Biomedical subjects
Publications and source records attributed to T Teshima.
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Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 --> B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-gamma knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-gamma is critical for this protective effect.
We synthesized seven O-glycosylated calcitonin derivatives, each with a single GalNAc residue attached to either Ser or Thr, and studied their three-dimensional structure and biological activity to examine site-dependent effects of O-glycosylation. The CD spectra in an aqueous trifluoroethanol solution showed that the GalNAc attachment at Thr6 or Thr21 reduced the helical content of calcitonin, indicating that the O-glycosylated residue functions as a stronger helix breaker than the original amino acid residue. Only the GalNAc attachment at Ser2 or Thr21 retained the hypocalcemic activity of calcitonin. This result corresponded well to that of the calcitonin-receptor binding assay. The GalNAc attachment other than Ser2 or Thr21 perturbed the interaction with the receptor, resulting in the loss of the hypocalcemic activity. The biodistribution did not change much among the seven derivatives, but some site dependency could also be observed. Thus, we can conclude that the O-glycosylation affects both the conformation and biological activity in a site-dependent manner.
PURPOSE: Early mobile tongue cancer can be controlled with interstitial radiotherapy (ISRT). We carried out a Phase III trial to compare the treatment results of low-dose-rate (LDR) ISRT and high-dose-rate (HDR) ISRT for early mobile tongue cancer. METHODS AND MATERIALS: From April 1992 through October 1996, 59 patients with cancer of the early mobile tongue were registered in this Phase III study. Eight patients were excluded from the evaluation because of violations of the requirements for this study. Of 51 eligible patients, 26 patients were treated with LDR-ISRT (70 Gy/4-9 days) and 25 patients with HDR-ISRT (60 Gy/10 fractions/1 week). For the hyperfractionated HDR-ISRT, the time interval between 2 fractions was more than 6 h. RESULTS: Five-year local control rates of the LDR and HDR groups were 84% and 87% respectively. Nodal metastasis occurred in 6 patients in each group. Five-year nodal control rates of the LDR and HDR groups were 77% and 76%, respectively. CONCLUSION: Hyperfractionated HDR-ISRT for early mobile tongue cancer has the same local control compared with continuous LDR-ISRT. Hyperfractionated HDR-ISRT is an alternative treatment for continuous LDR-ISRT.
In allogeneic bone marrow transplantation (BMT) donor T cells are primarily responsible for antihost activity, resulting in graft-versus-host disease (GVHD), and for antileukemia activity, resulting in the graft-versus-leukemia (GVL) effect. The relative contributions of the Fas ligand (FasL) and perforin cytotoxic pathways in GVHD and GVL activity were studied by using FasL-defective or perforin-deficient donor T cells in murine parent --> F1 models for allogeneic bone marrow transplantation. It was found that FasL-defective B6.gld donor T cells display diminished GVHD activity but have intact GVL activity. In contrast, perforin-deficient B6.pfp(-/-) donor T cells have intact GVHD activity but display diminished GVL activity. Splenic T cells from recipients of B6.gld or B6.pfp(-/-) T cells had identical proliferative and cytokine responses to host antigens; however, splenic T cells from recipients of B6.pfp(-/-) T cells had no cytolytic activity against leukemia cells in a cytotoxicity assay. In experiments with selected CD4(+) or CD8(+) donor T cells, the FasL pathway was important for GVHD activity by both CD4(+) and CD8(+) T cells, whereas the perforin pathway was required for CD8-mediated GVL activity. These data demonstrate in a murine model for allogeneic bone marrow transplantation that donor T cells mediate GVHD activity primarily through the FasL effector pathway and GVL activity through the perforin pathway. This suggests that donor T cells make differential use of cytolytic pathways and that the specific blockade of one cytotoxic pathway may be used to prevent GVHD without interfering with GVL activity.
Allogeneic bone marrow transplantation (BMT) is currently restricted to hematological malignancies because of a lack of antitumor activity against solid cancers. We have tested a novel treatment strategy to stimulate specific antitumor activity against a solid tumor after BMT by vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Using the B16 melanoma model, we found that vaccination elicited potent antitumor activity in recipients of syngeneic BMT in a time-dependent fashion, and that immune reconstitution was critical for the development of antitumor activity. Vaccination did not stimulate antitumor immunity after allogeneic BMT because of the post-BMT immunodeficiency associated with graft-versus-host disease (GVHD). Remarkably, vaccination was effective in stimulating potent and long-lasting antitumor activity in recipients of T-cell-depleted (TCD) allogeneic bone marrow. Recipients of TCD bone marrow who showed significant immune reconstitution by 6 weeks after BMT developed B16-specific T-cell-cytotoxic, proliferative, and cytokine responses as a function of vaccination. T cells derived from donor stem cells were, therefore, able to recognize tumor antigens, although they remained tolerant to host histocompatibility antigens. These results demonstrate that GM-CSF-based tumor cell vaccines after allogeneic TCD BMT can stimulate potent antitumor effects without the induction of GVHD, and this strategy has important implications for the treatment of patients with solid malignancies.
PURPOSE: To evaluate tongue hemiatrophy as a late effect of brachytherapy, a new grading system was designed and applied to patients who had received low dose rate (LDR) or high dose rate (HDR) brachytherapy for early tongue cancer. METHODS AND MATERIALS: Between December 1998 and April 1999, 49 patients who had received brachytherapy for early tongue cancer (T1/T2=22:27) at Osaka University Hospital were investigated. All patients had undergone either LDR or HDR brachytherapy with Ir-192 (LDR/HDR=30:19) between 1980 and 1998. Atrophic changes in their tongue were classified into four categories (G0-G3): G3, not able to protrude the tongue beyond incisors; G2, hemiatrophy is seen on the irradiated side in the resting position of the tongue; G1, deviation of the tip of the tongue to the irradiated side is seen when protruded; and G0, none of these signs. The relationship between tongue hemiatrophy and tumor factors, treatment factors, and patients' functional impairment was then investigated. The median time from treatment to assessment was 75 months (range 8-219 months). Volume index was defined as the number of needles that were implanted vertically into the tongue. RESULTS: Fourteen patients were classified as G0, 29 as G1, five as G2, and one as G3. None of the G0 patients showed any speech or swallowing dysfunction, pain or contracted feeling, or general dissatisfaction with post-treatment tongue status. There was a tendency for such problems to increase with the tongue hemiatrophy grade. The frequency of T2 and non-superficial type tumors also tended to increase with the tongue hemiatrophy grade. The volume index of the G2-3 hemiatrophy group was significantly larger than that of the G0-1 group (P=0.041). CONCLUSION: This new grading system makes evaluation of atrophic changes in the tongue after brachytherapy easy and effective.
OBJECTIVE: The incidence and severity of acute graft-vs-host disease after allogeneic transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) are not greater than those after conventional bone marrow transplantation despite infusion of more than one log greater number of donor T cells in PBSC. It has been postulated that monocytes from G-CSF-mobilized donors suppress alloreactivity of donor T cells. MATERIALS AND METHODS: We investigated the phenotype and function of monocytes in normal individuals receiving 10 microg/kg of G-CSF for 4 days. RESULTS: Monocytes were phenotypically and functionally different after G-CSF administration from steady-state monocytes. They were characterized by an increased CD14(+)CD16(+) subpopulation, reduced expression of HLA-DR, and diminished ability to produce tumor necrosis factor-alpha and interleukin-10 to lipopolysaccharide, compared with steady-state monocytes. These alterations were not replicated by culturing monocytes with G-CSF in vitro, suggesting an indirect effect of G-CSF. In addition, the antigen-presenting function of G-CSF-mobilized monocytes was impaired. CONCLUSION: Hyporesponsiveness of G-CSF-treated monocytes to lipopolysaccharide with regard to tumor necrosis factor-alpha production, together with impaired antigen-presenting function, may be responsible for the unexpectedly low incidence of graft-vs-host disease after G-CSF-mobilized PBSC transplantation.
BACKGROUND: Recently, as the number of elderly people in Japan is growing, so is the number of new cancer cases. The number of patients treated with radiotherapy is therefore also on the increase, so that it is important to estimate the future demand for radiotherapy and to make preparations for it. METHODS: All the surveys were conducted for 106 facilities selected randomly out of 556 radiotherapy facilities in Japan. To obtain trends in the number of new cancer patients treated with radiotherapy in Japan, we conducted a survey with a self-administered mail questionnaire designed to obtain the number of new patients treated with radiotherapy for each year of the past decade (1990-99). The future number of new patients treated with radiotherapy was estimated from the data thus obtained. To investigate structural problems of Japanese radiotherapy, surveys about the number of treatment machines and full-time equivalent (FTE) radiation oncologists were conducted according to data from the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) structure survey and the Patterns of Care Study (PCS). We also compared the structure of Japanese radiotherapy with that in the USA. RESULTS: The number of patients treated with radiotherapy has increased for every institutional stratum, with an overall increase of 1.4-fold over the past 10 years in Japan. It is estimated that the number of cancer patients treated with radiotherapy will reach 190 000 in 2015. In Japanese non-academic institutions, less than one FTE radiation oncologist has been managing many of these patients. In both equipment and manpower, academic institutions exceed nonacademic institutions. CONCLUSION: The future demand for Japanese radiotherapy will grow substantially, so that it is of vital importance to prepare for it. Specifically, the number of FTE radiation oncologists must be increased.
Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-alpha levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.
The aim of this study was to examine the relationship between renal cortical retention on delayed CT and contrast medium-associated and/or transarterial chemoembolisation (TACE)-associated nephropathy following TACE. The authors reviewed the findings on 180 treatments in 121 patients with normal serum creatinine levels who underwent TACE for liver tumours. Nephropathy was defined as an increase in the creatinine level of greater than 0.5 mg x dl(-1) (44 micromol x l(-1)) and greater than 25% on days 1, 3, 7 or 14 post TACE. Renal cortical retention was recognized when CT values for the renal cortex showed either mild renal cortical retention (CT value >50) or severe renal cortical retention (CT value >100). There was evidence of renal cortical retention in 81 (45%) cases and of nephropathy in 11 (6%) cases. Only 2% of patients without renal cortical retention showed nephropathy, whereas 11% of those with renal cortical retention showed nephropathy (p=0.02). Stepwise selection using a multivariate logistic regression model showed renal cortical retention and gender to be significant factors for nephropathy following TACE. In conclusion, renal cortical retention is a useful predicator for nephropathy following TACE. Delayed CT could be used not only for assessment of lipiodol retention but also for predicting nephropathy.
Carboxylated poly(styrene/acrylamide) (P(St/AAm)-H) microspheres with different acrylamide contents were prepared by emulsifier-free emulsion polymerization. Thermus thermophilus holo-chaperonin (cpn) was covalently immobilized onto these microspheres with high yield. The T. thermophilus holo-cpn-immobilized microspheres were used for refolding of guanidine hydrochloride (Gdn-HCl)-denatured enzymes and showed sufficiently high ability to facilitate refolding of Leuconostoc mesenteroides glucose-6-phosphate dehydrogenase (G6PD) and pig heart lactate dehydrogenase (LDH) at 30 degrees C and Bacillus stearothermophilus LDH at 60 degrees C. The specific ability of T. thermophilus holo-cpn-immobilized microspheres increased with increasing immobilization amount and reached plateau at around 10-15 mg/m(2). When the immobilization amounts of T. thermophilus holo-cpn were approximately 10 mg/m(2), the microspheres retained sufficiently high ability to facilitate protein refolding during repeated use. Therefore, the P(St/AAm)-H microspheres on which approximately 10 mg/m(2) of T. thermophilus holo-cpn is immobilized are very effective for refolding of various (Gdn-HCl)-denatured enzymes over a wide temperature range.
BACKGROUND: The Patterns of Care Study (PCS) was imported to Japan from the United States in July 1996. A preliminary outcome analysis of the PCS for esophageal cancer patients in Japan was made with special reference to age, because the elderly population is rapidly increasing in Japan. PATIENTS AND METHODS: From July 1996 to February 1998, external PCS audits were performed for 37 institutions nationwide and detailed information of 561 esophageal cancer patients treated during the period 1992-1994 was collected by using the fifth PCS data format developed in the United States. This format was provided courtesy of the American College of Radiology. For this study, patients who had not undergone surgery (n = 336) were selected. The patients were classified into three age groups: < 65 years old (n = 119), between 65 and 74 years (n = 93), and 75 years or older (n =123). Cox's proportional hazards model was used for the statistical analysis, with survival, acute/subacute complication and late complication of grade 3 or more based on RTOG criteria, as the endpoints. RESULTS: Significant prognostic factors for the entire non-surgery group were Karnofsky Performance Status (KPS) (p = 0.0007), stage (p = 0.0001), and external irradiation dose (p = 0.0001). For the younger group, KPS (p = 0.0004), stage (p = 0.0197), and utilization of brachytherapy (p = 0.0010) were significant, while for the intermediate age group it was KPS (p = 0. 0027), history of pulmonary disease (p = 0.0339), stage (p = 0.0001), and external dose (p = 0.0001), and for the elderly group, stage (p = 0.0001) and external irradiation dose (p = 0.0224) were significant. Significant risk factors for complications for the entire group were stage (p = 0.0411), external dose (p = 0.0163), and stratification of institution (academic vs. nonacademic) (p = 0. 0114). Significant risk factors for the younger group were history of pulmonary disease (p = 0.0495) and external dose (p = 0.0037), and the other age groups showed no significant risk factors. CONCLUSION: Age was not a significant prognostic or risk factor for esophageal cancer patients in the non-surgery group treated with radiation therapy. Therefore, radiation therapy represented an important treatment modality for the elderly as well as for the younger esophageal cancer patients. External dose was a treatment-related prognostic factor for the elderly as well as for the intermediate age group.
Allogeneic peripheral blood stem cell transplantation (PBSCT) is increasingly used instead of bone marrow transplantation, particularly in HLA identical sibling pairs. Despite the presence of significantly increased numbers of T cells in the PBSC graft, acute graft-versus-host disease (GVHD) is not increased. We have investigated whether granulocyte-colony stimulating factor (G-CSF) administration to PBSCT recipients, both with and without donor G-CSF pretreatment, further modulates acute GVHD in a murine model of PBSCT. Recipients of G-CSF mobilized splenocytes showed a significantly improved survival (P<0.001) and a reduction in GVHD score and serum LPS levels compared with control recipients. G-CSF treatment of donors, rather than recipients, had the most significant effect on reducing levels of tumor necrosis factor (TNFalpha) 7 days after transplantation. As a potential mechanism of the reduction in TNFalpha, we demonstrate G-CSF decreased dendritic cells TNFalpha, and interleukin-12 production to lipopolysaccharide. In conclusion, G-CSF modulates GVHD predominantly by its effects on donor cells, reducing the production of TNFalpha. G-CSF treatment of bone marrow transplantation recipients, without pretreatment of the donor, does not have an impact on acute GVHD.
TNF-alpha is known to be an important mediator of tissue damage during allograft rejection and graft-vs-host disease (GVHD), but its role in supporting T cell responses to allogeneic Ags is unclear. We have studied this question by comparing normal mice with those lacking the p55 (p55 TNFR-/-) or p75 (p75 TNFR-/-) TNF-alpha receptors as donors in well-defined bone marrow transplant (BMT) models. Recipients of p55 TNFR-/- cells had significantly reduced mortality and morbidity from GVHD compared with the other two sources of T cells. In vitro, T cells lacking the p55 (but not the p75) TNF-alpha receptor exhibited decreased proliferation and production of Th1 cytokines in MLC. This defect was only partially restored by exogenous IL-2 and affected both CD4+ and CD8+ populations. CD8+ p55 TNFR-/- proliferation was impaired independently of IL-2 whereas CTL effector function was impaired in an IL-2-dependent fashion. Inhibition of TNF-alpha with TNFR:Fc in primary MLC also impaired the proliferation and Th1 differentiation of wild-type T cells. BMT mixing experiments demonstrated that the reduced ability of p55 TNFR-/- donor cells to induce GVHD was due to the absence of the p55 TNFR on T cells rather than bone marrow cells. These data highlight the importance of TNF-alpha in alloreactive T cell responses and suggest that inhibition of the T cell p55 TNF-alpha receptor may provide an additional useful therapeutic maneuver to inhibit alloreactive T cell responses following bone marrow and solid organ transplantation.
Despite a 10-fold increase of T cell dose, the incidence and severity of acute GVHD following allogeneic transplantation of G-CSF-mobilized PBSC is not increased compared to BMT. Experimental murine studies demonstrate that G-CSF polarizes donor T cells toward a type 2 cytokine response. To determine whether G-CSF alters T cell cytokine responses, we investigated the effects of G-CSF administration on T cell proliferative and cytokine responses to alloantigen and Con A in nonadherent PBMC (NAC) and CD3+ T cells obtained from normal individuals before and after G-CSF administration (10 microg/kg x 4 days). Although T cell proliferative and cytokine (IFN-gamma and IL-4) responses to alloantigen stimulation and Con A were significantly reduced in post-G-CSF NAC, they were restored by the removal of non-T cells from post-G-CSF NAC. Furthermore, there was less T cell alloreactivity in MLR in the presence of autologous post-G-CSF monocytes than in the presence of pre-G-CSF monocytes. This alteration was not replicated in vitro by culturing PBMC with G-CSF. These results suggest that G-CSF administration suppresses T cell proliferative and cytokine (IFN-gamma and IL-4) responses to allogeneic stimulation by indirectly modulating monocyte function. Bone Marrow Transplantation (2000).
To investigate the incidence of cleft lip or palate or both (CLP) in Japan, 303738 babies born in 1532 institutions between 1994 and 1995 were examined and 437 (0.14%) were found to have abnormalities. Of these babies, 32.1% had cleft lip, 43.3% had cleft lip and palate, and 24.8% had cleft palate (Table 2). These results show that the incidence of cleft lip and palate has declined compared with the period from 1981 to 1982.
A bisecting GlcNAc-binding protein was purified from a Triton X-100 extract of a porcine spleen microsomal fraction using affinity chromatography, in conjunction with an agalacto bisected biantennary sugar chain-immobilized Sepharose. Since the erythroagglutinating phytohemagglutinin (E-PHA) lectin preferentially binds to sugar chains which contain the bisecting GlcNAc, during purification the binding activity of the protein was evaluated by monitoring the inhibition of lectin binding to the N-acetylglucosaminyltransferase III (GnT-III)-transfected K562 cells which express high levels of the bisecting GlcNAc. The molecular mass of the purified protein was found to be 33 kDa, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. By sequencing analysis, the isolated protein was identified as annexin V. Flow cytometric analysis showed that fluorescein-labeled annexin V binds to the GnT-III-transfected cells but not to mock cells, and that the binding was not affected by the addition of phospholipids. Furthermore, surface plasmon resonance measurements indicated that annexin V binds to the agalacto bisected biantennary sugar chain with a K(d) of 200 microM while essentially no binding was observed in the case of the corresponding non-bisected sample. These results suggest that annexin V has a novel carbohydrate binding activity and may serve as an endogenous lectin for mediating possible signals of bisecting GlcNAc, which have been implicated in a variety of biological functions.