Predominant Regeneration of B-Cell Lineage, Instead of Myeloid Lineage, of the Bone Marrow after 1 Gy Whole-Body Irradiation in Mice: Role of Differential Cytokine Expression between B-Cell Stimulation by IL10, Flt3 Ligand and IL7 and Myeloid Suppression by GM-CSF and SCF

Tsuboi, Isao; Hirabayashi, Yoko; Harada, Toshiro; Hara, Masaki; Kanno, Jun; Inoue, Tohru; Aizawa, Shin

doi:10.1667/rr1182.1

Cited by 10 publications

(8 citation statements)

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“…Peripheral blood smeared on glass slides was stained with WrightGiemsa reagent and then counted differentially according to the type of white blood cells (WBCs) based on 100 cells. 16) BM cells were harvested from the femur of each mouse as described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide

Tsuboi

Harada

Hirabayashi³

et al. 2016

Biological & Pharmaceutical Bulletin

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Chronic lipopolysaccharide (LPS) exposure to mice reduces the lymphoid compartment and skews the hematopoietic cell compartment toward myeloid-cells, which is considered to be a direct effect of LPS on hematopoietic stem cells. However, the effect of chronic LPS exposure on stromal-cells, which compose the hematopoietic microenvironment, has not been elucidated. Here, we investigated early-and late-phase effects of repeated LPS exposure on stromal-cells. During the early phase, when mice were treated with 5 or 25 µg LPS three times at weekly intervals, the numbers of myeloid-progenitor (colony forming unit-granulocyte macrophage (CFU-GM)) cells and B lymphoid-progenitor (CFU-preB) cells in the bone-marrow (BM) rapidly decreased after each treatment. The number of CFU-GM cells recovered from the initial decrease and then increased to levels higher than pretreatment levels, whereas the number of CFU-preB cells remained lower than pretreatment levels. In the BM, expression of genes for positive-regulators of myelopoiesis including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-6 and negative-regulators of B lymphopoiesis including tumor necrosis factor (TNF)-α was up-regulated, whereas expression of positive-regulators of B lymphopoiesis including stromal cell-derived factor (SDF)-1, IL-7, and stem cell factor (SCF) was down-regulated. During the late phase, the number of CFU-preB cells remained lower than pretreatment levels 70 d after the first treatments with 5 and 25 µg LPS, whereas the number of CFU-GM cells returned to pretreatment levels. IL-7 gene expression in the BM remained down-regulated, whereas gene-expression levels of SDF-1 and SCF were restored. Thus, chronic LPS exposure may impair stromal-cell function, resulting in prolonged suppression of B lymphopoiesis, which may appear to be senescence similar to the hematological phenotype.Key words hematopoiesis; stromal cell; inflammation; cytokine; local regulation Inflammation and infection alter hematopoiesis output of bone marrow (BM) by favoring myelopoiesis, especially granulopoiesis, over B lymphopoiesis.1,2) Lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, induces inflammation via Toll-like receptor (TLR) 4 expressed on the cell surface. In the BM, TLR4 is expressed not only on hematopoietic cells, but also on non-hematopoietic cells such as stromal cells. Thus, LPS is a useful agent to study how hematopoiesis is regulated by stromal cells during inflammation and infection.A single injection of LPS in mice augments myelopoiesis and suppresses B lymphopoiesis, which is similar to the phenomenon observed in mice during inflammation and infection. In the BM, hematopoietic stem cells and hematopoietic progenitor cells are regulated by positive and negative factors produced by stromal cells. 3,4) This reciprocal regulation of myelopoiesis and B lymphopoiesis after LPS treatment is likely an indirect effect via stromal cells rather than a dire...

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Section: Methodsmentioning

confidence: 99%

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide

Tsuboi

Harada

Hirabayashi³

et al. 2016

Biological & Pharmaceutical Bulletin

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“…6A) 45) CFU-pre B CFU-GM CFU-pre B CFU-GM (Fig. 6B) It is well known that B lymphopoiesis in the bone marrow (BM) is attenuated with aging, whereas myelopoiesis is not affected.…”

Section: Samp1mentioning

confidence: 99%

Age-related Changes in the Regulation of Hematopoiesis

Tsuboi¹,

Harada²,

Aizawa³

2012

Nichidai Igaku Zasshi

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The hematopoietic microenvironment is composed of heterogeneous mesenchymal cells, such as osteoblasts, epithelial cells, fibroblastoid cells, adipocytes and macrophages, which are referred to as stromal cells. Stromal cells regulate hematopoietic stem cell (HSC) by producing positive-and negative-regulators to supply mature hematopoietic cells for the lifetime. It is well known that B lymphopoiesis in the bone marrow (BM) is attenuated with aging, whereas myelopoiesis is not affected. One standing issue is whether age-associated defects in B lymphopoiesis reflect intrinsic defects and/or extrinsic defects of the cells, such as stromal cell defects. Although extensive studies have revealed that age-associated intrinsic defects occur in B cell development, the age-associated stromal cell defects have not been fully elucidated. Since B lymphopoiesis in the BM is more dependent on stromal cells than the other lineages, B lymphopoiesis is a good model to investigate the effect of aging on stromal cells. Senescence accelerated mice (SAMP1) exhibit premature senescence-like stromal cell impairment after 30 weeks of age. Thus, this model mouse is a useful tool to clarify the role of stromal cells during the development of senescence-associated defects in B lymphopoiesis. In the steady state, SAMP1 mice exhibit simultaneous down-regulation of positive-and negative-regulators of B lymphopoiesis in the BM during premature aging, resulting in suppressive homeostasis of B cell development. While both regulators are downregulated, the relative cytokine levels are barely maintained in the steady-state. Under perturbed conditions induced by 5-fluorouracil or irradiation, aged SAMP1 mice exhibit prolonged dysregulation of cytokine production, resulting in a further diminution of B lymphopoiesis. These results suggest that, in part, age-related deterioration of B cell development may be due to functional impairment of stromal cells, which induces vicious suppressive homeostasis of B cell development. Taken together, age-associated changes in hematopoiesis seem to be due not only to intrinsic-defects but also to extrinsic defects of hematopoietic cells.

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“…Individual clones were obtained from the bulk population, after several cycles of restimulation, by limiting dilution. Human TERT CTLs were obtained from splenocytes (5 ϫ 10 6 ) of vaccinated HHD mice grown in presence of 0.1M of either hTERT [865][866][867][868][869][870][871][872][873] (RLVDDFLLV) or hTERT [30][31][32][33][34][35][36][37][38] (RLGPQGWRV) peptide. Human HER2/neu CTLs were obtained from HHD-vaccinated splenocytes stimulated with 1M HER-2 369-377 (TYVPANASL) peptide.…”

Section: In Vitro Leukocyte Culturesmentioning

confidence: 99%

“…However, repeated stimulation cycles were necessary for the selection of a polyclonal T-cell population able to produce IFN-␥ when incubated with a panel of human tumor cells lines. Whereas T cells reactive against hTERT [865][866][867][868][869][870][871][872] epitope acquired this capacity, T cells recognizing hTERT [30][31][32][33][34][35][36][37][38] never did ( Figure 7A). Only prostate-derived cells LnCap, deficient in the class I HLA heavy chain, were never recognized.…”

Section: B-cell Reduction Induced By Tert Ctls Is Transientmentioning

confidence: 99%

“…26 The 3 hTERT immunogenic regions that were found corresponded to epitopes already described (supplemental Figure 3A-C). 25,27,28 T cells specific for the 2 epitopes hTERT 865-872 and hTERT [30][31][32][33][34][35][36][37][38] , showing the strongest reactivity ex vivo (supplemental Figure 3D), were further enriched from splenocytes through repeated peptide stimulations. Specific recognition of 293 cells stably transfected with HLA-A2 molecule (293-A2) and loaded with the relevant peptides was readily demonstrated ex vivo (supplemental Figure 3C).…”

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confidence: 99%

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Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

Ugel

Scarselli

Iezzi

et al. 2010

Blood

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IntroductionAttempts to treat experimental tumors with adoptive T lymphocyte transfer started in 1960, soon after the demonstration that the cellular arm of the immune system was responsible for tissue rejection. 1 The translation of this approach to the clinic, however, became possible when human tumor-infiltrating lymphocytes (TILs) could be expanded in vitro and injected back into cancer patients. 2 Only recently, however, an objective cancer regression was achieved in approximately 50% of patients with metastatic tumor after the introduction of host preconditioning by lymphodepletion before the treatment, followed by high-dose interleukin-2 (IL-2) to sustain in vivo expansion of T cells. 3,4 So far, this approach has been limited to melanoma patients, from whom TILs of known specificity are easily cultured in vitro, whereas for tumors other than melanoma the rescue of TILs is problematic.Telomerase is considered an attractive target as universal antigen for the immunotherapy of cancer. Telomerase reverse transcriptase (TERT) is the protein component of the telomerase complex responsible for elongation of telomeres and plays an essential role in sustaining cancerous cell proliferation. 5 TERT is silent in most human somatic tissues but reactivated in 85% of tumors. Active immunization against telomerase and cancer vaccination clinical trials have been attempted that demonstrate little toxicity, but results concerning therapeutic efficacy are not conclusive. 6,7 Although T lymphocytes against telomerase were isolated and extensively characterized in vitro, 8,9 the use of adoptive cell therapy (ACT) with telomerase-specific lymphocytes has never been investigated. To evaluate therapeutic efficacy and determine the potential immunopathology associated with TERT-based ACT, we generated and analyzed the activity of TERT-specific CD8 ϩ T cells. Methods Mice and cell linesC57BL/6 mice were from Charles River Laboratories Inc. Transgenic adenocarcinoma mouse prostate (TRAMP) mice, a gift from N. M. Greenberg (Fred Hutchinson Cancer Research Center), were maintained in the mouse facility of Istituto Oncologico Veneto. Heterozygous TRAMP used in the experiments were obtained and screened as described. 10 C57BL/6-CD45.1 ϩ mice were a gift from M. P. Colombo (National Institutes of Tumors), pmel-1 TCR transgenic mice were a gift from N. Restifo (National Institutes of Health), and human leukocyte antigen (HLA)-A*0201-transgenic (HHD) mice were obtained by F. A. Lemonnier (Institut Pasteur) and maintained at Istituto di Ricerca di Biologia Molecolare. Rag2 Ϫ/Ϫ ␥ c Ϫ/Ϫ were purchased form Taconic. Mice were treated in accordance with European guidelines (http://ec.europa.eu/environment/chemicals/ lab_animals/legislation_en.htm). B16 melanoma cells were provided by N. Restifo (NIH). B16-B7.1 cells, genetically modified to express mouse B7.1 (provided by P. Della Bona, Istituto Scientifico San Raffaele) were cultured in the An Inside Blood analysis of this article appears at the front of this issue.The online version of thi...

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Predominant Regeneration of B-Cell Lineage, Instead of Myeloid Lineage, of the Bone Marrow after 1 Gy Whole-Body Irradiation in Mice: Role of Differential Cytokine Expression between B-Cell Stimulation by IL10, Flt3 Ligand and IL7 and Myeloid Suppression by GM-CSF and SCF

Cited by 10 publications

References 28 publications

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide

Differential Regulation of Lympho-Myelopoiesis by Stromal Cells in the Early and Late Phases in BALB/c Mice Repeatedly Exposed to Lipopolysaccharide

Age-related Changes in the Regulation of Hematopoiesis

Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

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