Biomedical subjects

Takashi Nishimura

Publications and source records attributed to Takashi Nishimura.

At least 19 recordsLinked to original sources

PubMed2007

A case of scirrhous gastric cancer with peritonitis carcinomatosa controlled by TS-1 + paclitaxel for 36 mo after diagnosis.

A 34-year-old female complaining of abdominal fullness was diagnosed as scirrhous gastric cancer (type 4') with peritonitis carcinomatosa in July 2002. A combined chemotherapy regimen was selected to control massive ascites; TS-1 80 mg/m(2) was given orally on d 1-14, 22-35, and paclitaxel 50 mg/m(2) was administered intravenously on d 1, 8, 22 and 29. After 2 courses of this regimen, the primary tumor was markedly reduced, and ascites completely vanished. Alopecia (grade 1, since d 30), leukocytopenia (grade 2, on d 34) and anemia (grade 2, on d 34) were the only adverse events throughout the following courses. The chemotherapy was effective for 28 mo, and then it was discontinued upon the patientos own request, and she survived for 36 mo after diagnosis.

Abdomen↗

PubMed2007

AsialoGM1+CD8+ central memory-type T cells in unimmunized mice as novel immunomodulator of IFN-gamma-dependent type 1 immunity.

In unimmunized specific pathogen-free mice, there are unique memory-type CD8(+) T cell populations expressing asialoGM1 (ASGM1). These cells were classified into central memory-type T cells (T(CMT)) judging from their expression profile of CD44, IL-2Rbeta, CD62L and CCR7 cell-surface molecules. Among CD44(high)CD8(+) so-called memory CD8(+) T cell population, ASGM1(+)CD44(high)CD8(+) T(CMT), but not ASGM1(-)CD44(high)CD8(+) memory T cells, produced IFN-gamma by stimulation with anti-CD3 mAb. The physiological significance of ASGM1(+)CD8(+) T(CMT) as early source of IFN-gamma was also demonstrated in vivo. Namely, intravenous injection of anti-CD3 mAb (2 microg) resulted in early activation of IFN-gamma-producing ASGM1(+)CD8(+) T(CMT) cells as well as NKT and NK cells. Unexpectedly, however, few IFN-gamma-producing CD4(+) T cells were detected until 4 h after anti-CD3 mAb administration. Thus, ASGM1(+)CD8(+) T(CMT) were demonstrated to be early IFN-gamma producer, which may be crucial for T(h)1-dependent cellular immunity. Indeed, co-culture of naive CD4(+) T cells with ASGM1(+)CD8(+) T(CMT) but not ASGM1(-)CD8(+) T cells caused a great acceleration of IFN-gamma-producing T(h)1 cells in vitro. Finally, we found that T(h)1-prone C57BL/6 mice possessed higher percentage (10%) of ASGM1(+)CD8(+) T(CMT) in CD8(+) T cells compared with that (3%) of T(h)2-prone BALB/c mice. Moreover, ASGM1(+)CD8(+) T(CMT) derived from C57BL/6 mice produced higher levels of IFN-gamma compared with those from BALB/c mice. Thus, ASGM1(+)CD8(+) T(CMT), whose differentiation in vivo is genetically controlled, appear to play a critical role in the control of type 1 immunity, which is essential for therapy of tumors and infectious diseases.

Animals↗

PubMed2007

Identification of CLUAP1 as a human osteosarcoma tumor-associated antigen recognized by the humoral immune system.

Since the prognosis of human osteosarcoma in advanced stage remains poor, the development of new and effective therapies including immunotherapy is required. To identify tumor-associated antigens of osteosarcoma applicable to the immunotherapy of this malignancy, we employed the serological analysis of recombinant cDNA expression library (SEREX) technique that defines tumor antigens recognized by the humoral immune system. Screening a cDNA library derived from an osteosarcoma cell line MG63 with sera from osteosarcoma patients identified 43 positive clones, representing 14 distinct antigens. Among them, CLUAP1 (clusterin-associated protein 1) was highly expressed in osteosarcoma tissue samples and cell lines. Overexpression of CLUAP1 was observed in other malignancies including ovarian, colon, and lung cancers. Our results suggest that CLUAP1 may be useful as a prognostic/diagnostic marker and/or for a target of immunotherapy of osteosarcoma.

Adolescent↗

PubMed2007

[Case of ulcerative colitis associated with drug-induced hypersensitivity syndrome (DIHS) by salazosulfapyridine].

We experienced a case of drug-induced hypersensitivity syndrome (DIHS) for salazosulfapyridine (SASP). After we started administration of SASP in a 26-year old man with ulcerative colitis (UC), he had symptoms resembling infectious mononucleosis, high fever, skin eruption, cervical lymphadenopathy, elevate white blood cell count with atypical lymphocyte, and liver dysfunction. We diagnosed the illness as drug-induced hypersensitivity syndrome (DIHS) due to SASP. We halted SASP and started administration of methylprednisolone and prednisolone but his condition deteriorated. We changed to administration of betamethasone and he recovered. In cases of DIHS accompanied by UC, we should administer drugs carefully and recognize serious complications.

Adult↗

PubMed2006

Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs.

We have previously described a method for adoptive immunotherapy of cancer based on antigen-specific T(h)1 cells. However, efficient induction of anti-tumor responses using T(h)1 cells remains a formidable challenge, especially for MHC class II-negative tumors. In the present study, we sought to develop a novel strategy to eradicate established tumors of the MHC class II-negative, ovalbumin (OVA)-expressing EG-7 cells. Tumor-bearing mice were intradermally treated with OVA-specific T(h)1 cells, combined with the model tumor antigen (OVA), near the tumor-draining lymph node (DLN). We found that tumor growth was significantly inhibited by this strategy and approximately 50-60% of tumor-bearing mice were completely cured. Tumor eradication was crucially dependent on the generation of OVA/H-2K(b)-specific CTLs in the tumor DLNs and tumor site. The injected T(h)1 cells were mainly distributed in tumor DLNs, where they vigorously proliferated and enhanced the activation of dendritic cells. Strikingly, we also found that the accumulation of CD4(+)CD25(+) regulatory T cells (Tregs) was significantly inhibited in tumor DLNs by T(h)1 cell adjuvant therapy and this abrogation was associated with IFNgamma secreted by T(h)1 cells. These results identify T(h)1 cell adjuvant therapy combined with tumor vaccination as a novel approach to the treatment of human cancer.

Animals↗

PubMed2006

Importance of luxury flow for critically ill patients receiving a left ventricular assist system.

The presence of a significant organ dysfunction does not immediately exclude patients from consideration for treatment with a left ventricular assist system (LVAS). However, in treating morbid circulatory shock patients with multiple organ failure, it is important to know the preoperative and postoperative factor or factors related to the recovery of the damaged organ function. In this study, we retrospectively analyzed patients receiving a LVAS at our institution and tried to determine the important factors related to the survival of patients with multisystem failure. Twenty-seven patients who underwent LVAS placement at Saitama Medical School Hospital between 1993 and 2003 were included in this study. The preoperative risk factors analyzed were renal dysfunction, respiratory dysfunction, hepatic dysfunction, the existence of active infection, and the combination of all four factors. As a postoperative factor, the pump flow index (mean LVAS pump flow during the first 2 weeks after LVAS surgery divided by the body surface area) was analyzed. None of the analyzed preoperative factors could predict survival after LVAS surgery, but a pump flow index of less than 2.5 l/min/m2 had a significant relationship with death after LVAS surgery. Further analysis revealed that all the patients with a pump flow index of 3.0 l/min/m2 or more could overcome preoperative organ dysfunction. Congestive heart failure patients with multisystem failure need luxury pump flow for successful LVAS surgery; this factor could be especially important in device selection and postoperative management.

Cardiac Output↗

PubMed2006

Interleukin-12-responding asialoGM1+CD8+ central memory-type T cells as precursor cells for interferon-gamma-producing killer T cells.

While investigating CD8(+) memory T cells in unimmunized C57BL/6 mice, we found that there were unique memory-type CD8(+) T cells expressing asialoGM1 (ASGM1), CD62L and CCR7 cell surface molecules, which occupied approximately 10% of CD8(+) T cells and 35% of CD44(+) memory CD8(+) T cells. Culture of freshly isolated ASGM1(+)CD8(+) T cells with interleukin (IL)-12 plus IL-2 caused the proliferation and generation of killer T cells. Moreover, ASGM1(+)CD8(+) T cells, but not ASGM1(-)CD8(+) T cells, produced high levels of interferon (IFN)-gamma in response to IL-12 plus IL-2. Although ASGM1(+)CD8(+) T cells showed no significant responses to IL-12 alone or IL-2 alone, pulse incubation of ASGM1(+)CD8(+) T cells with IL-12 at an earlier time (0-12 h), and subsequently with IL-2 at a later time (12-24 h), caused the same levels of proliferation, killer cell generation and IFN-gamma production as when they were incubated simultaneously with IL-12 plus IL-2 for 24 h. Thus, ASGM1(+)CD8(+) T cells appeared to respond to IL-12 directly to acquire IL-2 responsiveness and differentiate into IFN-gamma-producing killer T cells. Indeed, freshly isolated ASGM1(+)CD8(+) T cells, but not ASGM1(-)CD8(+) T cells, expressed higher levels of IL-12R beta2 mRNA. The fact that IL-12 administration in vivo caused the generation of ASGM1(+)CD8(+) killer T cells in an IFN-gamma-dependent manner further indicated a physiological significance of ASGM1(+)CD8(+) central memory-type T cells in IL-12-induced immunoregulation for the therapy of tumors and infectious diseases.

Adjuvants, Immunologic↗

PubMed2006

Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cells.

To generate tumor-specific and interferon (IFN)-gamma-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3zeta. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2-/- mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-gamma in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer.

Carcinoembryonic Antigen↗

PubMed2006

An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy.

Prior studies have shown that transfer of ovalbumin (OVA)-specific T helper type 1 (Th1) cells into mice bearing MHC class II+ OVA-expressing tumor cells (A20-OVA) causes complete tumor rejection. Here we show that, although Th1 cell therapy alone was not effective against MHC class II- OVA-expressing tumor cells (EG-7), treatment of mice bearing established EG-7 tumors by i.v. transfer of Th1 cells combined with i.t. injection of the model tumor antigen OVA induced complete tumor rejection. Transferred Th1 cells enhanced the migration of tumor-infiltrating antigen-presenting cells (APC) that had processed OVA into the draining lymph node (DLN). Although transferred Th1 cells were randomly distributed in DLN, distal LN, spleen, and tumor tissue, active proliferation of Th1 cells always initiated in DLN, where Th1 cells efficiently interacted with APC that presented OVA. In parallel, OVA-tetramer+ CTLs, showing EG-7-specific cytotoxicity, were highly induced in DLN and the local tumor site. The OVA-tetramer+ CTL functioned systemically because two bilateral tumor masses were both completely rejected on treatment of one tumor. Furthermore, either active proliferation of transferred Th1 cells or generation of tetramer+ CTL was not induced in MHC class II-deficient mice and LN-deficient Aly/Aly mice. These results indicate that DLN is an indispensable organ for initiating active APC/Th1 cell interactions, which is critical for inducing complete eradication of tumor mass by tumor-specific CTL.

Animals↗

PubMed2006

An indispensable role of type-1 IFNs for inducing CTL-mediated complete eradication of established tumor tissue by CpG-liposome co-encapsulated with model tumor antigen.

We have evaluated the capacity of a novel, nanoparticle-based tumor vaccine to eradicate established tumors in mice. C57BL/6 mice were intradermally (i.d.) inoculated with ovalbumin (OVA)-expressing EG-7 tumor cells. When the tumor size reached 7-8 mm, the tumor-bearing mice were i.d. injected near the tumor-draining lymph node (DLN) with liposomes encapsulated with unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotides (CpG-ODN) (CpG-liposomes) co-encapsulated with OVA. This vaccination protocol markedly prevented the growth of the established tumor mass and approximately 50% of tumor-bearing mice became completely cured. Tumor eradication correlated with the generation of OVA/H-2K(b)-tetramer(+) CTLs in the tumor DLN and at the tumor site with specific cytotoxicity toward EG-7 cells. Interestingly, tetramer(+) CTLs failed to be induced in lymph node-deficient Aly/Aly mice. Thus, tetramer(+) CTLs appeared to be generated in the tumor DLN and subsequently migrated into the tumor site. In vivo antibody blocking experiments revealed that CD8(+) T cells, but not CD4(+) T, NK or NKT cells, were the major effector cells mediating tumor eradication. CTL induction was also inhibited when vaccinated tumor-bearing mice were treated with both anti-IFN-alpha and anti-IFN-beta mAbs but not with anti-IFN-alpha or anti-IFN-beta mAb alone. Neither IFN-gamma(-/-) nor IL-12(-/-) mice showed impaired induction of tetramer(+) CTLs. Thus, these findings revealed that CpG-ODN-induced IFN-alpha/beta, but not IL-12 or IFN-gamma, is critical for the generation of tumor-specific CTLs in response to vaccination. These results highlight the potential utility of CpG-liposomes co-encapsulated with protein tumor antigens as therapeutic vaccines in cancer patients.

Adjuvants, Immunologic↗

PubMed2006

Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2.

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Evidence for pestivirus infection in free-living Japanese serows, Capricornis crispus.

Sixteen serum samples collected from free-living Japanese serows, Capricornis crispus, between 2001 and 2004 in Morioka and its vicinity were examined for the presence of pestivirus by reverse transcription-nested PCR procedure. Three out of the 16 samples produced a visible band in electrophoresed agarose gels. The nucleotide sequences of the three PCR products were found to be identical. The pestivirus found in the serow was identified as Bovine viral diarrhea virus 1 (BVDV-1) based on nucleotide sequence analyses by phylogeny as well as palindromic nucleotide substitutions at the 5' untranslated regions. Our data first indicated that BVDV-1 infection occurred continuously among the free-living serow populations though the role of BVDV-1 in wild ungulates is currently unknown.

Animals↗

PubMed2006

1alpha,25-Dihydroxyvitamin D3 downmodulates the functional differentiation of Th1 cytokine-conditioned bone marrow-derived dendritic cells beneficial for cytotoxic T lymphocyte generation.

Various dendritic cell subsets are induced from bone marrow cells under different cytokine conditions. We have demonstrated previously that the Th1-cytokine-conditioned bone marrow-derived dendritic cell (BMDC) subset BMDC1 (generated in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF] + interleukin [IL]-3 + interferon [IFN]-gamma+ IL-12) induces a much stronger type 1 immune response than BMDC0 (GM-CSF + IL-3). In the present study, we investigated the effect of 1alpha,25-dihydroxyvitamine D3 (VitD3), which is a known immunomodulating drug, on the differentiation of BMDC subsets. The addition of VitD3 significantly influenced the functional differentiation of BMDC1 compared with BMDC0. Specifically, the addition of VitD3 greatly decreased the expression levels of MHC class I, CD80, CD40 and leukocyte function-associated antigen (LFA)-1 molecules on BMDC1. In addition, VitD3-treated BMDC1 (VD3-BMDC1) almost completely lost their immunostimulating activity for inducing type 1 immunity and cytotoxic T lymphocyte generation. A failure in the induction of type 1 immunity by VD3-BMDC1 appeared to be due to the following: (i) the expression of co-stimulatory molecules on VD3-BMDC1 was strongly downmodulated compared with BMDC1 generated without VitD3; and (ii) VD3-BMDC1 showed significantly lower mRNA expression of IFN-gamma and IFN-beta, factors that are essential for cytotoxic T lymphocyte induction. VitD3 inhibited the differentiation of functionally competent BMDC1 during the early phase of differentiation but not during the late differentiation period. A possible reason for the inhibition of BMDC1 differentiation by VitD3 is reduced phosphorylation of STAT1 during early differentiation. Taken together, VitD3 strongly suppressed T-cell responses by inhibiting functional differentiation of precursor dendritic cells into functional BMDC1 that are feasible for inducing Th1-dependent cellular immunity.

Animals↗

PubMed2006

Tetramer-blocking assay for defining antigen-specific cytotoxic T lymphocytes using peptide-MHC tetramer.

Peptide-MHC tetramers have been engineered to allow accurate detection of antigen-specific cytotoxic C lymphocytes (CTL) by flow cytometry. Here, we propose a novel use for peptide-MHC tetramers in the specific and sensitive analysis of the cytotoxic function of antigen-specific CTL by blocking MHC-restricted antigen-specific cytotoxicity. We found that pretreatment of ovalbumin (OVA)-specific CD8(+) CTL (OT-1 CTL), derived from OT-1 T-cell receptor (TCR)-transgenic mice, with OVA(257-264) peptide-H-2K(b) tetramer caused a marked inhibition of the cytotoxicity against OVA-expressing EG-7 tumor cells. OVA(257-264) peptide-H-2K(b) tetramer did not block the cytotoxicity mediated by 2C mouse (H-2(b))-derived CD8(+) CTL, which recognize allo (H-2L(d)) antigens. Moreover, OT-I CTL activity was not inhibited by an irrelevant HBV(208-216) peptide-H-2K(b) tetramer. These results indicate that the blocking of CTL activity with peptide-MHC tetramer was caused by interference with the interaction between the TCR and H-2K(b)-OVA(257-264) peptide complex, but not with the CD8-MHC class I interaction. The blocking activity of OVA(257-264) peptide-H-2K(b) tetramer was reversible because OT-I CTL pretreated with the tetramer recovered their cytotoxicity after culturing with interleukin-2 for 24 h. The same results were also demonstrated in freshly isolated, in vivo-primed OT-1 CTL sorted by the tetramer. These results demonstrate that peptide-MHC tetramer is a useful tool for defining MHC-restricted antigen-specific CTL function. Moreover, our finding implies that the measurement of CTL activity immediately after tetramer-guided sorting is not a suitable method for evaluating the function of in vivo-induced tetramer-positive CTL. We believe that the tetramer-blocking assay presented here will be useful for functionally monitor the induction of MHC-restricted antigen-specific CTL during vaccination therapy against tumor and infectious diseases.

Animals↗

PubMed2006

Immunomodulating effect of vitamin D3 derivatives on type-1 cellular immunity.

1 alpha,25-dihydroxyvitamin D3 [Calcitriol or 1,25(OH)(2)D(3)] is an important active metabolite involved in multiple functions but its calcemic effect in vivo limits its therapeutic applications. On the other hand, 22-oxa-1 alpha,25-dihydroxyvitamin D(3) (22-oxacalcitriol or 22-Oxa-1 alpha,25-D(3)), a low calcemic analog of vitamin D3 (VitD3), has been widely used as a drug for the secondary hyperparathyroidism. Here, we investigated immunomodulating effect of these two VitD3 derivatives on the differentiation of type-1 immunoregulatory cells such as dendritic cells (DC1), cytotoxic T cells (Tc1) and helper T cells (Th1). BALB/c mouse bone marrow-derived DC (BMDC1) induced by culture with Th1 condition (GM-CSF, IL-3, IL-12 and IFN-gamma) expressed higher levels of MHC Class I and Class II molecules and co-stimulatory molecules compared with BMDC0 induced by neutral condition (GM-CSF+IL-3). In addition, BMDC1 showed stronger immunostimulating activity to induce alloantigen (H-2(d))-specific cytotoxic T lymphocytes (CTL) compared with BMDC0. However, if VitD3 derivatives were added into the culture for BMDC1 induction, the expression of functional molecules and type-1 IFNs were greatly inhibited. Moreover, VitD3 derivative-treated BMDC1 lost their immunostimulating activity to induce alloantigen-specific IFN-gamma-producing Tc1. In addition, it was demonstrated that the addition of VitD3 derivatives inhibited the differentiation of IFN-gamma-producing Th1 cells from ovalbumin (OVA)-specific naive Th cells, while it rather augmented the differentiation of IL-4- or IL-10-producing Th2 cells. There was no significant difference in immunomodulating activity between 1,25(OH)(2)D(3) and 22-Oxa-1 alpha,25-D(3). Thus, VitD3 derivatives are demonstrated to inhibit the functional differentiation of DC1, Tc1 and Th1 cells, which play a critical role in type-1 cellular immune responses.

Animals↗

PubMed2006

Expression of the MAGE-A4 and NY-ESO-1 cancer-testis antigens and T cell infiltration in non-small cell lung carcinoma and their prognostic significance.

Cancer-testis (CT) antigens were identified as a group of highly attractive targets for cancer immunotherapy because of their expression in a variety of malignant tumors but solely in the testis among the normal adult tissues. To evaluate the potential of two members of this family, MAGE-A4 and NY-ESO-1 antigens, for cancer vaccine in non-small cell lung carcinoma (NSCLC), we examined the expression of these antigens and T cell infiltration in tumor tissue, and evaluated their prognostic significance. One hundred fifty-seven patients with NSCLC were studied. Reverse transcription-PCR was performed to evaluate MAGE-A4 and NY-ESO-1 expression. Immunohistochemistry was performed for NY-ESO-1 expression and T cell infiltration into the tumor site. Survival analysis was also performed. MAGE-A4 and NY-ESO-1 were expressed in 40 of 141 (28.4%) and 13 of 157 (8.3%) NSCLC respectively. Both CT antigens were more frequently expressed in squamous cell carcinoma (SCC) than in adenocarcinoma. An inverse correlation was found between MAGE-A4 expression and patient survival in advanced stage cancers. Combined infiltration of both CD4+ and CD8+ T cells into tumor nest predicted better survival. There was no correlation, however, between lymphocyte infiltration and antigen expression in the tumor. MAGE-A4 expression in advanced group and T cell infiltration may provide prognostic information. Lastly, these CT antigens, especially MAGE-A4, may represent potential targets for cancer immunotherapy in patients with NSCLC.

Adult↗

PubMed2006

[Critical role of IFN-alpha/beta and IFN-gamma in the regulation of airway inflammation].

Immune balance, which is controlled by IFN-gamma-producing Th1 cells and IL-4-producing Th2 cells, plays a critical role in the regulation of airway inflammation. We have demonstrated that Th1 cells induced neutrophilia, airway hyperresponsiveness (AHR) but not mucus hypersecretion, while Th2 cells induced eosinophilia, AHR and mucus hypersecretion. Here, we indicated that IFN-gamma produced by Th1 cells accelerated neutrophilia and AHR but inhibited eosinophilia and mucus hypersecretion. We also demonstrated an important role of type 1 IFN-alpha/beta during inhibition of Th2-dependent airway inflammation by TLR-9-ligand, CpG-ODN. CpG-ODN-induced IFN-alpha/beta partially appeared to act against Th2 cells to inhibit the production of IL-4 and IL-13, which are key cytokines to regulate the activation and migration of Th2 cells in the lung.

Adjuvants, Immunologic↗

PubMed2005

Development of a functional cDNA array for evaluation of the Th1/Th2 balance.

The immune balance controlled by CD4(+) helper T cell subsets (T helper 1 (Th1) and T helper 2 (Th2)) is crucial for immunoregulation and its imbalance causes various immune diseases including infections, allergic disorders and autoimmune diseases. Therefore, it is of great importance to develop a system of diagnosing Th1/Th2 imbalances for curing immune diseases. Here we developed a functional cDNA array filter useful for assessing the Th1/Th2 balance in mice. To overcome the disadvantages of conventional microarrays carrying thousands of genes, we prepared an array filter containing 40 Th1-specific and 32 Th2-specific genes, which were selected from over 8700 genes based on (i) the specificity of expression in Th1 or Th2 cells and (ii) an expression level which is high enough for detection using a DNA array. This array filter provided a prompt and precise evaluation for the skewing of the Th1/Th2 balance combined with our calculation algorithm. The bias toward Th1 or Th2 was evaluated visually at a glance by aligning the genes on the filter. Moreover, we succeeded in evaluating the skewing of the Th1/Th2 balance in vivo during acute graft versus host disease (GVHD). Thus, this array filter will provide a novel tool for evaluation of the Th1/Th2 balance in a variety of immune diseases.

Acute Disease↗