Hypophosphatemic rickets/osteomalacia with inappropriately low serum 1,25-dihidroxyvitamin D level is commonly observed in X-linked hypophosphatemic rickets/osteomalacia, autosomal dominant hypophosphatemic rickets/osteomalacia and tumor-induced osteomalacia. Although the involvement of a newly identified factor, FGF-23, in the pathogenesis of ADHR and TIO has been suggested, clinical evidence indicating the role of FGF-23 has been lacking. We have previously shown that FGF-23 is cleaved between Arg(179) and Ser(180), and this processing abolished biological activity of FGF-23 to induce hypophosphatemia. Therefore, sandwich ELISA for biologically active intact human FGF-23 was developed using two kinds of monoclonal antibodies that requires the simultaneous presence of both the N-terminal and C-terminal portion of FGF-23. The serum levels of FGF-23 in healthy adults were measurable and ranged from 8.2 to 54.3 ng/L. In contrast, those in a patient with TIO were over 200 ng/L. After the resection of the responsible tumor, the elevated FGF-23 level returned to normal level within 1 h. The increase of serum concentrations of 1,25-dihidroxyvitamin D and phosphate, and the decrease of serum 24,25-dihydroxyvitamin D followed the change of FGF-23. In addition, the elevated serum FGF-23 levels were demonstrated in most patients with XLH. It is likely that increased serum levels of FGF-23 contributes to the development of hypophosphatemia not only in TIO but also in XLH.

The aim of this study was to examine the effect of cytokines on different subsets of NK cells, while especially focusing on CD16− CD56dim cells and CD16− CD56bright cells. When human peripheral blood mononuclear cells (PBMC) were cultured with a combination of IL‐2, IL‐12 and IL‐15 for several days, a minor population of CD56bright NK cells expanded up to 15%, and also showed potent cytotoxicities against various cancer cells. Sorting experiments revealed that unconventional CD16− CD56+ NK cells (CD16− CD56dim NK cells and CD16− CD56bright NK cells, both of which are less than 1% in PBMC) much more vigorously proliferated after cytokine stimulation, whereas predominant CD16+ CD56dim NK cells proliferated poorly. In addition, many of the resting CD16− CD56bright NK cells developed into CD16+ CD56bright NK cells, and CD16− CD56dim NK cells developed into CD16− CD56bright NK cells and also further into CD16+ CD56bright NK cells by the cytokines. CSFE label experiments further substantiated the proliferation capacity of each subset and the developmental process of CD16+ CD56bright NK cells. Both CD16− CD56dim NK cells and CD16− CD56bright NK cells produced large amounts of IFN‐γ and Fas‐ligands. The CD16+ CD56bright NK cells showed strong cytotoxicities against not only MHC class I (−) but also MHC class I (+) tumours regardless of their expression of CD94/NKG2A presumably because they expressed NKG2D as well as natural cytotoxicity receptors. The proliferation of CD16+ CD56bright NK cells was also induced when PBMC were stimulated with penicillin‐treated Streptococcus pyogenes, thus suggesting their role in tumour immunity and bacterial infections.

We studied the therapeutic effect of OK-432 combined with adoptive immunotherapy in 19 cases of liver metastases from breast cancer. Of the 14 patients who received intraarterial OK-432 injection and transfer of cultured lymphocytes, 9 responded to this therapy, whereas no patients responded to intravenous administration. The minimum cell number for a therapeutic response was 8 x 10(8) cells. Metastatic lesions other than those in the liver regressed after therapy in 4 patients. The serum carcinoembryonic antigen level paralleled the therapeutic effect. There were no severe side-effects accompanying this therapy. These results indicate that intraarterial adoptive immunotherapy combined with OK-432 is effective as a new therapeutic approach against liver metastases from breast cancer.

No abstract

No abstract