Growth hormone and insulin-like growth factor I induce immunoglobulin (Ig)E and IgG4 production by human B cells.

We studied the effects of growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-II, and insulin on human immunoglobulin E (IgE) and IgG4 production. GH and IGF-I induced IgE and IgG4 production by normal donors' mononuclear cells (MNC) depleted of sIgE+ and sIgG4+ B cells without affecting IgM, IgG1, IgG2, IgG3, IgA1, or IgA2 production, whereas IGF-II and insulin failed to do so. GH-induced IgE and IgG4 production was specific, and was not mediated by IGF-I, interleukin 4 (IL-4), or IL-13, since it was blocked by anti-GH antibody (Ab), but not by anti-IGF-I Ab, anti-IL-4 Ab, or anti-IL-13 Ab. Conversely, IGF-I-induced IgE and IgG4 production was blocked by anti-IGF-I Ab, but not by anti-GH Ab, anti-IL-4 Ab, or anti-IL-13 Ab. Moreover, interferon alpha (IFN-alpha) or IFN-gamma, which counteracted IL-4-and IL-13-induced IgE and IgG4 production, had no effect on induction by GH or IGF-I. In contrast to MNC, GH or IGF-I failed to induce IgE and IgG4 production by purified sIgE-, sIgG4- B cells. However, in the presence of anti-CD40 monoclonal antibody (mAb), GH or IGF-I induced IgE and IgG4 production by these cells. Purified sIgE+, but not sIgE-, B cells from atopic patients spontaneously produced IgE. GH or IGF-I with anti-CD40 mAb failed to enhance IgE production by sIgE+ B cells, whereas they induced IgE production by sIgE- B cells. Similarly, whereas GH or IGF-I with anti-CD40 mAb failed to enhance IgG4 production by sIgG4+ B cells from atopic patients, they induced IgG4 production by sIgG4- B cells. Again, neither IgE nor IgG4 induction was blocked by anti-IL-4 Ab or anti-IL-13 Ab. These results indicate that GH and IGF-I induce IgE and IgG4 production by class switching in an IL-4- and IL-13-independent mechanism.

Histamine selectively enhances human immunoglobulin E (IgE) and IgG4 production induced by anti-CD58 monoclonal antibody.

We studied the effects of histamine on human immunoglobulin (IgE) and IgG4 production. Histamine selectively enhanced IgE and IgG4 production in purified surface IgE and IgG4 negative (sIgE-sIgG4-) B cells from normal donors stimulated with interleukin (IL)-4 plus anti-CD58 or IL-13 plus anti-CD58 monoclonal antibody (mAb) without affecting production of IgG1, IgG2, IgG3, IgM, IgA1, or IgA2. In cultures with IL-4 plus anti-CD58 mAb, histamine-induced enhancement of IgE and IgG4 production was specifically blocked by thioperamide (H3 receptor antagonist), and was inhibited by anti-IL-10 antibody (Ab). In contrast, in cultures with IL-13 plus anti-CD58 mAb, histamine-induced enhancement was blocked by dimaprit (H1 receptor antagonist), and was inhibited by anti-IL-6 mAb. Histamine also enhanced IgE and IgG4 production by in vivo-generated sIgE+ and sIgG4+ B cells, respectively, from atopic patients; enhancement was blocked by dimaprit and thioperamide, and was inhibited by anti-IL-6 mAb and anti-IL-10 Ab. In sIgE-sIgG4- B cells, IL-4 plus anti-CD58 mAb induced IL-10 production and IL-10 receptor expression, whereas IL-13 plus anti-CD58 mAb induced IL-6 production and IL-6 receptor expression. Histamine increased IL-10 and IL-6 production without affecting IL-10 and IL-6 receptor expression, in cultures with IL-4 plus anti-CD58 mAb and with IL-13 plus anti-CD58 mAb, respectively, which was blocked by thioperamide and dimaprit, respectively. In contrast, sIgE+ and sIgG4+ B cells spontaneously produced both IL-6 and IL-10 and constitutively expressed IL-6 and IL-10 receptors, and histamine increased IL-6 and IL-10 production without affecting IL-6 or IL-10 receptor expression, which was blocked by thioperamide and dimaprit. These results indicate that histamine enhanced IgE and IgG4 production by increasing endogenous IL-6 and IL-10 production via H1 and H3 receptors, respectively.

Interleukin 8 (IL-8) selectively inhibits immunoglobulin E production induced by IL-4 in human B cells.

The effect of interleukin 8 (IL-8) on IL-4-induced immunoglobulin E (IgE) production was studied. IL-4 induced IgE and IgG4 production by tonsillar mononuclear cells (MNC) without affecting IgM, IgG1, IgA, IgG2, or IgG3 production. IL-8 inhibited IL-4-induced IgE and IgG4 production, whereas it had no effect on IgM, IgG1, IgA, IgG2, and IgG3 production. The inhibitory effect by IL-8 was specific, since it was blocked by anti-IL-8 mAb, but not by control IgG1. Although interferon gamma (IFN-gamma) also inhibited IgE and IgG4 production by MNC stimulated with IL-4, the inhibitory effect of IL-8 was not mediated by IFN-gamma, since the IL-8-induced inhibition could not be blocked by anti-IFN-gamma. Furthermore, anti-IL-8 mAb had no effect on IFN-gamma-induced inhibition. Moreover, addition of IL-5 or IL-6 did not reverse IL-8-induced inhibition of IgE production. In contrast to these observations with MNC, IL-4 failed to induce IgE and IgG4 production by purified B cells. However, combined treatment of purified B cells cells with IL-4 and anti-CD40 antibody resulted in IgE but not IgG4 production. IL-8 inhibited this IgE production without affecting IgM, IgG1, IgG2, IgG3, IgG4, or IgA production, whereas IFN-gamma, IFN-alpha, or prostaglandin E2 (PGE2) failed to do so. These results indicate that IL-8 antagonizes IL-4-induced IgE production by directly affecting B cells through a specific mechanism that is different from IFN-gamma, IFN-alpha, or PGE2.

RANTES and macrophage inflammatory protein 1 alpha selectively enhance immunoglobulin (IgE) and IgG4 production by human B cells.

We studied the effects of various chemokines including neutrophil-activating peptide 2 (NAP-2), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), melanoma growth stimulating activity (GRO), gamma interferon-induced protein (IP-10), regulated on activation, normal T expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, and monocyte chemotactic protein 1 (MCP-1) on Immunoglobulin (IgE) and IgG4 production by human B cells. None of these chemokines with or without interleukin (IL-4), anti-CD40 or -CD58 monoclonal antibody (mAb), induced IgE and IgG4 production by B cells from nonatopic donors. However, RANTES and MIP-1 alpha selectively enhanced IgE and IgG4 production induced by IL-4 plus anti-CD40 or -CD58 mAb without affecting production of IgM, IgG1, IgG2, IgG3, IgA1, or IgA2, whereas other chemokines failed to do so. Enhancement of IgE and IgG4 production by RANTES and MIP-1 alpha was specifically blocked by anti-RANTES mAb and anti-MIP-1 alpha antibody (Ab), respectively, whereas anti-IL-5 mAb, anti-IL-6 mAb, anti-IL-10 Ab, anti-IL-13 Ab, and anti-tumor necrosis factor-alpha mAb failed to do so. Purified surface IgE positive (slgE4) and slgG4+ B cells generated either in vitro or in vivo spontaneously produced IgE and IgG4, respectively, whereas sIgE- and sIgG4- B cells failed to do so. RANTES and MIP-1 alpha enhanced spontaneous IgE and IgG4 production in slgE+ and slgG4- B cells, respectively, whereas neither RANTES nor MIP-1 alpha did so in sIgE- or sIgG4- B cells. Purified sIgE4+ and sIgG4+, but not sIgE- or sIgG4- B cells, generated in vitro and in vivo expressed receptors for RANTES and MIP-1 alpha, whereas they failed to express receptors for other chemokines. These findings indicate that RANTES and MIP-1 alpha enhance IgE and IgG4 production by directly stimulating sIgE+ and sIgG4+ B cells.

Subset of natural killer cells is induced by immune complexes to display Fc receptors for IgE and IgA and demonstrates isotype regulatory function.

Expression of Fc receptors for IgE (FcER) or IgA (FcAR) on purified natural killer (NK) cells was investigated. No FcER+ and a few FcAR+ NK cells were detectable on freshly separated NK (NKH-1+) cells from normal donors. Incubation of NK cells with IgE-anti-IgE immune complexes or IgA-anti-IgA immune complexes induced up to 10 and 20% FcER+ or FcAR+ cells, respectively. These FcR were induced on CD3- but not on CD3+ NKH-1+ cells. In contrast, NK cells from patients with various dysgammaglobulinemias could not be induced to express FcER or FcAR corresponding to their abnormal circulating IgE and/or IgA levels. Enriched FcER+ or FcAR+ induced NK cell supernatants from normals enhanced IgE or IgA synthesis from Ig secreting B cell lines in an isotype-specific fashion without increasing proliferation. Thus NK cells, after interaction with specific Ig isotypes in complexes, express FcR and produce differentiation factors for that isotype.

Designed transfer of specific immune responses with bone marrow transplantation.

Bone marrow transplant donors were immunized with tetanus/diphtheria toxoids 6-7 d before bone marrow donation to investigate the role of B cell subpopulations in reconstitution of humoral immunity. Lymphoblastoid B cells spontaneously producing IgG antitetanus and/or antidiphtheria toxoid were detected in the donor marrows at the time of transplantation. Recipients rapidly demonstrated 3-90-fold increases in serum IgG antitetanus and antidiphtheria toxoid levels. Antidiphtheria fragment A antibody in three donor/recipient pairs demonstrated spectrotypic identity indicating transfer of the donors' response. Reimmunization of three recipients 64-154 d after transplant revealed an IgG antibody response associated with reappearance of spontaneous antibody-producing B cells and an antidiphtheria fragment A response characteristics of the donor's immune response. These observations extend the understanding of the role of B cell subpopulations and provide a basis for specific modulation of immunity in the setting of bone marrow transplantation.

Kissing selectively decreases allergen-specific IgE production in atopic patients.

OBJECTIVE: Stress enhanced allergic skin wheal responses and allergen-specific IgE production. In contrast, mothers' kissing caused relaxation in infants, and kissing by lovers or spouses to atopic patients reduced allergic skin wheal responses. I studied the effect of kissing on production of allergen-specific IgE and cytokines in atopic patients. METHODS: Twenty-four patients with mild atopic eczema and 24 patients with mild allergic rhinitis kissed with lovers or spouses freely for 30 min while listening to soft music. Just before and immediately after kissing, blood mononuclear cells were separated cultured for allergen, and production of allergen-specific immunoglobulin and cytokine was measured. RESULTS: Kissing selectively decreased allergen-specific IgE production with skewing cytokine pattern toward Th1 type. CONCLUSION: Kissing may alleviate allergic symptoms by decrease in allergen-specific IgE production.

Brain-derived neurotrophic factor selectively enhances allergen-specific IgE production.

We studied the effect of brain-derived neurotrophic factor (BDNF) on in vitro Japanese cedar pollen (JCP)-specific IgE production by mononuclear cells from atopic keratoconjunctivitis patients with JCP allergy. BDNF enhanced JCP-specific IgE production in a dose-dependent fashion in cultures of mononuclear cells stimulated with JCP, and maximal enhancement was achieved at 10 ng/ml. In contrast, BDNF had no effect on JCP-specific IgA or IgG4 production. On the other hand, other neurotrophins, NGF, NT-3, or NGF failed to enhance JCP-specific IgE production. Moreover, anti-BDNF mAb specifically blocked BDNF-induced enhancement of JCP-specific IgE production. Study for cytokine production revealed that BDNF decreased production of Th1 cytokines, IFN-gamma and IL-12, while it had no effect on production of TH2 cytokines, IL-4, IL-10 and IL-13, in cultures of mononuclear cells stimulated with JCP. These results indicate that BDNF relatively skews cytokine pattern toward Th2 type. Collectively, BDNF may increase allergen-specific IgE production, which may in turn aggravate allergic symptoms.

Drinking deep-sea water restores mineral imbalance in atopic eczema/dermatitis syndrome.

OBJECTIVE: The effect of drinking deep-sea water on hair minerals was studied in patients with atopic eczema/dermatitis syndrome (AEDS). Study of hair minerals revealed an imbalance of essential minerals and an increase in toxic minerals in AEDS patients. DESIGN: After drinking deep-sea water (Amami no Mizu) for 6 months in AEDS patients, hair minerals (essential minerals and toxic minerals), clinical evaluation of the skin symptoms were compared before drinking with after drinking. SUBJECTS: After obtaining informed consent, 33 patients (mean age 26 y, range 1-50 y, 13 male and 20 female subjects) with mild to moderate AEDS were enrolled. RESULTS: After drinking deep-sea water, the levels of the essential mineral, potassium (K), were significantly decreased, while the levels of selenium (Se) increased. On the other hand, drinking deep-sea water significantly decreased the levels of the toxic minerals, mercury and lead. Moreover, after drinking deep-sea water, the skin symptoms were improved in 27 out of 33 patients. CONCLUSION: These results indicate that the mineral abnormalities/imbalance may be involved in the pathogenesis of AEDS, and that drinking deep-sea water may be useful in the treatment of AEDS.

Effect of growth hormone and insulin-like growth factor-I on immunoglobulin production by and growth of human B cells.

The effect of human GH and insulin-like growth factor-I (IGF-I) on immunoglobulin (Ig) production by and proliferation of human B cells was studied in serum- and hormone-free medium. GH enhanced the production of Ig by and thymidine uptake of the human lymphoblastoid B cell lines, CBL and GM-1056. IGF-I, but not IGF-II or insulin, also enhanced Ig production by and proliferation of CBL and GM-1056. However, the GH-induced enhancement was not mediated by IGF-I inasmuch as enhancement was blocked by anti-GH antibody but not by anti-IGF-I antibody or anti-IGF-I receptor antibody. Conversely, the IGF-I-induced enhancement was blocked by either anti-IGF-I antibody or anti-IGF-I receptor antibody but not by anti-GH antibody. GH and IGF-I also enhanced Ig production by and proliferation of the human lymphoblastoid B cell lines, CESS, GM-1500, SKW, and GM-3332. Furthermore, GH and IGF-I enhanced production of IgG1, IgG2, IgG3, IgG4, IgA1 IgA2, and IgM by and thymidine uptake of tonsillar B cells stimulated with Staphylococcus aureus Cowan strain I. Again, the GH-induced enhancement was blocked by anti-GH antibody whereas the IGF-I-induced enhancement was blocked by either anti-IGF-I antibody or anti-IGF-I receptor antibody but not vice versa.

Vasoactive intestinal peptide enhances immunoglobulin production and growth in human plasma cells via mechanisms that may involve protein kinase C.

The effects of various neuropeptides on human plasma cells were studied. Of the various neuropeptides tested, vasoactive intestinal peptide (VIP) enhanced Ig production and growth in human plasma cell lines, IM-9 and AF-10, and in plasma cells generated in vivo (four out of four patients with plasma cell leukemia) and in vitro. In contrast, other neuropeptides (neuropeptide Y, somatostatin, substance P, peptide YY, neurokinin A, calcitonin gene-related peptide, chole-cystokinin octapeptide, and beta-endorphin) were ineffective. Moreover, VIP-induced enhancement was specifically blocked by VIP receptor antagonist. Among the various cytokines, IL-6, GH, and insulin-like growth factor I (IGF-I) also enhanced Ig production and thymidine uptake in plasma cells. However, VIP-induced enhancement was not mediated by IL-6, GH, or IGF-I because antibodies to these cytokines failed to block VIP-induced enhancement. Phorbol 12,13 dibutyrate enhanced Ig production and thymidine uptake in plasma cells, and the Phorbol 12,13 dibutyrate-induced enhancement was blocked by H7 (a protein kinase C inhibitor) but not by H8 (a protein kinase A inhibitor). Similarly, VIP-induced enhancement was blocked by H7 but not by H8. Collectively, VIP enhances plasma cell responses via mechanisms that may involve protein kinase C.

Ultimate observation of tungsten atoms and clusters adsorbed on single crystalline MgO films.

Tungsten single atoms and clusters composed of four and five atoms deposited on MgO (001) thin films were observed by high-resolution transmission electron microscopy at R.T. The observation was realized by optimizing the thickness of the MgO films and by using special imaging techniques such as an off-Bragg HREM method. The multislice simulation for the interpretation of the image contrast showed a possibility of discrimination of the atomic configuration of clusters, such as "b.c.c.," "on-top," or "f.c.c." type clusters, from details of the image-contrast. The image intensity at the center of the clusters with the b.c.c. configuration was evidently smaller than that of the clusters with the f.c.c. configuration. The reason for the difference was clarified through the multislice image simulation, suggesting that the lattice mismatch between the clusters and the MgO lattice was a key factor in determining the intensity of the center of the clusters.

Ciliary neurotrophic factor preferentially enhances spontaneous IgE production by B cells from atopic patients.

The effect of ciliary neurotrophic factor (CNTF) on IgE production by purified B cells from atopic patients was studied. CNTF significantly enhanced spontaneous IgE production by B cells from patients with atopic eczema/dermatitis syndrome (AEDS) in a dose-dependent fashion, and maximum enhancement was achieved at 1 ng/ml. CNTF-induced enhancement of IgE production was blocked by anti-CNTF mAb or anti-gp 130 mAb, but not by anti-IL-6 mAb. On the other hand, CNTF did not significantly enhance spontaneous production of IgGl, IgG2, IgG3, IgG4, IgM, IgAl or IgA2 by B cells from AEDS patients. In contrast to B cells from AEDS patients, B cells from non-atopic subjects failed to produce IgE spontaneously, and CNTF did not induce IgE production by non-atopic subjects' B cells. B cells from atopic patients contained surface IgE positive B cells (sIgE+ B cells), which spontaneously produced IgE, while surface IgE negative B cells (sIgE- B cells) failed to do so. CNTF enhanced IgE production by sIgE+ B cells from patients with AEDS, allergic rhinitis or bronchial asthma, while CNTF failed to induce IgE from sIgE- B cells from these patients. Stimulation of sIgE- B cells with IL-4 plus anti-CD40 mAb induced IgE production. However, stimulation of sIgE- B cells with CNTF plus IL-4, or CNTF plus anti-CD40 mAb did not induce IgE production by sIgE- B cells. Collectively, these results indicate that CNTF preferentially enhanced spontaneous IgE production by post-switched sIgE+ B cells, while CNTF failed to induce IgE by pre-switched sIgE- B cells. These results suggest that CNTF may be involved in the allergic diseases.

Gene therapy for pancreatic cancer.

Despite improvements in surgical care and locoregional therapy, the prognosis of patients with pancreatic cancer has seen little improvement over the last several decades. It is difficult to diagnose pancreatic cancer at its earliest stages when it is amenable to cure by surgical resection because it is too small to produce symptoms in the affected patient. Recent improvements in radiographic modalities aimed at earlier detection and extent of cancer spread have enabled the clinician to provide the most efficacious treatment regimen possible. Nevertheless, pancreatic cancer is very aggressive locally and frequently metastasizes to the liver and peritoneum. New strategies are necessary to treat pancreatic cancer and gene therapy offers hope in this regard. Many studies have revealed the promise of gene therapy in the treatment of pancreatic cancer in rodent models. Early clinical trials are ongoing to evaluate the success of these gene therapy regimens in humans. In this article we review the gene therapy strategies currently employed in the fight against pancreatic cancer, including antisense strategies, gene-directed prodrug activation therapy, promoter gene strategies, and oncolytic viral therapy.

Beta-ray photography of lyophilized animal sections.

A new photographic method that images the density distribution of lyophilized animal sections approximately 50 microns in thickness is described. The new method involves sandwiching the animal section between a radiation sensor and a 147Pm planar radiation source. Either conventional photographic film or an imaging plate for radioluminography can be used as the sensor. The method described herein will find promising applications in whole body autoradiography as well as in the study of osteoporosis in experimental animals.

Determination of 14C in microplates by radioluminography.

A method alternative to liquid scintillation counting for detecting 14C was developed. The new method involves putting an aqueous radioactive sample onto the flat-bottomed wells of a polystyrene microplate, preparing a pellicle by lyophilization, and determining the radioactivity using radioluminography. It provides a simple, inexpensive, sensitive and reliable technique for determining the radioactivity of a few hundred samples simultaneously.

[Postoperative antibiotic prophylaxis for gastric cancer in surgery. Comparative study of 2 and 4 times daily administrations of cefotiam].

Comparative study of prophylaxis with cefotiam (CTM) was carried out in 47 patients undergoing surgery for gastric cancer. The patients were randomized in 2 treatment groups. The first group A received a single intravenous drip dose of 0.5 g CTM, given 4 times daily for 5 days after surgery. The second group B received a single intravenous drip dose of 1 g CTM, given twice daily for 5 days. Postoperative infections occurred in 8.7% (2/23) of the patients receiving CTM in group A, and in group B 8.3% (2/24). The number of infections was similar in both groups of patients. Prophylactic efficacy of CTM has also been evaluated in fever index of A and B groups. Fever index was 16.36 +/- 4.00 degree hours in A group, and in B group 7.91 +/- 2.30 degree hours, respectively. The difference between the 2 groups are statistically significant tendency. A single dose of 1 g CTM, given twice daily for 5 days, provide effective prophylaxis against infections in patients undergoing surgery for gastric cancer. CTM can be recommended for surgical prophylaxis.

[Experimental study on therapeutic plasmapheresis with the biliary decompression in the treatment of obstructive jaundice].

The effectiveness of therapeutic plasmapheresis with the biliary decompression was evaluated using animal model in the treatment of obstructive jaundice. Plasma exchange (PE) using fresh frozen plasma was carried out with biliary decompression on canine jaundice model made by means of ligation and resection of bile duct. Routine biochemical analysis was performed following the PE and biliary drainage and the result was compared with the external biliary drainage group. Plasma level of total bilirubin decreased after PE and kept lower level while plasma level of bilirubin in external biliary drainage group decreased slowly. M-GOT and GOT level, those are the indicators of liver cell injury, was lower in PE group. Mitochondrial function of liver cell was evaluated following partial hepatectomy carried out two days after PE with biliary decompression on jaundiced rat. Mitochondrial respiratory control ratio and ADP/O ratio was improved in PE group. The effectiveness of PE is speculated as the combined mechanism of the removal of hepatotoxic factors in the jaundiced plasma and the addition of hepatotrophic factors within the fresh frozen plasma. These results support the effectiveness of PE to shorten the biliary drainage period and to improve the hepatic function for perioperative management.