human endothelial cells promote transendothelial neutrophil migration.

We explored the effect of leukotriene B4 (LTB4) on endothelial cells in LTB4-induced transendothelial migration (TEM) of neutrophils as an in vitro model of neutrophil extravasation. Chemotactic response of human neutrophils to LTB4 was significantly lower than that in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP), whereas the extent of TEM in response to LTB4 was significantly higher than that to fMLP. The study on random migration induced by LTB4 and fMLP also showed similar results, which indicated that LTB4 might affect the human umbilical cord vein endothelial cell (HUVEC) barrier. Neutrophil TEM was induced by pretreatment of HUVEC monolayer with LTB4 but not with fMLP. Treatment of endothelial cells by ONO-4057, a LTB4 receptor antagonist, abolished the effect of LTB4 almost completely whereas neutrophils treated with ONO-4057 could transmigrate through HUVEC treated with LTB4. These findings indicated that LTB4 could induce neutrophil TEM by acting on HUVEC.

Cell Movement↗

PubMed1997

Demonstration of functionally distinct human polymorphonuclear leukocyte fractions by simultaneous measurement of phagocytosis and oxygen radical generation.

Phagocytosis and oxygen radical generation by human polymorphonuclear leukocytes (PMNLs) were studied by a two-color flow cytometric analysis, where the red fluorescent product(s) of hydroethidine was used as an indicator of intracellular generation of oxygen radicals and opsonized zymosan (OZ) as an indicator of phagocytosis. Unstimulated cells formed a single population of cells without any significant fluorescence. PMNLs stimulated by OZ exhibited a high red fluorescence. Most PMNLs phagocytosed OZ and generated oxygen radicals when stimulated by zymosan particles opsonized with human AB serum at concentrations of more than 10%, whereas three distinct subpopulations (designated as R1, R2 and R3) appeared when stimulated by zymosan particles opsonized with 3% serum; R1 cells enhanced neither green nor red fluorescence, R2 cells enhanced green fluorescence but not red fluorescence, and R3 cells enhanced both green and red fluorescence. The R2 cells completely disappeared by the addition of Trypan blue. Most of the R3 cells disappeared by the addition of cytochalasin B. These findings on the three fractions were confirmed by the observation under fluorescence microscopy of cells in each fraction obtained by sorting. In conclusion, PMNLs could be separated into three functionally distinct subpopulations when stimulated by zymosan particles opsonized with a suboptimal concentration of serum.

Cell Differentiation↗

PubMed1995

Histamine chloramines have a persistent stimulating effect on histamine H2 receptors and gastric acid secretion.

Histamine plays an important role in the control of gastric acid secretion. Recently, chlorinated derivatives of histamine have been identified as having multiple effects on the intestinal tract. The aim of this study was to investigate the role of histamine chloramines on gastric acid secretion. We compared the effects of histamine and histamine chloramines on the histamine H2 receptors in vitro using guinea pigs and on gastric acid secretion in rats. With respect to the effects on histamine H2 receptors, histamine monochloramine showed agonist effects similar to those seen with histamine, but the agonist effects of histamine dichloramine were about half those of histamine. Unlike histamine effects, the histamine H2 receptor agonist effects of histamine monochloramine and histamine dichloramine did not disappear after repeated washout. With respect to the stimulation of gastric acid secretion in vivo, histamine monochloramine was similar to histamine, while the effect of histamine dichloramine was 42.2-52.7% of that of histamine. The recovery time to the basal secretory level after completion of stimulation by histamine chloramines was significantly prolonged compared with histamine. These results suggest that histamine chloramines, which bind strongly with histamine H2 receptors, may delay the termination of gastric acid secretion and increase the burden on the gastric and duodenal mucosa.

Animals↗

PubMed1995

Products of neutrophil metabolism increase ammonia-induced gastric mucosal damage.

Recent studies have indicated that ammonia is involved in the pathophysiology of Helicobacter pylori-associated gastric mucosal damage. Helicobacter pylori-associated chronic active gastritis is characterized by an invasion of neutrophils. We investigated the interrelationship among hypochlorous acid (oxidant produced by neutrophil), ammonia (product of Helicobacter pylori urease), and monochloramine (product of ammonia and hypochlorous acid) in the development of gastric mucosal damage in rats. Gastric mucosal lesions were produced by exposure of the gastric mucosa to ammonia, urea with urease, or urea with Helicobacter pylori in rats subjected to ischemia. Pretreatment with taurine (scavenger of hypochlorous acid) or antineutrophil serum significantly attenuated gastric mucosal lesions induced by the above test agents. Ammonia-induced gastric mucosal lesions were exacerbated in the presence of hypochlorous acid with concomitant generation of monochloramine. These results suggest that the ammonia, hypochlorous acid, and monochloramine triad may be important in Helicobacter pylori-mediated gastric mucosal damage.

Ammonia↗