Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages.

Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3(TYR705) phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients' monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET(+) and indoleamine 2,3-dioxygenase(+) cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4(+)CD25(high+)/FOXP3(+) T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.

A comparative evaluation between new ternary zirconium alloys as alternative metals for orthopedic and dental prosthetic devices.

PURPOSE: We assessed in vitro the corrosion behavior and biocompatibility of four Zr-based alloys (Zr97.5 Nb1.5VM1.0  ; VM, valve metal: Ti, Mo, W, Ta; at%) to be used as implant materials, comparing the results with grade-2 titanium, a biocompatible metal standard. METHODS: Corrosion resistance was investigated by open circuit potential and electrochemical impedance spectroscopy measurements as a function of exposure time to an artificial physiological environment (Ringer's solution). Human bone marrow stromal cells were used to evaluate biocompatibility of the alloys and their influence on growth kinetics and cell osteogenic differentiation through histochemical and gene expression analyses. RESULTS: Open circuit potential values indicated that Zr-based alloys and grade-2 Ti undergo spontaneous passivation in the simulated aggressive environment. High impedance values for all samples demonstrated improved corrosion resistance of the oxide film, with the best protection characteristics displayed by Zr97.5  Nb1.5Ta1.0. Cells seeded on all surfaces showed the same growth kinetics, although matrix mineralization and alkaline phosphatase activity were maximal on Zr97.5  Nb1.5Mo1.0 and Zr97.5   Nb1.5Ta1.0. Markers of ongoing proliferation, however, such as podocalyxin and CD49f, were still overexpressed on Zr97.5   Nb1.5   Mo1.0 even upon osteoinduction. No relevant effects were noted for the CD146-expressing population of bone progenitors. Nonetheless, the presence of a more differentiated cell population on Zr97.5Nb1.5Ta1.0 samples was inferable by comparing mineralization data and transcript levels of osteogenic markers (osteocalcin, osteopontin, bone sialoprotein, and RUNX2). CONCLUSIONS: The combination of passivation, corrosion resistance and satisfactory biotolerance to bone progenitors make the Zr-based alloys promising implant materials. Among those we tested, Zr97.5Nb1.5Ta1.0 seems to be the most appealing.