scholarly journals Serglycin proteoglycan is required for secretory granule integrity in mucosal mast cells

2007 ◽  
Vol 403 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Tiago Braga ◽  
Mirjana Grujic ◽  
Agneta Lukinius ◽  
Lars Hellman ◽  
Magnus Åbrink ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Crucial Importance ◽  
Carboxypeptidase A ◽  
Mucosal Mast Cells ◽  
Individual Granule ◽  
Electron Dense Core ◽  
Partial Dependence

SG (serglycin) PGs (proteoglycans) are strongly implicated in the assembly of MC (mast cell) granules. However, this notion has mainly been on the basis of studies of MCs of the connective tissue subtype, whereas the role of SG PG in mucosal MCs has not been explored. In the present study, we have addressed the latter issue by using mice with an inactivated SG gene. Bone marrow cells were differentiated in vitro into the mucosal MC phenotype, expressing the markers mMCP (mouse MC protease) -1 and -2. Biosynthetic labelling experiments performed on these cells revealed an ∼80% reduction of 35SO42− incorporation into PGs recovered from SG−/− cells as compared with SG+/+ counterparts, indicating that SG is the dominating cell-associated PG of mucosal MCs. Moreover, the absence of SG led to defective metachromatic staining of mucosal MCs, both in vivo and in the in vitro-derived mucosal MCs. Ultrastructural analysis showed that granules were present in similar numbers in SG+/+ and SG−/− cells, but that their morphology was markedly affected by the absence of SG, e.g. with electron-dense core formation only seen in SG+/+ granules. Analysis of the MC-specific proteases showed that mMCP-1 and mMCP-7 were completely independent of SG for storage, whereas mMCP-2 showed a partial dependence. In contrast, mMCP-4 and -6, and carboxypeptidase A were strongly dependent on SG for storage. Together, our data indicate that SG PG is of crucial importance for assembly of mature mucosal MC granules, but that the specific dependence on SG for storage varies between individual granule constituents.

scholarly journals Regulation of the growth and functions of cloned murine large granular lymphocyte lines by resident macrophages.

1985 ◽  
Vol 162 (4) ◽  
pp. 1161-1181 ◽  
Author(s):  
N Minato ◽  
T Amagai ◽  
J Yodoi ◽  
T Diamanstein ◽  
S Kano
Keyword(s):  
Bone Marrow Cells ◽  
Interleukin 2 ◽  
Functional Expression ◽  
Suppressive Effect ◽  
Leukemic Cells ◽  
Target Cells ◽  
Significant Heterogeneity

Using cloned lines with the morphology of large granular lymphocytes (LGL) from BALB/c mice, we studied the exact requirements for proliferation and their functional characteristics, as well as their regulation. Although these cloned LGL lines were interleukin 2 (IL-2) dependent for growth, experiments using human recombinant IL-2 (rIL-2), known to be active on murine cells, indicated that IL-2 was a necessary but not sufficient factor. Coexistance of normal macrophages in addition to rIL-2 was found to support continuous proliferation of cloned LGL in vitro. This role of macrophages could be replaced by partially purified IL-1 derived from macrophage-conditioned medium. An IL-2 binding assay using 125I-rIL-2 suggested that the role of normal macrophages was to selectively induce and/or maintain high affinity IL-2 receptors (IL-2R) (Kd, 0.2-0.5 nM) without affecting low affinity ones (Kd, 10-30 nM). Functional studies indicated that most of the LGL clones killed various combinations of representative groups of natural killer (NK)-susceptible target cells, including leukemic cells (YAC-1, RL male 1), virus-infected cells (HeLa-measles, HeLa-herpes simplex virus), and normal bone marrow cells (BMC), whereas none of them affected any of NK-resistant target cells, including uninfected HeLa cells. Some of these clones also suppressed in vitro hematopoiesis. Such characteristic cytotoxic spectra, as well as serological phenotypes (Thy-1+, Lyt-1-2-, asialo GM1-positive, T200+, TdT-, Fc receptor-positive) indicated that these LGL clones exactly represent endogenous NK cells, rather than a variety of anomalous killer cells generated in various culture conditions. Although there was significant heterogeneity of cytotoxic spectrum among LGL clones, no clonotypic distribution of specificities was observed. Normal macrophages were found to modulate the functional expression of LGL clones. They augmented the cytotoxic potential of the clones against leukemic and virus-infected targets, but suppressed intrinsic reactivity against normal BMC. Similarly, LGL clones maintained with macrophages showed much less suppressive effect on in vitro hematopoiesis. The present observations on the interaction of cloned LGL and normal macrophages provide a basic explanation for the mechanisms by which the immediate responsiveness to IL-2 of the NK effector system, without exogenous stimulation, and the functional selectivity toward abnormal rather than normal cells, are actively maintained in vivo.

CIAPIN1 is a potential target for apoptosis of multiple myeloma

2019 ◽  
Vol 9 (9) ◽  
pp. 1106-1111
Author(s):  
Xiao-Bo Wang ◽  
Le-Ping Yan ◽  
Li-Hua Yuan ◽  
Bo Lu ◽  
Dong-Jun Lin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Xenograft Model ◽  
Soft Agar ◽  
Normal Human ◽  
Related Proteins

This study firstly aimed to reveal the gene expression differences of CIAPIN1 between myelomas cells from bone marrow cells of multiple myeloma patients and normal human, and subsequently investigate the regulation role of this gene on tumorigenicity ability of multiple myeloma (MM) cell line U266 via in vitro colony formation and in vivo xenograft studies. RT-PCR results obtained from 18 MM patients and 10 health people showed that the expression of CIAPIN1 gene was 4 times higher in normal human compared to MM patients. Besides, CIAPIN1 siRNA (si-CIAPIN1) transfected U266 cells presented higher proliferation ratio and superior colony forming ability than U266 cells and U266 cells transfected with non-coding siRNA (controls) evaluated by CCK8 test and soft agar colony formation assay, respectively. In a mice MM xenograft model, the si-CIAPIN1 transfected U266 cells induced the biggest tumor compared to the controls. Furthermore, CIAPIN1 overexpressed U266 cells were developed and compared with the si-CIAPIN1 transfected U266 cells to study the role of CIAPIN1 in the production of apoptosis related proteins in U266 cells. Results indicated that CIAPIN1 facilitated apoptosis promoting proteins expression in U266 cells, such as upregulation of BAX, BAK, Bcl-xs and BIM, and downregulation of p38, PKC, Bcl-2 and Bcl-xl proteins. Therefore, CIAPIN1 can be a potential suppression target gene in multiple myeloma.

In Vitro expanded STAT1−/− Regulatory T Cells Prevent Acute Graft Versus Host Disease (GVHD) and Promote Donor Cell Engraftment In Allogeneic Fully MHC-Mismatched Bone Marrow Transplant

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 732-732
Author(s):  
Huihui Ma ◽  
Caisheng Lu ◽  
Judy Ziegler ◽  
Suzanne Lentzsch ◽  
Markus Y Mapara
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Cells ◽  
Donor Cell ◽  
Treg Cells ◽  
Cell Engraftment ◽  
Lethal Irradiation

Abstract Abstract 732 Treg cells have been recognized as critical regulators of the immune response and shown to prevent the development of GVHD. However, little is known about of the role of STAT1 signaling in Treg cells during the development of GVHD. In this study, we tried to investigate how STAT1 signaling controls donor Treg development and function in the setting of GVHD. For this purpose we studied the role of STAT1 in natural and inducible Treg (nTreg and iTreg, respectively). To better understand the influence of STAT1-deficiency on the proliferation of nTreg cells, purified splenic STAT1−/− or STAT1+/+ CD4+CD25+ cells were labeled with Carboxyfluorescein succinimidyl ester (CFSE) and cultured on anti-CD3 coated plates in the presence of anti-CD28 and IL-2 for 3 days and analyzed for proliferation and viability. After 72h of in vitro culture 50% of the STAT1+/+ starting population were no longer viable compared to only 10% of STAT1−/− cells. Furthermore, we noted a significantly increased expansion of STAT1-deficient CD4+CD25+Foxp3+ Treg cells compared to STAT1+/+ Treg cells (p<0.001). In line with these findings, STAT1-deficiency resulted in a significantly higher proportion of CFSElo cells indicating vigorous proliferation (85% Foxp3+CFSElo in STAT1−/− compared to only 65% Foxp3+CFSElo in STAT1+/+ Treg cells. Furthermore, at the end of the culture 30% of the STAT1+/+ CD4+CD25+ population were Foxp3-negative compared to only 10% of the STAT1−/− cells. We next determined the impact of STAT1 on the generation of iTreg cells in vitro. For this purpose CD4+CD25− cells from STAT1−/− or STAT1+/+ mice were cultured for 3 days on anti-CD3 coated plates in the presence of anti-CD28 antibodies, hTGF-β, mIL-2, anti-IFN-γ and anti-IL-4 for 3 days. Compared to STAT1+/+, we observed significantly enhanced generation of iTregs from STAT1−/− splenocytes (19.9%±3.0% vs. 10.6%±1.3%, p=0.008). We then performed studies to assess the in vivo generation of iTreg. For that purpose BALB/c mice were reconstituted with T Cell Depleted (TCD) 129.STAT1+/+Bone Marrow Cells (BMC) following lethal irradiation and recipients were co-injected with CD4+CD25− cells purified from either 129.STAT1+/+ or 129.STAT1−/− splenocytes. We again noted a significantly higher proportion of CD4+CD25+ Foxp3+ cells in recipients of CD4+CD25−STAT1−/− cells compared to recipients of STAT1+/+ T cells indicating a significantly increased conversion of CD4+CD25- cells into Treg cells. To confirm the in vitro results we tested the functional ability of in vitro expanded (using anti-CD3, anti-CD28, IL-2 and TGF-β) STAT1+/+ or STAT1−/− Treg cells to block induction of GVHD. GVHD was induced in BALB/c mice following lethal irradiation (800rad) and fully MHC-mismatched BMT using 129.STAT1+/+ bone marrow cells plus 129.STAT+/+ conventional T cells (Tcon). Animals were co-injected with expanded Treg cells from either 129.STAT1+/+ or 129.STAT1−/− donors at a ratio of 1:1 or 1:4 (Treg:Tcon). STAT1−/− or STAT1+/+ Treg cells were equipotent in completely preventing GVHD mortality. However, compared to recipients of STAT1+/+ Treg recipients of STAT1−/− Treg showed reduced signs of GVHD morbidity as determined by a significantly improved weight development. Furthermore, recipients of STAT1−/− Treg showed significantly increased donor cell engraftment compared to recipients of STAT1+/+Treg (donor CD4+ [87% vs. 60%, p=0.03], CD8+[99% vs. 96%, p=0.04], Mac1+[96% vs. 77%, p=0.02] and B220+[100% vs. 96%, p=0.007]) cells in the recipient spleen. These observations clearly demonstrate that STAT1 is a critical regulator of Treg cell development and expansion and that targeting STAT1 in CD4+ T cells may facilitate in vitro and in vivo generation/expansion of Treg cells for therapeutic use in GVHD while also promoting donor cell engraftment. Disclosures: Lentzsch: Celgene Corp: Research Funding. Mapara:Resolvyx: Research Funding; Gentium: stocks.

ROLE OF VASOPRESSIN IN THE MITOTIC RESPONSE OF RAT BONE MARROW CELLS TO HAEMORRHAGE

1977 ◽  
Vol 72 (1) ◽  
pp. 5-16 ◽  
Author(s):  
N. H. HUNT ◽  
A. D. PERRIS ◽  
P. A. SANDFORD
Keyword(s):  
Bone Marrow ◽  
Mitotic Activity ◽  
Bone Marrow Cells ◽  
Cell Numbers ◽  
Severe Haemorrhage ◽  
Mitogenic Action ◽  
Stimulate Bone Marrow

SUMMARY Two days after a severe haemorrhage plasma calcium concentrations and bone marrow mitotic activity in rats were significantly increased and so remained for a further 5–6 days until the haematocrit had returned to normal. The first 48 h after bleeding were characterized by hypocalcaemia. During this phase two significant peaks in mitotic activity were observed at 4 and 18 h after haemorrhage. The mitotic surge 4 h after bleeding was still present in adrenalectomized and parathyroidectomized animals but in rats which were either hypophysectomized or had congenital diabetes insipidus this mitotic response was absent. Vasopressin was shown to stimulate bone marrow mitotic activity both in vivo and in vitro whereas angiotensin, aldosterone and erythropoietin had no rapid, direct mitogenic action on these cells. This novel hypophysial–bone marrow system suggests that vasopressin may assist in post-haemorrhagic recovery in blood cell numbers in the circulation.

scholarly journals The role of phosphoinositide 3-kinase in spreading osteoclasts induced by colony-stimulating factor-1

2001 ◽  
pp. 431-440 ◽  
Author(s):  
S Palacio ◽  
R Felix
Keyword(s):  
Bone Marrow Cells ◽  
Colony Stimulating Factor ◽  
Lipid Kinase ◽  
Growth And Survival ◽  
Phosphoinositide 3 Kinase ◽  
Stimulating Factor ◽  
K Activity

BACKGROUND: Colony-stimulating factor-1 (CSF-1), a growth and survival factor for osteoclasts, stimulates these cells to spread and migrate towards a gradient of CSF-1. This may support the translocation of osteoclasts to new sites on the bone surface to be resorbed. Phosphoinositide 3-kinase (PI 3-K) is a lipid kinase participating in various signal transduction pathways. OBJECTIVE: To investigate the role of PI 3-K in the CSF-1-induced spreading of osteoclasts. METHODS: In isolated rat osteoclasts treated with or without CSF-1, the distribution of PI 3-K and proteins phosphorylated on tyrosine were investigated using immunofluorescence. In murine osteoclast-like cells grown from bone marrow cells co-cultured with osteoblasts, the activation of the PI 3-K by CSF-1 was determined both in vivo and in vitro. In vivo, the enzyme product in the cell was determined after extraction and separation with thin layer chromatography; in vitro, PI 3-K activity was measured in the pellet immunoprecipitated from the cell lysate. RESULTS: Inhibition of PI 3-K blocked the CSF-1-induced spreading of osteoclasts. In spreading osteoclasts, a portion of PI 3-K was translocated to the periphery where proteins phosphorylated on tyrosine appeared simultaneously. In osteoclast-like cells, CSF-1 stimulated PI 3-K activity. This activity could be immunoprecipitated with antibody against phophotyrosine residues. CONCLUSION: PI 3-K participates in the CSF-1-induced spreading of osteoclasts. The activated PI 3-K may induce the reorganization of the cytoskeleton resulting in spreading and migration.

scholarly journals FOXM1 Controls Leukemia Stem Cell Fate in MLL-Rearranged AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2742-2742
Author(s):  
Yue Sheng ◽  
Chao Hu ◽  
Chunjie Yu ◽  
Rui Ma ◽  
Zhijian Qian
Keyword(s):  
Bone Marrow Cells ◽  
Leukemia Cells ◽  
Leukemia Stem Cell ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Primary Bone ◽  
Primary Bone Marrow

Abstract Relapse after initial achievement of complete remission remains a major issue in the treatment of Acute Myeloid Leukemia (AML). Emerging evidence suggest a critical role of Leukemia Stem Cells (LSCs) during AML relapse. FOXM1 is a member of the forkhead family of transcription factors. Here we report a novel role of Foxm1 as a key regulator of LSCs. MLL-rearranged AML patients have a very poor prognosis and are more resistant to traditional chemotherapy. Recently, we found that high FOXM1 expression is associated with MLL-rearranged AMLs and AMLs with a complex karyotype. We also found that loss of Foxm1 significantly reduced serial replating capacity of MLL-AF9 (MA9)-induced myeloid progenitor cells and increased apoptosis of MA9-induced leukemia stem cell (MA9-LSC)-enriched cells but not mature leukemia cells in vitro. In addition, we showed that Foxm1 loss in mice markedly delayed the initiation and progression of MLL-AF9-induced AML. Notably, Foxm1 loss reduced the number of MA9-LSCs as well as quiescence of MA9-LSCs. However, Foxm1 loss significantly increased apoptosis of LSCs but not normal HSCs in vivo. Our RNA-seq data revealed that expression of both Bcl2, a survival factor and p21Cip1, known as cyclin-dependent inhibitor 1, are significantly decreased as a consequence of Foxm1 deletion in MA9-LSCs. In addition, Foxm1 loss led to down-regulation of Itga1. Of interest, Chip-PCR revealed that Foxm1 regulates Itga1 expression by directly binding to its promoter. Collectively, these data suggest that Foxm1 is required for the maintenance of quiescence and survival of MA9-LSCs. Mechanistically, we found that loss of Foxm1 inhibited leukemogenic function of MA9-LSCs, at least partially through down-regulating the a1b1-mediated integrin pathway. We next demonstrated that conditional deletion of single or both alleles of Foxm1 significantly delayed the progression of MA9-induced AML after initiation of disease in mice, and that pharmacological inhibition of Foxm1 prolonged disease latency of MA9-induced AML in mice. It has been reported that MA9-induced mouse leukemia cells are resistant to chemotherapeutic drugs. Notably, our data showed that deletion of Foxm1 or loss of a single allele of Foxm1 significantly increases the sensitivity of MA9-induced leukemia cells to chemotherapeutic drugs in mice. Furthermore, we found that human AML cell lines with expression of MA9, the MA9-transduced primary human CD34+ cells as well as primary bone marrow cells from patients with MA9-induced AML, are more sensitive to FOXM1 inhibition in vitro than the control human CD34+ cells. Moreover, inhibition of FOXM1 significantly prolonged the survival of xenografted mice with MA9-tranduced human CD34+ cells as well as primary bone marrow cells from a MLL leukemia patient. Of note, we found that FOXM1 inhibition also significantly induced the apoptosis of human CD34+ LSCs in vivo in xenografted mice. Our studies strongly suggest that inhibition of FOXM1 may benefit MLL leukemia patients by eliminating LSCs, thereby reducing the frequency of relapse in these patients after treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Rabindranath Bera ◽  
Ming-Chun Chiu ◽  
Ying-Jung Huang ◽  
Tung-Huei Lin ◽  
Ming-Chung Kuo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Mouse Bone Marrow ◽  
Myeloid Malignancies ◽  
Inhibitor Of Dna Binding

Abstract Background Additional sex combs-like 1 (ASXL1) mutations have been described in all forms of myeloid neoplasms including chronic myelomonocytic leukemia (CMML) and associated with inferior outcomes, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) remains poorly understood. Transformation of CMML to secondary AML (sAML) is one of the leading causes of death in CMML patients. Previously, we observed that transcription factor RUNX1 mutations (RUNX1-MT) coexisted with ASXL1-MT in CMML and at myeloid blast phase of chronic myeloid leukemia. The contribution of RUNX1 mutations in the pathogenesis of myeloid transformation in ASXL1-mutated leukemia, however, remains unclear. Methods To evaluate the leukemogenic role of RUNX1-MT in ASXL1-mutated cells, we co-expressed RUNX1-MT (R135T) and ASXL1-MT (R693X) in different cell lines and performed immunoblot, co-immunoprecipitation, gene expression microarray, quantitative RT-PCR, cell proliferation, differentiation, and clonogenic assays for in vitro functional analyses. The in vivo effect was investigated using the C57BL/6 mouse bone marrow transplantation (BMT) model. Results Co-expression of two mutant genes increased myeloid stem cells in animal model, suggesting that cooperation of RUNX1 and ASXL1 mutations played a critical role in leukemia transformation. The expression of RUNX1 mutant in ASXL1-mutated myeloid cells augmented proliferation, blocked differentiation, and increased self-renewal activity. At 9 months post-BMT, mice harboring combined RUNX1 and ASXL1 mutations developed disease characterized by marked splenomegaly, hepatomegaly, and leukocytosis with a shorter latency. Mice transduced with both ASXL1 and RUNX1 mutations enhanced inhibitor of DNA binding 1 (ID1) expression in the spleen, liver, and bone marrow cells. Bone marrow samples from CMML showed that ID1 overexpressed in coexisted mutations of RUNX1 and ASXL1 compared to normal control and either RUNX1-MT or ASXL1-MT samples. Moreover, the RUNX1 mutant protein was more stable than WT and increased HIF1-α and its target ID1 gene expression in ASXL1 mutant cells. Conclusion The present study demonstrated the biological and functional evidence for the critical role of RUNX1-MT in ASXL1-mutated leukemia in the pathogenesis of myeloid malignancies.

Role of p53 in Hematopoietic Recovery After Cytotoxic Treatment

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2998-3006 ◽  
Author(s):  
Pawel Wlodarski ◽  
Mariusz Wasik ◽  
Mariusz Z. Ratajczak ◽  
Cinzia Sevignani ◽  
Grazyna Hoser ◽  
...  
Keyword(s):  
Growth Factors ◽  
Bone Marrow Cells ◽  
Positive Impact ◽  
Hematopoietic Stem ◽  
Hematopoietic Recovery ◽  
Cytotoxic Treatment

Prompt reconstitution of hematopoiesis after cytoreductive therapy is essential for patient recovery and may have a positive impact on long-term prognosis. We examined the role of the p53 tumor suppressor gene in hematopoietic recovery in vivo after treatment with the cytotoxic drug 5-fluorouracil (5-FU). We used p53 knock-out (p53−/−) and wild-type (p53+/+) mice injected with 5-FU as the experimental model. Analysis of the repopulation ability and clonogenic activity of hematopoietic stem cells (HSCs) and their lineage-committed descendants showed a greater number of HSCs responsible for reconstitution of lethally irradiated recipients in p53−/− bone marrow cells (BMCs) recovering after 5-FU treatment than in the corresponding p53+/+ BMCs. In post–5-FU recovering BMCs, the percentage of HSC-enriched Lin− Sca-1+c-Kit+ cells was about threefold higher in p53−/− than in p53+/+ cells. Although the percentage of the most primitive HSCs (Lin− Sca-1+ c-Kit+CD34low/−) did not depend on p53, the percentage of multipotential HSCs and committed progenitors (Lin−Sca-1+ c-Kit+ CD34high/+) was almost fourfold higher in post–5-FU recovering p53−/− BMCs than in their p53+/+ counterparts. The pool of HSCs from 5-FU–treated p53−/− BMCs was exhausted more slowly than that from the p53+/+ population as shown in vivo using pre–spleen colony-forming unit (CFU-S) assay and in vitro using long-term culture-initiating cells (LTC-ICs) and methylcellulose replating assays. Clonogenic activity of various lineage-specific descendants was significantly higher in post–5-FU regenerating p53−/− BMCs than in p53+/+ BMCs, probably because of their increased sensitivity to growth factors. Despite all these changes and the dramatic difference in sensitivity of p53−/− and p53+/+ BMCs to 5-FU–induced apoptosis, lineage commitment and differentiation of hematopoietic progenitors appeared to be independent of p53 status. These studies suggest that suppression of p53 function facilitates hematopoietic reconstitution after cytoreductive therapy by: (1) delaying the exhaustion of the most primitive HSC pool, (2) stimulating the production of multipotential HSCs, (3) increasing the sensitivity of hematopoietic cells to growth factors, and (4) decreasing the sensitivity to apoptosis.

scholarly journals Role of mucosal mast cells in early vascular permeability changes of intestinal DTH reaction in the rat

1998 ◽  
Vol 274 (5) ◽  
pp. G832-G839 ◽  
Author(s):  
Aletta D. Kraneveld ◽  
Thea Muis ◽  
Andries S. Koster ◽  
Frans P. Nijkamp
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Vascular Leakage ◽  
Mast Cell Activation ◽  
Mucosal Mast Cell ◽  
Mucosal Mast Cells

Previously, it was shown that depletion and stabilization of the mucosal mast cell around the time of challenge were very effective in reducing delayed-type hypersensitivity (DTH) reactions in the small intestine of the rat. The role of mucosal mast cells in the early component of intestinal DTH reaction was further investigated in this study. In vivo small intestinal vascular leakage and serum levels of rat mast cell protease II (RMCP II) were determined within 1 h after intragastric challenge of rats that had been sensitized with dinitrobenzene 5 days before. A separate group of rats was used to study vasopermeability in isolated vascularly perfused small intestine after in vitro challenge. To investigate the effects of mast cell stabilization on the early events of the DTH reaction, doxantrazole was used. The influence of sensory nerves was studied by means of neonatal capsaicin-induced depletion of sensory neuropeptides. Within 1 h after challenge, a significant increase in vascular permeability was found in vivo as well as in vitro. This was associated with a DTH-specific increase in RMCP II in the serum, indicating mucosal mast cell activation. In addition, doxantrazole treatment and caspaicin pretreatment resulted in a significant inhibition of the DTH-induced vascular leakage and an increase in serum RMCP II. These findings are consistent with an important role for mucosal mast cells in early vascular leakage changes of intestinal DTH reactions. In addition, sensory nervous control of mucosal mast cell activation early after challenge is demonstrated.

Role of clozapine in the occurrence of chromosomal abnormalities in human bone-marrow cells in vivo and in cultured lymphocytes in vitro

1977 ◽  
Vol 38 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Sakari Knuutila ◽  
Eila Helminen ◽  
Leena Knuutila ◽  
Seppo Leisti ◽  
Martti Siimes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Marrow Cells
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