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Biomedical subjects

Ichiro Shimizu

Publications and source records attributed to Ichiro Shimizu.

At least 19 recordsLinked to original sources
PubMed2007

Efficacy and limitations of natural killer cell depletion in cyclophosphamide-induced tolerance.

PURPOSE: We previously developed a cyclophosphamide (CP)-induced tolerance protocol, consisting of an intravenous injection of 1 x 10(8) donor spleen cells (SC) given on day 0 and an intraperitoneal injection of 200 mg/kg CP given on day 2. In the present study, we modified this protocol with natural killer cell (NK) depletion in recipient mice, and evaluated the efficacy of tolerance induction. METHODS: We used B10.D2 (H-2d; IE+) and B10 (H-2b; IE-) mice as both donors and recipients. The recipient mice were treated with donor SC, CP, and donor bone marrow cells (BMCs) with or without NK depletion. RESULTS: A higher level of mixed chimerism was achieved in the NK-depleted recipients. Survival of both the skin and heart donor grafts was significantly prolonged in the NK-depleted recipients. Donor reactive Vbeta11+ T cells were found at the same level as in untreated control mice. Pretreatment with recipient NK cell depletion was effective in inducing higher levels of donor mixed chimerism; however, permanent engraftment of donor bone marrow was not achieved. CONCLUSION: Survival of donor grafts was remarkably prolonged in the NK cell-depleted group, but transplantation tolerance could not be induced. Our results suggest that NK cell depletion in CP-induced tolerance conditioning has some effect on the induction of donor-specific tolerance.

Animals↗
PubMed2006

Regulatory roles of NKT cells in the induction and maintenance of cyclophosphamide-induced tolerance.

We have previously reported the sequential mechanisms of cyclophosphamide (CP)-induced tolerance. Permanent acceptance of donor skin graft is readily induced in the MHC-matched and minor Ag-mismatched recipients after treatment with donor spleen cells and CP. In the present study, we have elucidated the roles of NKT cells in CP-induced skin allograft tolerance. BALB/c AnNCrj (H-2(d), Lyt-1.2, and Mls-1(b)) wild-type (WT) mice or Valpha14 NKT knockout (KO) (BALB/c) mice were used as recipients, and DBA/2 NCrj (H-2(d), Lyt-1.1, and Mls-1(a)) mice were used as donors. Recipient mice were primed with 1 x 10(8) donor SC i.v. on day 0, followed by 200 mg/kg CP i.p. on day 2. Donor mixed chimerism and permanent acceptance of donor skin allografts were observed in the WT recipients. However, donor skin allografts were rejected in NKT KO recipient mice. In addition, the donor reactive Vbeta6(+) T cells were observed in the thymus of a NKT KO recipient. Reconstruction of NKT cells from WT mice restored the acceptance of donor skin allografts. In addition, donor grafts were partially accepted in the thymectomized NKT KO recipient mice. Furthermore, the tolerogen-specific suppressor cell was observed in thymectomized NKT KO recipient mice, suggesting the generation of regulatory T cells in the absence of NTK cells. Our results suggest that NKT cells are essential for CP-induced tolerance and may have a role in the establishment of mixed chimerism, resulting in clonal deletion of donor-reactive T cells in the recipient thymus.

Animals↗
PubMed2006

B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-alphaGAL-producing B-1 cells.

B-1b cells produce IgM natural antibodies against alpha1-3Galbeta1-4GlcNAc (alphaGal). These can be tolerized by nonmyeloablative induction of mixed chimerism using alphaGal-positive (alphaGal+) donor marrow. We assessed the role of CR1/2 in this model for induction of tolerance of B-1b cells. Mixed hematopoietic chimerism was induced in alpha1-3galactosyltransferase (GalT-/-) and GalT-/-Cr2-/- mice with alphaGal+ BALB/c marrow donors. Anti-alphaGal Ab and anti-alphaGal Ab-producing B cells became undetectable in GalT-/- chimeras, whereas they persisted in chimeric GalT-/-Cr2-/- mice. To determine whether CR1/2 expression on stromal cells and/or hematopoietic cells was critical for B-1-cell tolerance, we generated GalT-/- radiation chimeras in which CR1/CR2 was expressed on either stromal cells, hematopoietic cells, neither, or both. After induction of mixed chimerism from alphaGal+ allogeneic bone marrow (BM) donors, anti-alphaGal-producing B cells were rendered tolerant in reconstituted recipients expressing only stromal CR1/CR2. Our results suggest a possible role for follicular dendritic cells that pick up immune complexes via CR1/CR2 receptors in the tolerization of B-1b cells.

Animals↗
PubMed2006

A patient with early syphilis complicated by fatty liver who showed an alleviation of hepatopathy accompanied by jaundice after receiving anti-syphilitic therapy.

A 42-year-old male with visceral obesity and a fatty liver presented with hepatopathy accompanied by jaundice and was diagnosed to have early syphilis based on the results of standard serologic tests and clinical findings. Both the subjective and objective findings including hepatopathy were rapidly alleviated by anti-syphilitic therapy. Severe hepatopathy accompanied by jaundice used to be considered a rare complication. However, due to contemporary unhealthy lifestyle patterns characterized by hypernutrition and a lack of exercise the occurrence of fatty liver is now dramatically increasing. Our findings suggest that the occurrence of fatty liver can exacerbate the damage to the hepatic parenchyma due to a Treponema pallidum infection.

Adult↗
PubMed2006

Effects of estradiol and progesterone on tumor necrosis factor alpha-induced apoptosis in human hepatoma HuH-7 cells.

Oxidative stress, including the generation of reactive oxygen species (ROS), is known to be involved in apoptosis. Preventing apoptosis may thereby induce a malignant transformation of liver tumor cells. Estradiol (E2) is a potent endogenous antioxidant. We examined the proapoptotic role of progesterone as well as the antiapoptotic role of E2 in human hepatoma HuH-7 cells in a state of early apoptosis induced by tumor necrosis factor (TNF) alpha. The TNF alpha-induced ROS generation, lipid peroxidation, antioxidant enzyme consumption, a proapoptotic predominant expression of Bcl-2 family proteins, and a disruption of mitochondrial membrane potential were all inhibited by E2, and then they were further stimulated by progesterone in HuH-7 cells. The inhibitory effects of E2 were blocked by coincubation with progesterone. Treatment with the progesterone receptor antagonist RU486 led to the blockage of the progesterone-mediated responses to E2 pretreatment in TNF alpha-induced apoptosis. These findings demonstrate that E2 inhibits the TNF alpha-induced early apoptosis in hepatoma cells, by suppressing the oxidative stress processes, whereas progesterone acts in a manner opposite from the effects of E2, and the inhibitory effects of E2 were blocked by progesterone, thus leading to the apoptosis of hepatoma cells.

Antibodies, Monoclonal↗
PubMed2006

Ochronotic arthropathy: pathological evidence of acute destruction of the hip joint.

Alcaptonuria is a hereditary disease, also known as black hip, where there is an accumulation of homogentisic acid pigmentation in joint cartilages. We describe a 74-year-old woman who showed acute destruction of her left hip joint. She received a total hip arthroplasty on her right side in July 2000, and was diagnosed with ochronosis. Her postoperative follow-up was at our institutions outpatient department. She first complained of increasing groin pain in July 2005, after which she had a left total hip arthroplasty in October 2005. Histopathologically, samples from this patient showed "fragmentation and cleft formation" in the cartilage of the femoral head. In addition, the samples revealed a remarkable degradation of proteoglycan, which is the secondary most abundant constituent of extra cellular matrix. These findings suggested that "cleft formation", where cracks develop toward the center, caused an acute destructive arthropathy with morphological fragility suggestive of ochronosis.

Acute Disease↗
PubMed2006

Intestinal Behcet's disease with esophageal ulcers and colonic longitudinal ulcers.

Intestinal Behcet's disease in a 38-year-old woman was diagnosed because of the history of recurrent oral aphthous ulcers, erythema nodosum-like eruptions, genital ulcer, and endoscopic findings of esophageal and ileocolonic punched-out ulcers with colonic longitudinal ulcers. Esophageal lesions and colonic longitudinal ulcers are rarely seen in intestinal Behcet's disease. The ulcers of esophagus and ileocolon healed with 3 wk of treatment with prednisolone and mesalazine without any adverse effect. Mesalazine may decrease the total dose of prednisolone required to treat the disease.

Adult↗
PubMed2006

Oral delivery of diclofenac sodium using a novel solid-in-oil suspension.

The present work reports on a new pharmaceutical formulation for oral delivery of diclofenac sodium (DFNa), a non-steroidal anti-inflammatory drug (NSAID). Although DFNa itself is water-soluble at neutral pH, it was readily suspended in soybean oil via complex formation with an edible lipophilic surfactant and a matrix protein. The resulting solid-in-oil (S/O) suspension containing stably encapsulated DFNa in an oil phase markedly reduced the risks for gastrointestinal ulcers upon oral administration even at the LD(50) level in rats (ca. 50 mg/kg DFNa). In addition, plasma concentration of DFNa upon administration of an S/O suspension was comparable with that of the aqueous counterpart at the same DFNa dose. These results indicate the potential use of S/O suspensions as novel oil-based pharmaceutical formulations for oral delivery of water-soluble drugs without causing severe mucitis.

Administration, Oral↗
PubMed2006

Decay-accelerating factor prevents acute humoral rejection induced by low levels of anti-alphaGal natural antibodies.

BACKGROUND: Hyperacute and delayed vascular rejection due to natural antibodies (NAb) present major obstacles in pig-to-primate xenotransplantation. Although "supraphysiologic" expression of human complement regulatory proteins (CRPs) can prevent hyperacute rejection in discordant xenogenic recipients, their physiologic role in the homologous setting is undefined. We have evaluated the effect of the absence of decay-accelerating factor (DAF) on cardiac allograft rejection in the presence of different levels of antidonor antibodies (Ab). METHODS: DAF1-deficient (DAF KO; B6129F2 H-2) mice were used as heart graft donors to alpha1,3-galactosyltransferase deficient (GalT KO; B6, H-2) recipients. Heterotopic heart grafting was performed with or without presensitization. Graft survival, histology, and anti-alphaGal Ab levels were monitored. RESULTS: DAF knockout (KO) but not wild-type (WT) grafts showed hyperacute or acute humoral rejection in nonsensitized GalT KO mice with low levels of anti-alphaGal IgM NAb. However, humoral rejection of both DAF KO and DAF WT donor grafts occurred in presensitized GalT KO recipients. CONCLUSIONS: The expression of DAF prevents hyperacute rejection in mice with low titers of anti-alphaGal antibody. These studies demonstrate the physiologic role of DAF in preventing humoral rejection in the presence of low levels of NAb and have implications for transplantation of discordant vascularized xenografts.

Acute Disease↗
PubMed2006

Sequential analysis of anti-alpha Gal natural antibody-producing B cells in GalT knockout mice in cyclophosphamide-induced tolerance.

Previously, we have shown that cyclophosphamide (CP)-induced tolerance, marked by permanent acceptance of donor skin graft and establishment of donor mixed chimerism, was readily induced with treatment with donor spleen cells (SC), CP, busulfan (BU) and donor bone marrow cells (BMC). Here, we investigated the mechanism of anti-donor natural antibody (nAb) producing B-cell tolerance in our CP-induced tolerance systems in alpha1,3-galactosyltransferase-deficient knockout mice (GalT KO; GalT-/-, H-2(b/d)). After induction of tolerance using donor AKR SC and BMC, survival of donor heart and skin grafts and production of anti-Galalpha1-3Galbeta1-4GlcNAc (anti-alphaGal) Ab in recipient GalT KO mice were analyzed. In addition, the production of anti-alphaGal Ab and the presence of Gal-BSA binding B cells in GalT KO mice were analyzed by flow cytometry (FCM) after treatments with rabbit red blood cells (RRBC) and CP. Permanent acceptance of donor skin and heart grafts and abrogation of anti-alphaGal Ab were achieved in GalT KO mice treated with donor SC + CP/BU + BMC. However, in the GalT KO mice treated with donor SC and CP, donor skin grafts were acutely rejected, even though anti-alphaGal Ab was undetectable. Similarly, anti-alphaGal Ab was undetectable in GalT KO mice treated with RRBC and CP. Our data strongly indicated the following mechanisms: the clonal destruction in the early stage and the clonal anergy or ignorance in the late stage after conventional conditioning with RRBC and CP. In conclusion, our drug-induced tolerance protocols are effective to induce tolerance in recipients that produce anti-donor nAb.

Animals↗
PubMed2006

A histochemical and immunohistochemical investigation of guanase and nedasin in rat and human tissues.

Human guanase is known as a specific enzyme in the liver, kidney, and brain. However, its functional significance remains poorly understood. In addition, interestingly, a different organ distribution between humans and rats was suggested. Here, we performed immunohistochemical staining with anti-human nedasin (neuronal and endocrine discs large/SAP102 associated protein), whose sequence was identical to that of guanase, antibody and histochemical staining for guanase in normal tissues of rat and human liver, kidney, and small intestine, and compared the results. Guanase activity was observed uniformly in the rat hepatocytes, biliary epithelium and vascular endothelium cells, while it was localized to the hepatocytes and biliary epithelium in the human liver. When the histochemical staining for guanase and the immunohistochemical staining for nedasin were compared, the stained regions were different in the rat liver but were almost consistent in all human tissues. Totally consistent staining results were also obtained between rats and humans in the other organization except the liver. Based upon the research reports to date, the experiments on guanase and nedasin in rat organs performed in this study are considered to have important implications in the investigation of their physiological significance.

Aminohydrolases↗
PubMed2005

Requirement of a higher degree of chimerism for skin allograft tolerance in cyclophosphamide-induced tolerance.

By using a cyclophosphamide (CP)-induced tolerance system, we previously raised the possibility that the degree of chimerism might determine the induction of heart and skin allograft tolerance. When C3H (H-2k; Thy1.2, Mls-1b) mice were intravenously primed with 1 x 10(8) spleen cells (SCs) from H-2 matched AKR (H-2k; Thy1.1, Mls-1a) mice and then treated intraperitoneally with 200 mg/kg CP, the survival of AKR skin grafts was permanently prolonged in a tolerogen-specific fashion. After this treatment, a minimal degree of mixed chimerism and the clonal destruction of Mls-1a-reactive CD4+Vbeta6+ T cells in the periphery were observed. When AKR SCs and 100 mg/kg CP were used for conditioning, the survival of the AKR skin grafts was mildly prolonged. The clonal destruction of CD4+Vbeta6+ T cells in the periphery was induced and a minimal degree of mixed chimerism was detectable. The degree of mixed chimerism induced with AKR SCs and 200 mg/kg CP was significantly higher than that with AKR SCs and 100 mg/kg CP during the observation. On the other hand, neither skin allograft prolongation nor permanent mixed chimerism could be induced when C3H mice were treated with AKR SCs and 50 mg/kg CP. In order to increase the degree of mixed chimerism, we injected 1 x 10(8) tolerant AKR SCs on day 3 into the recipient C3H mice that had been treated with AKR SCs on day 0 and with 100 mg/kg CP on day 2. The reason that we used tolerant SCs was that untreated AKR SCs caused graft-versus-host disease in most of the recipients. Tolerant AKR SCs were harvested from AKR mice that had been treated with C3H SCs and 200 mg/kg CP 2 weeks earlier, and did not contain regulatory cells. By adoptive transfer, the degree of chimerism was stably and significantly increased in all recipients, and AKR skin graft tolerance was induced in half of the recipients. T-cell-depleted bone marrow cells (BMCs) from untreated AKR mice induced skin allograft tolerance in 83% of recipients. Thus, the present study strongly confirmed the hypothesis that a higher degree of chimerism is required for the induction of skin allograft tolerance in CP-induced tolerance.

Adoptive Transfer↗
PubMed2005

Mixed hematopoietic chimerism for the simultaneous induction of T and B cell tolerance.

Nonmyeloablative induction of mixed hematopoietic chimerism provides a strategy for inducing T cell tolerance across allogeneic and xenogeneic barriers. We have utilized alpha1-3Gal transferase (GalT) knockout mice, which, like humans, produce anti-Gal natural antibodies, to investigate the ability of mixed chimerism to tolerize B cells producing antibodies of this important specificity, which limits xenotransplantation by causing hyperacute and delayed xenograft rejection. Mixed allogeneic or xenogeneic chimerism indeed tolerizes both preexisting anti-Gal-producing B cells and those developing de novo after establishment of mixed chimerism, even in presensitized mice. We present evidence that different mechanisms are involved in the tolerization of the preexisting and newly-developing antibody-secreting cells.

Animals↗
PubMed2005

Absent mRNA accumulation of Th1 or Th2 cytokines in heart allografts with chimerism-based drug-induced tolerance.

PURPOSE: We recently described using cyclophosphamide (CP) plus busulfan (BU) to create drug-induced skin and heart allograft tolerance capable of regularly overcoming fully H-2 mismatched barriers in mice. The present study investigates the intragraft mRNA expressions of Th1 and Th2 cytokines. METHODS: This method consists of the intravenous (i.v.) injection of 1 x 10(8) allogeneic spleen cells on day 0, the intraperitoneal injection of 200 mg/kg CP and 30 mg/kg BU on day 2, and the i.v. injection of 1 x 10(7) T cell-depleted allogeneic bone marrow cells from the same strain of mice on day 3. Heart grafting (HG) was performed on day 28. Chimerism in the peripheral blood was monitored by flow cytometric (FCM) analysis. The frequency of certain V(beta) families was determined by FCM to assess deletion of donor-reactive T cells. Th1 (interleukin [IL]-2, interferon [IFN]-gamma) and Th2 (IL-4, IL-10) cytokine expression in the heart grafts was analyzed with reverse transcription-polymerase chain reaction. RESULTS: In a fully MHC mismatched combination of B10.D2 (H-2d, IE+) --> B10 (H-2b, IE-), B10.D2 heart grafts were accepted permanently in a donor-specific manner, mixed chimerism was observed, and IE-reactive V(beta)11+ T cells were specifically reduced in the periphery from the recipient B10 mice. In the donor B10.D2 heart grafts, there was no accumulation of Th1 (IL-2, IFN-gamma) or Th2 (IL-4, IL-10) cytokines. CONCLUSIONS: These results show that the drug-induced tolerance we established can regularly induce long-lasting heart allograft tolerance without intragraft mRNA accumulation of Th1 or Th2.

Animals↗
PubMed2005

The regulatory functions of Ly-49A, Ly-49D and Ly-49G2 on NK cells in the recognition and rejection of the alloantigen in vivo.

Ly-49A is an inhibitory receptor that binds H-2Dd and H-2Dk. The downregulation of Ly-49A is thought to mediate NK self tolerance in vivo. In this study, we analyzed the regulation of Ly-49A, D and G2 on NK cells in an in vivo rejection model. After injection with 1 x 10(8) B10.D2 spleen cells (SC) into B 10 mice, we found Ly-49A downregulated within 3 h on NK cells of B10 mice, whereas expressions of Ly-49D and G2 were augmented. To investigate effects of different expression patterns of Ly-49 receptors on NK cells, Ly-49A, D or G2-depleted B10 mice were inoculated with B10.D2 SC. NK cells from SC of Ly-49A-depleted and B10.D2 SC-injected B10 mice showed enhanced cytotoxicity to Dd-positive targets in vitro. Furthermore, reduced numbers of B10.D2 SC were observed in Ly-49A or G2-depleted B10 mice, whereas increased numbers of B10.D2 SC were observed in Ly-49D-depleted B10 mice after inoculation with B10.D2 SC in vivo. These findings indicated that the downregulation of Ly-49A and the augmentation of Ly-49D expression may mediate NK cells to recognize and kill Dd antigen efficiently. In conclusion, each Ly-49 isoform may play independent roles in the regulation of activation or inhibition on NK cells.

Animals↗
PubMed2005

A patient with octopus pot-shaped cardial cancer that metastasized to multiple organs.

A 71-year-old male was admitted for abdominal fullness. The condition rapidly deteriorated in a short period (3 weeks), and the patient died. Autopsy revealed a protruding lesion measuring about 3 cm with erosion measuring 5 mm in diameter immediately below the esophago-gastric conjugation site, suggesting primary cardial undifferentiated adenocarcinoma. In the primary focus, changes on the mucosal surface were almost normal However, below the mucosa, infiltration of cancer cells was observed in an approximately 3 cm area along the gastric wall. Simultaneously, the site of infiltration was markedly increased in deep areas. Extraserous infiltration was observed. The morphology was special, and resembled an octopus pot, a trap used to catch octopuses in Japan, with a narrow top and a broad base. In our patient, metastatic lesions were detected in multiple organs, including the stomach.

Adenocarcinoma↗
PubMed2005

A patient with adult extrahepatic portal obstruction, of which distinction from intrahepatic cholangiocarcinoma was difficult.

A 51-year-old Japanese male with chief complaints of slightly high fever and epigastralgia was hospitalized at our facility. The inflammatory response was enhanced, and liver dysfunction was observed. Abdominal ultrasonography demonstrated a hyperechoic lesion occupying the left portal vein, and abdominal plain CT indicated a low density of the lesion with a clear boundary, measuring about 3 cm x 2 cm, between the porta hepatis and segment IV of the liver. Contrast CT showed no enhancement in the arterial and portal phases, but a reduction in the density inside the tumor in the equilibration phase was noted. MRI showed hypointensity by T1-weighted imaging and hyperintensity by T2-weighted imaging. Angiography demonstrated an obstruction of the left portal vein and superior mesenteric vein, and endoscopic retrograde cholangiography revealed a constriction in the left intrahepatic bile duct. Since the possibility of intrahepatic cholangiocarcinoma could not be excluded, extended left hepatectomy combined with caudate lobectomy was performed. The tumor, measuring 31 mm x 21 mm x 20 mm, was pathohistologically diagnosed as an extrahepatic portal obstruction. Extrahepatic portal obstruction is an important disease that is sometimes difficult to rule out oncologic origin.

Bile Duct Neoplasms↗