Cytokine network in peripheral blood mononuclear cells after allogeneic bone marrow transplantation.
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Bone Marrow Transplantation↗
Biomedical subjects
M Kasai
Publications and source records attributed to M Kasai.
In vitro expansion of murine hematopoietic progenitor cells by leukemia inhibitory factor, stem cell factor, and interleukin-1 beta.
Murine hematopoietic progenitor cells were markedly expanded in the presence of leukemia inhibitory factor (LIF), interleukin (IL)-1 beta and/or stem cell factor (SCF), although SCF+IL-1 beta +IL-3, LIF+SCF+IL-3, and SCF+IL-1 beta showed an appreciable effect on the in vitro expansion of hematopoietic progenitor cells as well. In the presence of LIF+SCF+IL-1 beta, highly proliferative potential colony-forming units (CFU-HPP) and colony forming units of mixed lineages (CFU-Mix) were more efficiently expanded than colony forming units granulocytes/macrophage (CFU-GM) and burst-forming units of erythroid lineage (BFU-E) compared with the colony formations of freshly obtained bone marrow cells. The cell yield on day 5 in the presence of LIF+SCF+IL-1 beta was comparable to that in SCF+IL-1 beta and SCF+IL-1 beta +IL-3. Nevertheless, colony formations were marked in LIF+SCF+IL-1 beta, thus suggesting that this combination can generate hematopoietic progenitor cells that possess greater potential for CFU-HPP, CFU-Mix, CFU-GM, and BFU-E colony formations. Hematopoietic cells expanded in the presence of LIF+SCF+IL-1 beta showed increased mRNA expressions of IL-1 beta, IL-3, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage (GM)-CSF, interferon gamma (IFN-gamma), and LIF compared with those of nontreated hematopoietic cells. Furthermore, LIF+SCF+IL-1 beta induced increased IL-3 and GM-CSF mRNA expression in hematopoietic cells but induced decreased macrophage inflammatory protein 1 alpha (MIP1 alpha) mRNA expression as compared with SCF+IL-1 beta +IL-3. These results suggest that the balance between stimulatory and inhibitory cytokines plays an important role in in vitro expansion of hematopoietic progenitor cells.
Animals↗
[Treatment of refractory hematologic malignancies by combination of cytarabine ocfosfate and etoposide].
We attempted a combination chemotherapy with cytarabine ocfosfate (SPAC) and etoposide for myelodysplastic syndrome (MDS), and acute non-lymphocytic leukemia developing after a prior history of MDS (MDS/ANLL). SPAC and etoposide were administered orally at the dose of 200 mg/day and 25 mg/day for 14 days, as standard regimen. Two cases complete remission (CR), 4 of partial remission (PR) were obtained among 9 patients. The plasma concentration of cytarabine (Ara-C) reached a plateau at around 4.5 ng/ml during the treatment period from the 7th to the 14th day, and it was detectable with a gradual decrease until the 28th day in spite of the last administration of SPAC on the 14th day. It is suggested that this combination chemotherapy is useful against MDS, MDS/ANLL and other resistant leukemia, especially in elderly patients who can not be treated by intensive combination chemotherapy.
Acute Disease↗
Renal Salmonella enteritidis abscess in a patient with severe aplastic anemia after allogeneic stem cell transplantation.
We describe an unusual case of a renal abscess by Salmonella enteritidis in a 32-year-old man with severe aplastic anemia undergoing allogeneic stem cell transplantation. He was receiving immunosuppressive therapy with CsA and corticosteroids for chronic GVHD. He was not neutropenic and had no history of enterocolitis or cholelithiasis before the onset. Four months after the transplantation, he developed an abscess in the upper pole of his right kidney from which Salmonella enteritidis was isolated in culture. He was successfully treated with a combination of percutaneous drainage and washing the cyst through the catheter using piperacillin sodium-containing solution. The possibility of salmonellosis should be considered in the differential diagnosis of such patients.
Abscess↗
Induction of humoral and cellular anti-idiotypic immunity by intradermal injection of naked DNA encoding a human variable region gene sequence of an immunoglobulin heavy chain in a B cell malignancy.
The idiotypic determinants of a B cell neoplasia could provide a tumor-specific target for vaccinating patients against their B cell tumors. Several approaches for inducing idiotype-specific immunization have been reported, but their major theoretical focus was related to the induction of humoral immunity. We have investigated an immunization procedure with naked DNA encoding human variable region gene sequences of an immunoglobulin heavy chain (VH), which may generate both humoral and cellular immune responses against the idiotype of a B cell acute lymphoblastic leukemia (ALL). Using polymerase chain reaction (PCR) amplification, we investigated heavy chain variable region genes obtained from an ALL patient and whether they could induce humoral and cellular immune responses in DBA/2 mice. The VH sequence was cloned into a mammalian expression vector for intradermal DNA vaccination and into a bacterial expression vector to obtain VH protein for Western blotting. The mammalian expression vector encoding the VH gene was injected into mice three times at 7-day intervals and was transduced into P1HTR which is a syngeneic tumor of DBA/2, to serve as target cells to detect cellular immunity. Spleen cells from the inoculated mice exhibited a significant cytotoxic T lymphocyte response to the target cells. By Western blotting, we could also detect trace levels of anti-VH antibodies in all mice serum. This approach for the induction of cellular immunity by intradermal injection is easy and variable region-specific, and may be used as vaccines after chemotherapy treatment of B cell malignancies.
Amino Acid Sequence↗
[Two cases of relapse or refractory germ cell tumor who had been treated with combination chemotherapy of cisplatin and carboplatin].
We tried a combination chemotherapy with cisplatin (CDDP) and carboplatin (CBDCA) (CDDP/CBDCA regimen) as salvage therapy for 2 cases with recurrent or refractory Germ Cell Tumor (GCT). Case 1 was a 29-year-old man with 2nd relapsed embryonal carcinoma and seminoma originating from testis. Case 2 was a 23-year-old man with primary refractory embryonal carcinoma and yolk sac tumor originating from mediastinum. CDDP and CBDCA were administered at the dose of 120 mg/m2 and 350 mg/m2 on day 1, and vinblastin was administered at the dose of 10 mg/body on day 2. In one of two cases, a complete response was obtained. Non-hematologic toxicity of CDDP/CBDCA regimen was tolerable. It is suggested that this combination chemotherapy is useful for GCT recurrence.
Adult↗
Tetrad-based perturbative approach to inhomogeneous universes: A general relativistic version of the Zel'dovich approximation.
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Journal Article↗
Differential expression of protein tyrosine kinases in the cortical and medullary thymic epithelial cell lines.
Expression of protein tyrosine kinase (PTK) was evaluated and compared between cortical and medullary thymic epithelial cell (TEC) lines, TEC 14C18 and TEC1C6, respectively. Reverse transcription-polymerase chain reaction (RT-PCR) methods using degenerate primers for conserved sequence in catalytic domain of PTK revealed the expression of 13 kinds of PTKs in these cell lines. These PTKs included 6 receptor and 7 non-receptor types. In the next step, we compared the intensity of mRNA expression level of these kinases between cortical and medullary TEC lines. Tyrosine kinases of receptor type were differentially expressed between cortical and medullary TEC lines; e.g., mRNA expression of flg was observed more intensively in the cortical TEC line than in the medullary one, while mRNA expression of bek, met and sky was vice versa. On the other hand, expression of non-receptor tyrosine kinases, including four JAK-tyk family members, are comparable in both lines. These results suggested that these PTKs, especially of receptor type, might play an important role in the development of the thymic microenvironment.
Amino Acid Sequence↗
Synthesis and antitumor activity of various 6-demethylmitomycins and 6-demethyl-6-halomitomycins.
A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et2NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED50). The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log kappa') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED50 or T/C) did not correlate with the quinone reduction potential (E1/2). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.
Animals↗
An anion channel from transverse tubular membranes incorporated into planar bilayers.
Transverse tubular (TT) vesicles from rabbit skeletal muscle were incorporated into planar lipid bilayers to characterize the chloride channel. The single channel conductance of the channel was 40 pS in choline-Cl solution (cis, 300 mM/100 mM, trans). The gating rate of the channel does not depend on membrane voltage. The channel was blocked by stilbene derivatives (DIDS and SITS), which are known as inhibitors of voltage-dependent Cl- channels of the Torpedo electric organ, from both sides of the membrane. An inhibitor of voltage-dependent Cl- channels of skeletal muscles, 9-anthracene carboxylic acid (9-AC) inhibited the channel from the cis side of the membranes, which corresponded to the cytoplasmic space. Ethacrynic acid (EA), which is reported to inhibit Cl- conductance of the kidney and trachea, decreased the open probability of the TT Cl- channel concentration dependently. Indanyloxyacetic acid (IAA), which is also reported to be an inhibitor of kidney and trachea Cl- channels, decreased the single channel current without affecting open probability of the TT Cl- channel.
Animals↗
Effects of interleukin 2 on leukemia development after bone marrow transplantation in AKR/J mice.
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Animals↗
DIDS binding 30-kDa protein regulates the calcium release channel in the sarcoplasmic reticulum.
The gating properties of the Ca2+ release channel in the heavy fraction of the sarcoplasmic reticulum (HSR) was monitored by measuring the choline permeation through the channel using a light scattering method. The choline permeation was increased by the treatment of the HSR vesicles with 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS), and this effect was only observed at low extravesicular Ca2+ concentrations. This result indicates that DIDS locked the Ca2+ channel at the open state. An SDS-PAGE of the junctional face membrane (JFM) that was treated with 3H2-DIDS showed that 3H2-DIDS binding protein is not the Ca2+ release channel but the 30 kDa protein. Furthermore, it was found that this 30 kDa protein is also one of the calsequestrin interacting proteins. These results suggest that this 30 kDa protein regulates the Ca2+ release channel.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Enzymic reconstruction of glycosaminoglycan oligosaccharide chains using the transglycosylation reaction of bovine testicular hyaluronidase.
The reconstruction of glycosaminoglycan chains using the transglycosylation reaction of testicular hyaluronidase was investigated. First, the optimal conditions for the transglycosylation reaction catalyzed by the enzyme were determined by incubation with the enzyme, using hyaluronic acid (M(r) = 800,000) as a donor and pyridylaminated hyaluronic acid hexasaccharide having glucuronic acid at the nonreducing terminal as an acceptor. The carbohydrate chains as reaction products were determined by high performance liquid chromatography and mass spectrometry. The optimal pH for hydrolysis by the enzyme was found to be about 5.0, whereas that for the transglycosylation reaction was about 7.0. Sodium chloride in the reaction medium inhibited the transglycosylation reaction. Under the optimal conditions, the carbohydrate chains were sequentially transferred along with disaccharide units to the nonreducing terminal of the acceptor and elongated up to docosasaccharide from the acceptor, pyridylaminated hexasaccharide. Using a combination of hyaluronic acid, chondroitin, and chondroitin 4- and 6-sulfate as an acceptor and a donor, it was possible to reconstruct hybrid chains, which were natural or unnatural types of glycosaminoglycan chains. Therefore, it is highly likely that application of the transglycosylation reaction using testicular hyaluronidase would facilitate artificial reconstruction of glycosaminoglycans having some physiological functions.
Animals↗
Clinical application of allogeneic peripheral blood stem cells transplantation.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF)-mobilized peripheral blood stem cells (PBSC) are now widely used for autologous transplantation to provide hematopoietic stem cells after intensive chemoradiotherapy. However, PBSC which contain a large number of T cells represent a potential risk for graft-versus-host disease (GVHD) in allogeneic (allo) transplantation. There are about 50 case reports of clinical trials of rhG-CSF-mobilized allo PBSC transplantation (PBSCT) with relatively rapid hematological recovery, without severe acute GVHD except in a few cases. Therefore, the risk of inducing severe acute GVHD is not as high as was expected when allo PBSCT began. However, whether allo PBSCT will increase the risk of chronic GVHD is not clear, because the period of observation has been too short. Also, it will be of interest to determine the clinical effect of allo PBSCT on relapse of hematological malignancy post-transplant. Whether allo PBSCT will increase life-threatening acute and chronic GVHD, and whether PBSC allografting will result in permanent hematological and immunological reconstitution has to be determined by prospective randomized clinical trials.
Graft vs Host Disease↗
Enhancing and suppressive effects of immunosuppressants cyclosporin A, FK506, and KM2210 on the colony formation of murine bone marrow cells.
Immunosuppressants cyclosporin A (CsA), FK506, and KM2210 modulated colony formations of murine hematopoietic progenitor cells. In a 4-h treatment with CsA, 10 micrograms/ml increased the formation of colony-forming units of mixed lineages (CFU-Mix) but decreased the formation of highly proliferative potential colony-forming units (CFU-HPP); 1 microgram/ml of CsA increased the formations of CFU-HPP, CFU-Mix, and colony-forming units of granulocytes/macrophages (CFU-GM); 0.1 microgram of CsA increased the formation of CFU-Mix and burst-forming units of erythroid lineage (BFU-E). Lower doses of CsA appeared to induce an increase in various colony formations. FK506 increased CFU-HPP and CFU-Mix formations at lower doses. Another immunosuppressant, KM2210, increased CFU-HPP and CFU-GM formations but decreased CFU-Mix and BFU-E formations. In a 24-h treatment, 10 micrograms/ml and 1 microgram/ml of CsA inhibited all the colony formations, but 0.1 microgram/ml of CsA increased CFU-Mix, CFU-GM, and BFU-E formations. Similarly, 100 ng/ml and 10 ng/ml of FK506 decreased all the colony formations but 1 ng/ml of FK506 increased CFU-HPP and CFU-GM formations. KM2210 inhibited all the colony formations. These findings showed that lower doses of CsA and FK506 appeared to increase the colony formations, although higher doses of these drugs decreased the colony formations, similar to the findings in a 4-h treatment. On the other hand, KM2210 showed opposing effects on colony formation with 4-h and 24-h treatments.
Animals↗
A novel gene, Translin, encodes a recombination hotspot binding protein associated with chromosomal translocations.
We have identified a novel gene, Translin, encoding a protein which specifically binds to consensus sequences at breakpoint junctions of chromosomal translocations in many cases of lymphoid malignancies. The encoded protein, Translin, is a previously undescribed type with no significant similarity to known proteins. In the native form, Translin polypeptides form a multimeric structure which is responsible for its DNA binding activity. Nuclear localization of Translin is limited to lymphoid cell lines, raising the intriguing possibility that nuclear transport of Translin is regulated in a physiologically significant way such that active nuclear transport is associated with the lymphoid specific process known as Ig/TCR gene rearrangement.
Amino Acid Sequence↗
The role of thymus in the aging of Th cell subpopulations and age-associated alteration of cytokine production by these cells.
Mouse CD4+ T cells were subdivided into two subpopulations, naive (CD44low CD45RBhigh) and memory (CD44high CD45RBlow) T cells, by flow cytometric analysis. Examination of spleen and peripheral blood of C57BL/6 mice of various ages revealed that there was a reciprocal age-associated change in these two subpopulations, i.e. naive T cells predominant in young mice decreased with age, while memory T cells increased. In order to investigate the role of the thymus in the age change of naive and memory T cells, we employed two experimental systems: radiation bone marrow chimeras constructed between young and old mice, and grafting of young or old thymus into nude mice. Data from these two experiments suggested that the young thymus has a greater ability to provide naive T cells than the old thymus, while the old thymus favors the maintenance of memory T cells rather than naive T cells. In reference to cytokine production by enriched naive and memory T cells, young naive T cells produced mainly IL-2 and young memory T cells mainly IL-4. On the other hand, in old mice, memory T cells produced twice as much IL-2 than naive T cells, although the level was significantly lower than that of young mice. In addition, old naive T cells produced twice as much IL-4 than old memory T cells. These results suggested a distinct age change in the profile of cytokine production and functional heterogeneity of two Th cell subpopulations.
Age Factors↗
Effect of KCl concentration on gating properties of calcium release channels in sarcoplasmic reticulum vesicles.
The effect of KCl concentration on the gating properties of the Ca2+ release channel in sarcoplasmic reticulum vesicles was studied through measurement of the permeation of choline and glucose by means of the light scattering method. The calcium concentration which activates the channel at micromolar range was shifted to higher concentration in the presence of KCl. This phenomenon can be explained by competition between Ca2+ and K+ at the Ca(2+)-binding sites. Five millimolar caffeine increased the apparent affinity of Ca2+ about 10 times but the effect of caffeine was not modified by K+. Inhibition of the channel by millimolar Ca2+ was also competed with by K+. These effects of K+ were not duplicated by choline, suggesting that the binding of choline to these sites is weak. Blocking of the channel by ruthenium red and Mg2+ was also competed with by K+, but blocking by procaine or tetracaine was not. After the opening of the channel by ryanodine, higher concentrations of these blockers were required to close the channel, and further, in the presence of K+ much higher concentrations of blockers were required. These results suggest that these drugs do not block the channel by plugging the pore directly but do so by regulating the gate, and that the Ca2+ release channel has many binding sites for activators and inhibitor to the gate.
Animals↗