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New York City, NY, United States

Foxp3(+) regulatory T cells (Tregs) play a pivotal role in control of autoimmunity and pathological immune responses. Helios, the Ikarus family transcription factor, binds to the Foxp3 promoter, stabilizing its expression, and is expressed in 70% of peripheral Tregs of healthy individuals. This frequency is altered during malignancy, infection, and autoimmunity, although the mechanisms that control proliferation and relative numbers of Helios(+/-) Tregs remain largely unknown. Using a T-cell-monocyte in vitro stimulation assay, we now show that proliferation of Helios(+) Tregs is inhibited by CD16(+) monocyte subset. Antibody blocking with anti-interleukin (IL)-12 reversed this inhibition, whereas addition of IL-12 suppressed Helios(+) Treg expansion, indicating that CD16(+) monocyte control of Helios(+) Treg numbers is mediated through IL-12. In contrast, proliferation of Helios(-) Tregs, which express higher levels of tumor necrosis factor receptor II (TNFRII), was suppressed by TNF-α, whereas anti-TNF-α and anti-TNFRII reversed the inhibition. CD16(-) monocyte subset was mainly responsible for TNF-α-mediated control of Helios(-) Treg expansion. Altogether, these data suggest a differential role for monocyte subsets in control of Helios(+/-) Treg development that is mediated by distinct inflammatory cytokines. These data may have important implications for understanding the pathogenesis as well as control of chronic inflammatory and autoimmune diseases. Source

Immune thrombocytopenia (ITP) results from decreased platelet production and accelerated platelet destruction. Impaired CD4(+) regulatory T-cell (Treg) compartment and skewed Th1 and possibly Th17 responses have been described in ITP patients. The trigger for aberrant T-cell polarization remains unknown. Because monocytes have a critical role in development and polarization of T-cell subsets, we explored the contribution of monocyte subsets in control of Treg and Th development in patients with ITP. Unlike circulating classic CD14(hi)CD16(-) subpopulation, the CD16(+) monocyte subset was expanded in ITP patients with low platelet counts on thrombopoietic agents and positively correlated with T-cell CD4(+)IFN-γ(+) levels, but negatively with circulating CD4(+)CD25(hi)Foxp3(+) and IL-17(+) Th cells. Using a coculture model, we found that CD16(+) ITP monocytes promoted the expansion of IFN-γ(+)CD4(+) cells and concomitantly inhibited the proliferation of Tregs and IL-17(+) Th cells. Th-1-polarizing cytokine IL-12, secreted after direct contact of patient T-cell and CD16(+) monocytes, was responsible for the inhibitory effect on Treg and IL-17(+)CD4(+) cell proliferation. Our findings are consistent with ITP CD16(+) monocytes promoting Th1 development, which in turn negatively regulates IL-17 and Treg induction. This underscores the critical role of CD16(+) monocytes in the generation of potentially pathogenic Th responses in ITP. Source

Terminal erythroid differentiation starts from morphologically recognizable proerythroblasts that proliferate and differentiate to generate red cells. Although this process has been extensively studied in mice, its characterization in humans is limited. By examining the dynamic changes of expression of membrane proteins during in vitro human terminal erythroid differentiation, we identified band 3 and α4 integrin as optimal surface markers for isolating 5 morphologically distinct populations at successive developmental stages. Functional analysis revealed that these purified cell populations have distinct mitotic capacity. Use of band 3 and α4 integrin enabled us to isolate erythroblasts at specific developmental stages from primary human bone marrow. The ratio of erythroblasts at successive stages followed the predicted 1:2:4:8:16 pattern. In contrast, bone marrows from myelodysplastic syndrome patients exhibited altered terminal erythroid differentiation profiles. Thus, our findings not only provide new insights into the genesis of the red cell membrane during human terminal erythroid differentiation but also offer a means of isolating and quantifying each developmental stage during terminal erythropoiesis in vivo. Our findings should facilitate a comprehensive cellular and molecular characterization of each specific developmental stage of human erythroblasts and should provide a powerful means of identifying stage-specific defects in diseases associated with pathological erythropoiesis. Source

Shaz B.H.,New York Blood Center

In this issue of Blood, McKenzie et al provide further insight into the mechanism of antibody-mediated transfusion-related acute lung injury (TRALI), and Silliman et al demonstrate the potential use of a novel filter to mitigate red blood cell (RBC) transfusion-associated TRALI. The first manuscript with studies performed in a murine model suggests that HLA class I antibody-mediated TRALI, which requires antibody binding to peripheral blood monocytes producing interleukin-8 (IL-8) which binds chemokine (C-X-C motif) ligand (CXCL), is a chemotactic for neutrophils and induces neutrophil degranulation; the antibody-coated monocytes also result in lung damage. The second manuscript shows that prestorage RBC filtration to absorb antibodies and lipids as well as white blood cells and platelets, decreases TRALI-associated antibodies and neutrophil-priming activity of the unit, mitigating TRALI in an animal model. © 2014 by The American Society of Hematology. Source

New York Blood Center | Date: 2015-07-10

Disclosed herein are trimeric polypeptide pharmaceutical compositions comprising three monomers, each monomer comprising a polypeptide having the amino acid sequence of the N-terminal heptad repeat (NHR or HR1) or C-terminal heptad repeat (CHR or HR2) of the transmembrane glycoprotein of human immunodeficiency virus (HIV) and a trimerization motif.

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