Immunology Unit, Department of Cell Biology, Immunology and Neurosciences, Medical School, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), C/Casanova 143, Barcelona, Spain.
The SLAM (CD150) family receptors are leukocyte cell-surface glycoproteins involved in leukocyte activation. These molecules and their adaptor protein SAP contribute to the effective germinal center formation, generation of high-affinity antibody-secreting plasma cells, and memory B cells, thereby facilitating long-term humoral immune response. Multi-color flow cytometric analysis was performed to determine the expression of CD48 (SLAMF2), CD84 (SLAMF5), CD150 (SLAM or SLAMF1), CD229 (Ly9 or SLAMF3), CD244 (2B4 or SLAMF4), CD319 (CRACC, CS1, or SLAMF7), and CD352 (NTB-A or SLAMF6) on human cell lines and B-cell subsets. The following subsets were assessed: pro-B, pre-B, immature-B, and mature-B cells from bone marrow; transitional and B1/B2 subsets from peripheral blood; and naïve, pre-germinal center, germinal center, memory, plasmablasts, and plasma cells from tonsil and spleen. All receptors were expressed on B cells, with the exception of CD244. SLAM family molecules were widely distributed during B-cell development, maturation and terminal differentiation into plasmablasts and plasma cells, but their expression among various B-cell subsets differed significantly. Such heterogeneous expression patterns suggest that SLAM molecules play an essential and non-redundant role in the control of humoral immune responses.
"Literature on the expression of CD319 on naïve B cells is not consistent, with studies showing no expression [9,11,33] and expression [30-32] on B cells prior to their activation and/or differentiation. PDL241 did not bind naïve B cells and did not deplete B cells in culture. "
[Show abstract][Hide abstract] ABSTRACT: Targeting the CD20 antigen has been a successful therapeutic intervention in the treatment rheumatoid arthritis (RA). However, in some patients with an inadequate response to anti-CD20 therapy, a persistence of CD20- plasmablasts are noted. The strong expression of CD319 on CD20- plasmablast and plasma cell populations in RA synovium led to the investigation of the potential of CD319 as a therapeutic target.
PDL241, a novel humanized IgG1 monoclonal antibody (mAb) to CD319, was generated and examined for its ability to inhibit immunoglobulin production from plasmablasts and plasma cells generated from peripheral blood mononuclear cells (PBMC) in the presence and absence of RA synovial fibroblasts (RA-SF). The in vivo activity of PDL241 was determined in a human PBMC transfer into NSG mouse model. Finally, the ability of PDL241 to ameliorate experimental arthritis was evaluated in a collagen-induced arthritis (CIA) model in rhesus monkeys.
PDL241 bound to plasmablasts and plasma cells but not naive B cells. Consistent with the binding profile, PDL241 inhibited the production of IgM from in vitro PBMC cultures by the depletion of CD319+ plasmablasts and plasma cells but not B cells. The activity of PDL241 was dependent on an intact Fc portion of the IgG1 and mediated predominantly by natural killer cells. Inhibition of IgM production was also observed in the human PBMC transfer to NSG mouse model. Treatment of rhesus monkeys in a CIA model with PDL241 led to a significant inhibition of anti-collagen IgG and IgM antibodies. A beneficial effect on joint related parameters, including bone remodeling, histopathology, and joint swelling was also observed.
The activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.
"À/À CTLs revealed similar levels of 2B4, SLAM, Ly108, CD84, Ly9, and CD48 (Figure S3A). In accord with published data (Cannons et al., 2010; De Salort et al., 2011), LPS-activated B cells showed high expression of multiple SLAM family receptors and ligands, including CD48 (the ligand for 2B4) and Ly108 (Figures 3D and S3B), two receptors implicated in cytolysis (Bottino et al., 2001; Parolini et al., 2000). In comparison, EL4 cells exhibited slightly reduced surface CD48 and SLAM, as well as very low Ly108 expression. "
[Show abstract][Hide abstract] ABSTRACT: X-linked lymphoproliferative syndrome, characterized by fatal responses to Epstein-Barr virus infection, is caused by mutations affecting the adaptor SAP, which links SLAM family receptors to downstream signaling. Although cytotoxic defects in SAP-deficient T cells are documented, the mechanism remains unclear. We show that SAP-deficient murine CD8(+) T cells exhibited normal cytotoxicity against fibrosarcoma targets, yet had impaired adhesion to and killing of B cell and low-avidity T cell targets. SAP-deficient cytotoxic lymphocytes showed specific defects in immunological synapse organization with these targets, resulting in inefficient actin clearance. In the absence of SAP, signaling through the SLAM family members Ly108 and 2B4 resulted in increased recruitment of the SHP-1 phosphatase, associated with altered SHP-1 localization and decreased activation of Src kinases at the synapse. Hence, SAP and SLAM receptors regulate positive and negative signals required for organizing the T cell:B cell synapse and setting thresholds for cytotoxicity against distinct cellular targets.
[Show abstract][Hide abstract] ABSTRACT: The SLAM family recently has been reported to show an important biological role in lymphocyte development and immunological function, and it is efficient to highly purify hematopoietic stem cells using a simple combination of SLAM family members. To elucidate the presence of this family on acute lymphoblastic leukemia (ALL), as well as its relationship with the leukemia-initiating potential, we analyzed the expression pattern of this family members on human ALL progenitor cells, combined with serial xenotransplantation assay.
Expression analysis was carried out by flow cytometry. We combined the expression pattern of human CD(150), CD(244) and CD(48) with serial xenotransplantation of B-ALL progenitor cells to indicate their relationship.
CD(48) and CD(244) were expressed on most B-ALL progenitor cells, the percentage being (93.08 ± 6.46)% and (63.37 ± 29.31)%, respectively. Interestingly, the proportion of CD(150)(+) cells declined obviously in engrafted cases ((24.94 ± 7.32)%) compared with non-engrafted cases ((77.54 ± 5.93)%, P < 0.01), which indicated that only blast cells with low percentage of CD(150)(+) population were able to reconstitute leukemia into primary, secondary and tertiary NOD/SCID mice.
SLAM family members are present on B-ALL progenitor cells and the leukemia-initiating potential of leukemic blasts is correlated negatively with the proportion of CD(150)(+) cells, the percentage of which can serve as a useful predictor for engraftment success of B-ALL to immune deficient mice.
Chinese medical journal 10/2011; 124(19):3074-9. · 1.05 Impact Factor
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