Genetic control of peripheral T-cell deficiency in the cataract Shionogi (CTS) mouse linked to chromosome 7.
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Animals↗
Biomedical subjects
M Harada
Publications and source records attributed to M Harada.
Early-appearing tumor-infiltrating natural killer cells play an important role in the nitric oxide production of tumor-associated macrophages through their interferon production.
Both natural killer (NK) cells and macrophages are thought to be the main effectors responsible for early antitumor defense. In this study, we investigated the role of tumor-infiltrating NK cells in initiating nitric oxide (NO) production by tumor-associated macrophages (TAM). The in vivo depletion of NK cells prior to the i.p. inoculation of melanoma cells resulted in a significant decrease in the NO production of the TAM prepared from the peritoneal exudate cells (PEC). Such prior NK cell depletion also decreased the ability of TAM to show any antitumor activity in vitro. The addition of NG-monomethyl-L-arginine (Me-L-Arg) to the culture partially inhibited the ability of TAM to suppress the proliferation of melanoma cells and also decreased their cytolytic activity against melanoma cells. These results suggest that the TAM exhibited both cytostatic and cytolytic activities through their NO production. In an in vivo assay, the administration of Me-L-Arg permitted the more rapid growth of i.p. inoculated melanoma cells compared with the control. On the other hand, the decreased NO production of TAM, resulting from the prior NK cell depletion, was restored by the i.p. administration of interferon gamma (IFN gamma). In addition, the in vivo administration of anti-IFN gamma mAb into mice inoculated i.p. with melanoma cells also significantly decreased the NO production of TAM in peritoneal exudate cells. Furthermore, the tumor-infiltrating NK cells produced a considerable level of IFN gamma. Overall, these results indicate that early-appearing tumor-infiltrating NK cells play an important role in the NO production of TAM through their IFN gamma production.
Animals↗
Antitumor vaccination effect of dendritic cells can be augmented by locally utilizing Th1-type cytokines from OK432-reactive CD4+ T cells.
In order to enhance the antitumor vaccination effect of dendritic cells (DC) pulsed with class I tumor peptide, we tried to utilize the local cytokine help of CD4+ T cells reactive to a streptococcal preparation OK432. DC were prepared from murine bone marrow cells by culture with both granulocyte/macrophage-colony-stimulating factor and interleukin(IL)-4. The peritumoral injections of OK432 induced OK432-reactive CD4+ T cells in the draining lymph nodes, and their in vitro production of interferon gamma was thus significantly enhanced by restimulation with OK432-pulsed DC. In addition, anti-P815 mastocytoma cytotoxic T lymphocytes were generated from the in vivo OK432-treated P815-draining lymph node cells only when the lymph node cells were restimulated in vitro with the DC pulsed with both P1A peptide and OK432. Moreover, the peritumoral injections of OK432 and the subsequent vaccination of the DC, pulsed with both OK432 and P1A peptide, significantly suppressed the growth of s.c. inoculated P815. Interestingly, a significant level of IL-12 was detected in the coculture supernatant of both OK432-pulsed DC and OK432-reactive CD4+ T cells. Collectively, our results suggest that the antitumor vaccination effect of DC pulsed with class I tumor peptide could thus be effectively augmented by locally utilizing the Th1-type cytokines from OK432-reactive CD4+ T cells.
Animals↗
Characterization of B16 melanoma-specific cytotoxic T lymphocytes.
A B16 melanoma-specific CD8+ T cell line (AB1) was established from the spleen cells of C57BL/6 mice cured of B16 melanoma with interleukin (IL)-12 treatment. The AB1 line exclusively used T cell receptor Vbeta11. The AB1 cells exhibited a cytolytic activity against both syngeneic B16 melanoma and allogeneic P815 mastocytoma, whereas a cold inhibition assay revealed specificity of the AB1 cells against B16 melanoma. Their lostability to kill a class I loss variant of B16 melanoma was restored by the transfection of H-2Kb gene. In addition, their interferon (IFN)-gamma production was significantly suppressed by the addition of anti-H-2Kb monoclonal antibody, and RT-PCR analysis showed that the AB1 line expressed the mRNA encoding IFN-gamma, but not IL-4 or IL-10. The experiment using synthetic peptides of tyrosinase-related protein-2 (TRP-2) revealed that the AB1 cells could recognize TRP-2(181-188) peptide. Moreover, the AB1 cells showed an in vivo antitumor effect against established pulmonary metastases of B16 melanoma. Overall, these results indicate that the Tc1-type Vbeta11+ AB1 cells exert an antitumor activity against syngeneic B16 melanoma through recognition of TRP-2(181-188) peptide in an H-2Kb-restricted manner.
Animals↗
Antitumor response of regional lymph node lymphocytes in human lung cancer.
We recently reported that regional lymph node lymphocytes (RLNL) from patients with primary lung cancer were in a more highly activated state than peripheral blood lymphocytes (PBL) when the activation-related molecules were studied by FACS analysis. To identify whether or not RLNL had the ability to respond to autologous tumor cells (AT), in the present study a mixed lymphocyte tumor cell reaction (MLTR) either with or without recombinant interleukin 2 (rlL-2) was performed in 41 cases with primary lung cancer. Significant proliferative responses to AT were found in RLNL from 20 of 41 cases (48.8%) without IL-2, and in 23 of 41 cases (56.1%) with IL-2. On the other hand, such responses were observed in the PBL from 8 of 30 cases (26.7%) without IL-2, and from 11 of 30 cases (36.7%) with IL-2. No significant correlation between MLTR and such clinical factors as tumor size, metastasis to lymph node, histology and stage of the disease was found. To further analyze the anti-AT response of RLNL, the cytokine production of RLNL was investigated after stimulation by AT. An increase in interferon-gamma (IFN-gamma) production was observed in RLNL with a positive reaction of MLTR, while no such increase was found in PBL. Finally, to elucidate whether the expression of MHC class II molecules was a key point in MLTR, tumor cells in primary lesions were examined for the expression of MHC class II by immunohistochemical staining, and the blocking assay of MLTR was performed with anti-MHC class II monoclonal antibody. Data suggested that there was a positive correlation between MHC class II expression of the tumor and MLTR and that MLTR were partially blocked by anti-MHC class II monoclonal antibody. These results demonstrated that RLNL were in a more highly activated state against AT than were PBL, and this finding is considered to be helpful in enhancing our understanding of the role of RLNL in lung cancer patients.
Antibodies, Monoclonal↗
Myelodysplastic syndrome with translocation (8;21): a distinct myelodysplastic syndrome entity or M2-acute myeloid leukemia with extensive myeloid maturation?
We report a case of refractory anemia with excess of blasts in transformation with the translocation (8;21), which is frequent in acute myeloid leukemia (AML) but not in myelodysplastic syndromes (MDS). Bone marrow blasts were 1.6% and an extensive myeloid differentiation was noted. Fluorescence in situ hybridization analysis revealed the presence of 21q22 translocations in mature neutrophils, indicating that clonogenic blast progenitors could actively undergo terminal differentiation to mature end cells in vivo. We consider that t(8;21)+ MDS may represent a rare clinical manifestation of M2-AML, in which blast progenitors have an extensive differentiation potential to mature neutrophils without maturation arrests.
Adult↗
Direct action of a protein-bound polysaccharide, PSK, on transforming growth factor-beta.
We investigated the action of a protein-bound polysaccharide, PSK, on transforming growth factor-beta (TGF-beta). (1) In in vitro-mixed culture of peripheral blood mononuclear cells (PBMC) from healthy human and mitomycin C-treated human colon cancer cells, PSK or polyclonal antibody to TGF-beta significantly enhanced incorporation of 3H-thymidine into PBMC, and apparently decreased TGF-beta1 levels of acid-treated culture supernatant. (2) PSK or the antibody interfered with the quantitation by enzyme immunoassay of TGF-beta1 in acid-treated supernatant of the mixed culture. (3) PSK was suggested to form a complex with 125I-human recombinant TGF-beta1 standard, when changes in molecular weight of radioactivities were assessed by gel filtration. Recombinant human TGF-beta1 inhibited growth of mink lung epithelial cell line Mv1Lu and promoted collagen synthesis in rat kidney fibroblast cell line NRK49F, but the complex did not have such activities. (4) In addition to TGF-beta1, PSK bound with TGF-beta2 and platelet-derived growth factor; however, PSK did not bind with 22 other species of cytokines and growth factors. (5) Protein moiety of PSK is suggested to play an important role in the expression of the activity. These results suggest that PSK modulates the biological activity of TGF-beta1 by binding to its active form.
Animals↗
Spontaneous biloma as a complication of small cell lung cancer.
Biloma is an extraductular collection of bile within a defined capsular space. Prior reports have documented an association between biloma and abdominal trauma, and between biloma and iatrogenic injury resulting from abdominal surgery, percutaneous catheter drainage, or transhepatic cholangiogram. To our knowledge, bilomas have not previously been associated with lung cancer. We report a case of spontaneous biloma that developed as a complication of small cell lung cancer.
Aged↗
Vaccination with activated B cells pulsed with tumor-lysates can induce tumor-specific CD4+ T cells in vivo.
Activated B cells, pulsed with tumor-lysates, were examined for their potential to induce tumor-specific CD4+ T cells in vivo, MH2 cells, which are CD4+ T cells and can also recognize purified protein derivative from mycobacterium tuberculosis (PPD), showed a proliferative response in the presence of both syngeneic activated B cells and PPD in a major histocompatibility complex class II-restricted manner. For B cells to function as efficient antigen presenting cells, they need to be activated. Both irradiation and several inhibitors for antigen-processing were observed to block the antigen-presenting ability of activated B cells. Based in these findings, the possibility of anti-tumor vaccination with activated B cells was thus investigated. The spleen cells from mice, which were immunized with activated B cells pulsed with B16 melanoma-lysates, produced a higher level of interferon (IFN)-gamma than those from mice, which were immunized with either non-pulsed activated B cells or the tumor-lysates alone, after in vitro restimulation. This IFN-gamma production was also dependent on the CD4+ T cells. Moreover, the splenic CD4+ T cells in such mice were suggested to increase their ability to generate B16 melanoma-specific cytotoxic T lymphocytes after in vitro restimulation. Even more importantly, immunization with B16 melanoma lysate-pulsed activated B cells elicited a protective immunity against B16 melanoma at rechallenge. Collectively, these results indicate that an anti-tumor effect could be induced by immunization with activated B cells, pulsed with the tumor-lysates, by eliciting tumor-specific IFN-gamma producing CD4+ T cells in vivo.
Animals↗
Proton magnetic resonance spectroscopy of the brain in patients with Prader-Willi syndrome.
Five patients with Prader-Willi syndrome underwent magnetic resonance imaging and proton magnetic resonance spectroscopy. Magnetic resonance images revealed mild abnormalities, including slight ventriculomegaly, cortical atrophy, and a small brainstem, in all cases. The N-acetylaspartate/Choline (NAA/Cho) and N-acetylaspartate/Creatine (NAA/Cr) ratios were decreased in one (Case 1) and two (Cases 1 and 4) patients, respectively. The Choline/Creatine (Cho/Cr) ratio did not differ from those in control subjects. Thus, in patients with Prader-Willi syndrome, it is thought that there may be neuron loss or a neuron dysfunction caused by a chromosome abnormality. Statistically significant relationships were observed between IQ (DQ) and the NAA/Cho and Cho/Cr ratios: r = 0.895 (P < .05, NAA/Cho ratio) and r = -0.898 (P < .05, Cho/Cr ratio). This suggests that the parietal lobe pathology detected on 1H-magnetic resonance spectroscopy may be associated with more global brain damage and with loss of cognitive functions.
Adolescent↗
Trisomy 12 and t(14;18) in B-cell chronic lymphocytic leukemia.
We report a case of B-cell chronic lymphocytic leukemia (B-CLL) in which trisomy 12 and t(14;18)(q32;q21) were simultaneously detected in the same leukemic clone. Southern blot analysis showed that the BCL2/IgJH rearrangement occurred at the major breakpoint region in the hot spot of the BCL2 gene. Double color fluorescence in situ hybridization analysis using multiple probes indicated that clonal B-cell with t(14;18) represented a subpopulation of the total leukemic cells and that trisomy 12 followed t(14;18) as the cytogenetic aberration in the development of B-CLL. Our findings suggests that both the t(14;18) and the trisomy are secondary chromosomal changes in the leukemogenesis of B-CLL.
Blotting, Southern↗
Graft rejection and recovery of host-derived hematopoiesis after allogeneic bone marrow transplantation: relation to conditioning with high dose etoposide and total body irradiation.
Engraftment failure following allogeneic bone marrow transplantation (BMT) is rare in patients with acute leukemia, after frequent conditioning with marrow-lethal chemoradiotherapy. We evaluated the efficacy of a preparatory regimen consisting of fractionated total body irradiation (TBI) (12 Gy in six fractions) and high dose etoposide (60 mg/kg) administered as an 8-h infusion for allogeneic BMT in 16 consecutive patients with acute leukemia. Although 14 patients showed complete and sustained engraftment, the remaining two patients rejected bone marrow grafts from HLA-identical sibling donors and showed subsequent recovery of host-derived hematopoiesis. Despite the limited number of patients, this observation suggests that the immunosuppressive potential of etoposide may be inferior to that of cyclophosphamide (CY) and that etoposide as an alternative to CY as an antileukemic and immunosuppressive agent in allogeneic BMT may increase the risk of graft rejection.
Acute Disease↗
Replating potential of colony-forming units of granulocytes/macrophages (CFU-GM) expanded ex vivo by stem cell factor, interleukin (IL)-3, IL-6, granulocyte colony-stimulating factor, erythropoietin with or without thrombopoietin.
Ex vivo expansion systems of hematopoietic progenitor cells (HPC) have been extensively studied and their clinical application is under investigation. However, it is not known whether HPC expanded ex vivo will be able to retain their replating potential. CD34+ cells isolated from cord blood were cultured in Iscove's modified Dulbecco's medium supplemented with 10% fetal bovine serum, 1.0% bovine serum albumin, 50 ng/ml stem cell factor, 50 ng/ml interleukin-3 (IL-3), 50 ng/ml IL-6, 100 ng/ml granulocyte colony-stimulating factor, and 3 U/ml erythropoietin for 0, 5, 7, 10, 14, and 21 days. After the expansion cultures, granulocyte/macrophage progenitor cells (CFU-GM) were assayed from each culture by the standard methylcellulose method. After 14 days of culture, CFU-GM-derived colonies were randomly picked up and processed for the replating assay. The fold increase of CFU-GM peaked at day 7 of the expansion culture (29.8 +/- 7.7-fold, n = 5), followed by a decline until day 21. In the replating assay of CFU-GM from freshly isolated CD34+ cells, the mean replating efficiency was 91.2 +/- 4.7%. The replating efficiency decreased gradually with the time of the expansion culture. At day 7 when the fold increase of CFU-GM reached its peak, the replating efficiency had dropped to 47.5 +/- 2.3%, followed by a further decline to 5.3 +/- 3.4% at day 21. Furthermore, the addition of 100 ng/ml thrombopoietin to this expansion system failed to prevent the decline of replating efficiency. These observations suggest that the replating potential of CFU-GM may decrease in the ex vivo expansion system, even when their fold increase reaches its peak. This should be taken into consideration when HPC expanded ex vivo are used in clinical transplantation.
Antigens, CD34↗
Two maize genes encoding omega-3 fatty acid desaturase and their differential expression to temperature.
We have isolated two maize cDNAs and the corresponding genes encoding fatty acid desaturase with Arabidopsis thaliana FAD7 gene as a probe. They shared almost 90% identity at DNA sequence level. Northern analysis revealed that both genes are expressed in leaves, but not in roots at normal temperature- and low temperature-growth condition. The overall level of these transcripts are elevated upon exposure to low temperature. The tissue-specific expression and DNA sequence data indicate that both genes encode plastidic omega-3 fatty acid desaturases. One of them is expressed exclusively at normal temperature but not at 5 degrees C, whereas the other is expressed inversely. We, therefore, termed them ZmFAD7 and ZmFAD8, respectively. Among other stresses, high-salt treatment induced the accumulation of the ZmFAD7 and ZmFAD8 transcripts in roots but drought had no effect on their expression. Cycloheximide induced the accumulation of the ZmFAD7 transcript in roots. The genomic clones of ZmFAD7 and ZmFAD8 consist of 8 exons and 7 introns as same as in the cases of A. thaliana FAD7 and FAD8 genes and the sizes of the 6 internal exons were identical among them. A phylogenetic analysis of ZmFAD7, ZmFAD8 amino acid sequences and those originated from other plant species is also presented.
Amino Acid Sequence↗
Large granular lymphocytic leukaemia with a mixed T-cell/B-cell phenotype.
We report a case of large granular lymphocytic leukaemia (LGLL) with mixed T-cell/B-cell phenotypes. The LGLL cells expressed T-cell markers such as CD1, CD2, CD3, CD5, CD7, CD8 and CD57. The CD8+ LGLL cells coexpressed B-cell markers including CD20 and PCA-1, and a fraction of purified CD8+ LGLL cells secreted double isotypes of immunoglobulins (IgG-kappa and IgA-kappa). Both TCRB and IGH genes were clonally rearranged. The LGLL cells could be divided into at least three subpopulations that were cytogenetically distinct, and all subpopulations involved the 11q23. The expression of both T- and B-cell markers on the LGLL cells suggests the involvement of a putative common lymphoid progenitor in leukaemic transformation.
Aged↗
Involvement of both donor cytotoxic T lymphocytes and host NK1.1+ T cells in the thymic atrophy of mice suffering from acute graft-versus-host disease.
It has been reported that a dramatic decrease in the number of thymocytes (thymic atrophy) in mice suffering from acute graft-versus-host disease (GVHD) is ascribed to glucocorticoids. In this study, we examined the possibility that cellular immune responses may thus be involved in thymic atrophy. In contrast to chronic GVHD mice, acute GVHD (C57BL/6 X DBA/2) F1 (BDF1) hybrid mice, which were injected intravenously with both spleen and lymph node cells from C57BL/6 mice, showed a dramatic decrease in the number of CD4 CD8 double-positive thymocytes 2 or 3 weeks after the induction of GVHD. A flow cytometric analysis revealed the donor-derived T cells with either CD4 or CD8 molecules to infiltrate the thymus of the mice undergoing acute GVHD for 10 days. In a cytolytic assay, such thymus-containing cells exhibited a cytolytic activity specific to the host cells. In addition, anti-H-2d cytolytic T cells showed a high level of cytolytic activity against BDF1 (H-2bXd) thymocytes, whereas they also showed a low level of cytolytic activity against C57BL/6 (H-2b) thymocytes, thus suggesting that the thymus-infiltrating donor-derived T cells killed the host thymocytes through both anti-H-2d-specific and non-specific mechanisms. Interestingly, a flow cytometric analysis revealed both the percentage and the absolute cell number of host-derived NK1.1+ CD3+ cells to increase in the thymus of mice suffering from acute GVHD for 10 days. In addition, they also showed the cytolytic activity against YAC-1 cells and the mRNA expression of interleukin-12 (IL-12) in the thymus to be also significantly augmented on day 7 after the induction of acute GVHD. Collectively, our results indicate that the cellular immune responses such as donor cytotoxic T lymphocytes and host NK1.1+ T cells are therefore involved in the thymic atrophy of mice suffering from acute GVHD.
Acute Disease↗
Aortitis syndrome (Takayasu's arteritis) with cataract and elevated serum level of vascular endothelial growth factor.
The aortitis syndrome is a chronic inflammatory process that affects the aorta and its primary branches. Patients with aortitis syndrome exhibit various ocular changes. We present a patient in whom cataract was the initial objective finding. The serum concentration of vascular endothelial growth factor, a cytokine that affects neovascularization, and vasopermeability, was elevated before the initiation of prednisolone treatment. Cataract should be considered as a possible characteristic initial finding in patients with aortitis syndrome. Vascular endothelial growth factor may be involved in the progression of aortitis syndrome.
Adult↗
Vascular endothelial growth factor in patients with rheumatoid arthritis.
To examine the role of vascular endothelial growth factor (VEGF), an endothelial cell specific growth factor, in rheumatoid arthritis (RA), serum concentration of VEGF was examined in patients with RA, osteoarthritis (OA), systemic lupus erythematosus (SLE), systemic sclerosis (SS) and control subjects. Serum C-reactive protein (CRP) level, erythrocyte sedimentation rate, white blood cell count and rheumatoid factor titer were also determined in patients with RA. The serum concentration of VEGF was significantly higher in patients with RA than in controls (p < 0.01), and patients with OA (p < 0.05), SLE (p < 0.05), and SS (p < 0.05). The serum concentration of VEGF correlated with serum levels of CRP (r = 0.698, p < 0.0001). The serum concentration of VEGF before treatment was significantly higher than that after treatment in patients with RA who experienced clinical remission (p < 0.05). Our data suggest that VEGF is involved in the pathogenesis of RA and that measurement of serum concentration of VEGF is a noninvasive, useful method for monitoring the disease activity of RA.
Adolescent↗