Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.

BACKGROUND: Patients with gene expression profiling-defined high-risk myeloma in relapse have poor outcomes with current therapies. We tested whether natural killer cells expanded by co-culture with K562 cells transfected with 41BBL and membrane-bound interleukin-15 could kill myeloma cells with a high-risk gene expression profile in vitro and in a unique model which recapitulates human myeloma. DESIGN AND METHODS: OPM2 and high-risk primary myeloma tumors were grown in human fetal bone implanted into non-obese diabetic severe combined immunodeficiency mice with a deficient interleukin-2 receptor gamma chain. These mice are devoid of endogenous natural killer and T-cell activity and were used to determine whether adoptively transferred expanded natural killer cells could inhibit myeloma growth and myeloma-associated bone destruction. RESULTS: Natural killer cells from healthy donors and myeloma patients expanded a median of 804- and 351-fold, respectively, without significant T-cell expansion. Expanded natural killer cells killed both allogeneic and autologous primary myeloma cells avidly via a perforin-mediated mechanism in which the activating receptor NKG2D, natural cytotoxicity receptors, and DNAX-accessory molecule-1 played a central role. Adoptive transfer of expanded natural killer cells inhibited the growth of established OPM2 and high-risk primary myeloma tumors grown in the murine model. The transferred, expanded natural killer cells proliferated in vivo in an interleukin-2 dose-dependent fashion, persisted up to 4 weeks, were readily detectable in the human bone, inhibited myeloma growth and protected bone from myeloma-induced osteolysis. CONCLUSIONS: These studies provide the rationale for testing expanded natural killer cells in humans.

Soy protein diet alters expression of hepatic genes regulating fatty acid and thyroid hormone metabolism in the male rat.

We hypothesized that consumption of soy protein isolate (SPI) or the soy isoflavone genistein (GEN) would modulate mRNA expression of genes underlying lipid and thyroid hormone metabolism in livers and small intestines of young adult male Sprague-Dawley rats. Early pregnant rat dams were placed on AIN-93G diets containing casein (CAS, control protein), SPI, or CAS+GEN. Litters were weaned to the same diet as their dam. SPI-fed (but not GEN-fed) male rats of 48 days of age had significant reductions in body weight, abdominal fat pad weight and hepatic content of lipid droplets and triglycerides. Hepatic peroxisome proliferator-activated receptor α (Ppara) transcripts were elevated with SPI but not GEN diet. Hepatic pyruvate dehydrogenase kinase-4 (Pdk4) and cytochrome P450 4A10 (Cyp4a10) mRNA abundance was reduced with SPI; the SPI effect on Cyp4a10 was recapitulated by GEN diet. SPI (but not GEN) suppressed Pdk4 and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) mRNA abundance in duodenum. Liver iodothyronine deiodinase types 1 and 2 (Dio1 and Dio2) mRNA levels were increased with SPI diet; the effect on Dio2, but not Dio1 mRNAs, also was observed with GEN. SPI and GEN increased hepatic types 1 and 2 iodothyronine deiodinase (D1 and D2) activities. Effects of SPI and GEN on the above gene expression may contribute to the observed reductions in body and adipose tissue weight and liver lipid content in this model. Identification of the regulation, by genistein and soy protein, of iodothyronine deiodinase synthesis has potential applications for treatment and prevention of fatty liver disease and obesity.