Clinical experiment of mutant herpes simplex virus HF10 therapy for cancer.

We reviewed our clinical trial using mutant herpes simplex virus "HF10". We have evaluated the safety and effect of HF10 against recurrent breast cancer since 2003 and also applied HF10 to non-resectable pancreatic cancer since 2005. An oncolytic herpes simplex virus type 1, mutant HF10, has been isolated and evaluated for anti-tumor efficacy in syngeneic immunocompetent mouse models. From long time before clinical trial, we have found that the mutant virus can have remarkable potential to effectively treat cancer in experimental studies using animals, and that all of the surviving mice acquire resistance to rechallenge of the tumor cells. A number of studies have shown that HF10 is effective and safe for use in localized or peritoneally disseminated malignant tumors of non-neuronal origin in animals. Pilot studies using HF10 have been initiated in patients with metastatic breast cancer. For each patient, 0.5 ml HF10 diluents at various doses were injected into test nodule, and 0.5 ml sterile saline was injected into a second nodule. All patients were monitored for local and systemic adverse effects, and the nodules were excised 14 days after viral injection for histopathological studies. All patients tolerated the clinical trial well. While no adverse effects occurred, there was cancer cell death and 30-100% regression histopathologically in recurrent breast cancer. As mentioned above, intratumoral injection of mutant herpes simplex virus HF10 for recurrent metastatic breast cancer was safe and effective. Also a trial for non-resectable pancreatic cancer being carried out on the basis of the above result has proved to be innocuous and has been in progress to assess the clinical benefit and enhance the potentiality of HF10 against cancer.

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.

Increased incidence of latex allergy in children with allergic diseases in Japan.

The incidence of latex allergy is increasing in Japanese adults. However, the changing incidence of latex allergy in children with or without allergic diseases has not been reported in detail. After obtaining written informed consent from parents, Japanese children under 14 years of age were studied. In total, 776 non-atopic children, 802 children with allergic rhinitis (AR), 706 children with bronchial asthma (BA) and 844 children with atopic eczema/dermatitis syndrome (AEDS) were asked about symptoms of latex allergy, and tested by serum latex-specific IgE, skin prick test to latex allergen and latex-glove-wearing test between 2001 and 2003. All the patients were outpatients at Ujitakeda Hospital, while the non-atopic children were children of the staff of Ujitakeda Hospital or Unitika Ltd. This was a retrospective study. The incidence of latex allergy in 2001/2002/2003 was 1.4/3.1/4.7% in non-atopic children, 3.1/5.1/9.1% in AR patients, 3.6/6.5/10.3% in BA patients and 6.1/11.3/15.9% in AEDS patients, respectively. Moreover, although no cases of anaphylactic shock were noted in allergic patients in 2001, two and eight cases were noted in 2002 and 2003, respectively. These results indicate that the incidence of latex allergy is increasing in paediatric patients with allergic diseases. A latex-reduced environment may be desirable in future.

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.

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.

Exfoliation of Helicobacter pylori from gastric mucin by glycopolypeptides from buttermilk.

In the human stomach, Helicobacter pylori, an ulcer pathogenic bacterium, colonizes the gastric mucosal layer primarily. The ability of glycopolypeptides (GPP) prepared from buttermilk to exfoliate H. pylori bound to gastric mucin was investigated. The GPP were prepared from buttermilk by digestion with trypsin, papain, pancreatin, bromelain, or pepsin. Helicobacter pylori ATCC 43504T and 43579 adhered more strongly to all of the GPP tested than to whole buttermilk, the soluble fraction of buttermilk, gastric mucin prepared from mouse stomach, or commercial pig gastric mucin. The GPP digested with trypsin, papain, or pancreatin were significantly more adherent. When the GPP concentration was 10 mg/mL, bound H. pylori ATCC 43504T, 43579, and 5 clinical isolates were exfoliated markedly from immobilized porcine gastric mucin following treatment with GPP digested with trypsin or pancreatin. This ability of GPP did not correlate with sialic acid content, indicating that sialic acid content is not important in the exfoliation of this microorganism. Such an ability may depend on the structure or number of sugar chains, or the position of sialic acid. We conclude that GPP promote the exfoliation of H. pylori bound to gastric mucin and prevent the de novo adherence of this microorganism. As such, GPP are a promising food material for preventing H. pylori infection.

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.