IntroductionIn recent years, mesenchymal stem cells (MSCs) have become a promising tool for novel therapeutic approaches aimed at inhibition of the immune responses. [1][2][3] In particular, MSCs may be used to prevent/suppress graft-versus-host disease (GVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) 4 or for the treatment of certain autoimmune diseases. 5,6 So far, results of phase 1 trials have revealed the feasibility of MSC isolation, in vitro expansion, and infusion with no reports of major adverse reactions. 7,8 The first in vitro evidences of an effective MSC-mediated immunoregulatory activity rapidly evolved into clinical use of these cells in novel protocols of adoptive immunotherapy. Therefore, it is particularly important to clarify the mechanism(s) underlying the inhibitory effect exerted by MSCs on immunocompetent cell populations.Natural killer (NK) cells are major effector cells of the innate immunity and are generally thought to play a fundamental role in antiviral and antitumor responses. 9,10 As first described by Ruggeri and colleagues 11,12 and subsequently confirmed by other groups, 13 donor-derived NK cells would be responsible for eradication of leukemic cells in acute myeloid leukemia (AML) patients who received haploidentical HSCT. Remarkably, such a graft-versusleukemia (GVL) effect was evident only in donor-recipient couples in which a killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch was present. Therefore, after selection of the most suitable donor, NK cells could be used in novel HSCT-associated immunotherapeutic strategies either as cells originating directly from transplanted CD34 ϩ hematopoietic precursors or as mature NK cells that had been highly purified from peripheral blood and infused intravenously.MSCs and NK cells have been shown to interact in vitro. [14][15][16][17] The outcome of this interaction may depend on the state of NK-cell activation and/or on the cytokines present in the milieu. Thus, it may result in altered cell function and/or survival of either one or the other cell type. We previously described that the cytokineinduced proliferation of freshly isolated, resting NK cells is highly susceptible to MSC-mediated inhibition. 14 We asked whether such inhibitory effects could be exerted also on NK-cell effector functions, such as cytotoxic activity and cytokine production. These NK-cell functions are regulated by a series of surface receptors that can transduce either inhibitory or activating signals. [18][19][20] Exposure of resting NK cells to activating cytokines, such as interleukin-2 (IL-2), induces either de novo expression or increase of surface density of the activating receptors NKp44, CD69, NKp30, and NKG2D. As the levels of surface expression of activating NK receptors are positively correlated with NK-cell function, 21,22 we analyzed whether MSCs could exert an inhibitory effect on the IL-2-induced upregulation of the major activating receptors. Thus, in parallel with the phenotypic analysis, we perf...

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The prognosis for patients with B-cell chronic lymphocytic leukemia (B-CLL) is generally less favorable for those expressing CD38. Our working hypothesis is that CD38 is not merely a marker in B-CLL, but that it plays a receptor role with pathogenetic potential ruling the proliferation of the malignant clone. CD38 levels were generally low in the patients examined and monoclonal antibody (mAb) ligation was inefficient in signaling. Other cellular models indicated that molecular density and surface organization are critical for CD38 functionality. Interleukin 2 (IL-2) induced a marked up-modulation and surface rearrangement of CD38 in all the patients studied. On reaching a specific expression threshold, CD38 becomes an efficient receptor in purified B-CLL cells. Indeed, mAb ligation is followed by

Human transferrin receptor-2 (TFR-2) is a protein highly homologous to TFR-1/ CD71 and is endowed with the ability to bind transferrin (TF) with low affinity. High levels of TFR-2 mRNA were found in the liver and in erythroid precursors. Mutations affecting the TFR-2 gene led to hemochromatosis type 3, a form of inherited iron overload. Several issues on distribution and function of the receptor were answered by raising a panel of 9 monoclonal antibodies specific for TFR-2 by immunizing mice with murine fibroblasts transfected with the human TFR-2 cDNA. A polyclonal antiserum was also produced in mice immunized with 3 peptides derived from the TFR-2 sequence, exploiting an innovative technique. The specificity of all the reagents produced was confirmed by reactivity with TFR-2 ؉ target cells and simultaneous negativity with TFR-1 ؉ cells. Western blot analyses showed a dominant chain of approximately 90 kDa in TFR-2 transfectants and HepG2 cell line. Analysis of distribution in normal tissues and in representative cell lines revealed that TFR-2 displays a restricted expression pattern-it is present at high levels in hepatocytes and in the epithelial cells of the small intestine, including the duodenal crypts. Exposure of human TFR-2 ؉ cells to TF-bound iron is followed by a significant up-regulation and relocalization of membrane TFR-2. The tissue distribution pattern, the behavior following exposure to iron-loaded TF, and the features of the disease resulting from TFR-2 inactivation support the hypothesis that TFR-2 contributes to body iron sensing. (Blood. 2002;100:3782-3789)

CD157 is a pleiotropic ectoenzyme which belongs to the CD38 family and to the growing number of leukocyte surface molecules known to act independently as both receptors and enzymes. A 45-kDa surface structure with a GPI anchor, the CD157 molecule displays two distinct domains in its extracellular component. The first is implicated in the enzymic activities of the molecule and the second features adhesion/signalling properties. CD157 shares several characteristics with CD38, including a similar amino acid sequence and enzymic functions. Both molecules are involved in the metabolism of NAD(+), and the CD157 gene is synthenic on 4p15 with CD38, with which it also shares a unique genomic organization. Their conservation in phylogeny is striking evidence for their relevance in the life and death cycle of the cell.

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