Herein we describe that in classic Hodgkin lymphomas (cHL, n ؍ 25) the lymph node (LN) stroma displayed in situ high levels of transcription and expression of the disulfide-isomerase ERp5 and of the disintegrin-metalloproteinase ADAM10, able to shed the ligands for NKG2D (NKG2D-L) from the cell membrane. These enzymes were detected both in LN mesenchymal stromal cells ( IntroductionIt is now accepted that the so-called stress surveillance contributes to the anti-neoplastic immunity, both in solid tumors and hematologic malignancies, through the activation of the NKG2D receptor that recognizes NKG2D ligands (NKG2D-L) on cancer cells, including the MHC class-I related chain-A and -B (MIC-A/B) and the UL16-binding proteins 1-4 (ULBPs). [1][2][3][4][5] These ligands are commonly expressed at very low levels or retained in the cytoplasm, in healthy tissues, but their transcription and surface expression are enhanced on viral infection or tumor transformation. [5][6][7][8][9] Besides natural killer cells and CD8 ϩ T lymphocytes, ␥␦ T cells can recognize these molecules and activate an antitumor response in different cancers. [10][11][12][13][14][15][16][17] In this regard, we have described that ␥␦ T lymphocytes belonging to the V␦1 subset are expanded in patients with chronic lymphocytic leukemia (CLL) and nonHodgkin lymphomas (NHLs), where they proliferate in response to tumor cells, provided they express NKG2D-L, exert cytotoxicity, and produce anti-neoplastic or pro-differentiating cytokines, such as TNF-␣ and IL-4. 15,16 However, NKG2D-L can be shed by tumor cells and, in their soluble form, interact with NKG2D expressed by effector lymphocytes and hinder the recognition of tumor cells. 18,19 Proteolytic cleavage of MIC-A has been shown to depend on the thiol isomerase ERp5 and the disintegrins and metalloproteinases ADAM10 and ADAM17, which are also able to cleave ULBPs. 19,22 Overexpression of these enzymes has been reported in multiple myeloma and other tumors. [19][20][21][22][23] In turn, soluble (s) NKG2D-L and cytokines produced at the tumor site can down-regulate the expression of the NKG2D receptor on effector lymphocytes, contributing to tumor escape from immunosurveillance. [22][23][24][25] Indeed, the TGF- has been shown to reduce the surface density of the NKG2D receptor on CD8 ϩ T and NK cells, impairing their antitumor reactivity in cancer patients. [24][25][26] Moreover, we and others reported that plasma levels of sNKG2D-L correlate with disease progression in multiple myeloma, CLL, NHL, and acute myeloid leukemias; in particular, among sNKG2D-L, both sMIC-A and sULBP2 have been shown as a prognostic marker for multiple myeloma and for the identification of early-stage CLL patients with risk of disease progression. [14][15][16]21,27,28 In this paper, we studied 25 classic HL (cHL) and found that the tumor microenvironment is prone to inhibit the development of an antitumor response. This is mainly because of the release of soluble MIC-A and ULBP3 by lymph node mesenchymal stromal cells (LN MS...
NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.
Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies and dysregulation of B cell function. The leukocyte associated Immunoglobulin (Ig)-like receptor (LAIR)1 is a transmembrane molecule belonging to Ig superfamily which binds to different types of collagen. Herein, we have determined the expression and function of LAIR1 on B lymphocyte from SLE patients. LAIR1 expression in peripheral blood B lymphocytes from 54 SLE, 24 mixed connective tissue disease (MCTD), 20 systemic sclerosis (SSc) patients, 14 rheumatoid arthritis (RA) and 40 sex and age matched healthy donors (HD) have been analyzed by immunofluorescence. The effect of LAIR1 ligation by specific monoclonal antibodies, collagen or collagen producing mesenchymal stromal cells from reactive lymph nodes or bone marrow on Ig production by pokeweed mitogen and B cell receptor (BCR)-mediated NF-kB activation was assessed by ELISA and TransAM assay. The percentage of CD20+ B lymphocytes lacking or showing reduced expression of LAIR1 was markedly increased in SLE and MCTD but not in SSc or RA patients compared to HD. The downregulation of LAIR1 expression was not dependent on corticosteroid therapy. Interestingly, LAIR1 engagement by collagen or collagen-producing mesenchymal stromal cells in SLE patients with low LAIR1 expression on B cells delivered a lower inhibiting signal on Ig production. In addition, NF-kB p65 subunit activation upon BCR and LAIR1 co-engagement was less inhibited in SLE patients than in HD. Our findings indicate defective LAIR1 expression and function in SLE B lymphocytes, possible contributing to an altered control of B lymphocytes behavior.
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