Potential Role of Decoy B7-H4 in the Pathogenesis of Rheumatoid Arthritis: A Mouse Model Informed by Clinical Data

Finding an association between soluble B7-H4 and rheumatoid arthritis severity, Lieping Chen and colleagues use a mouse model to show that the soluble form blocks the inhibitory function of cell-surface B7-H4

Histograms indicating the frequency of mono-, bi- and tri-functional cell subsets in CD45RO⁺ and CD45RA⁺ T-cell populations of convalescent patients.

<p>Mean values are illustrated throughout. The black axis indicates percentages for mono-functional IFN-γ-positive and all bi- and tri-functional T-cell subsets. The red axis indicates percentages for MIP-1β- and CD107a-positive mono-functional T cell subsets.</p

Histograms indicating the frequency of mono-, bi- and tri-functional cell subsets in CD45RO⁺ and CD45RA⁺ T-cell populations of vaccinees.

<p>Mean values are illustrated throughout. The black axis indicates percentages for mono-functional IFN-γ-positive and all bi- and tri-functional T-cell subsets. The red axis indicates percentages for MIP-1β- and CD107a-positive mono-functional T cell subsets.</p

Stimulation indices for the proliferative responses of human PBMC to recall stimulation with ffLVS for five days.

<p>Median values ± SEM per donor group of 12–16 individuals are shown. “pat” indicates convalescent tularemia patients, “vc” LVS vaccinees, and “nv” naïve individuals.</p

Histograms indicating the frequency of mono-, bi- and tri-functional cell subsets in CD45RO⁺ and CD45RA⁺ T-cell populations of non-vaccinated individuals.

<p>Mean values are illustrated throughout. The black axis indicates percentages for mono-functional IFN-γ-positive and all bi- and tri-functional T-cell subsets. The red axis indicates percentages for MIP-1β- and CD107a-positive mono-functional T cell subsets.</p

Levels of cytokines secreted by human PBMC after recall stimulation with ffLVS or ffSchu S4 for five days.

<p>Cytokine concentrations were measured in cell culture supernatants using multiplex analysis. Median values ± SEM from PBMC samples of 14–16 individuals per donor group are shown (black bars indicate convalescent patients; grey bars indicate LVS vaccinees; white bars indicate naïve donors). Statistically significant differences between immune and naïve donors are marked by asterisks (<i>P</i><0.05).</p

Levels of cytokines secreted by human PBMC after recall stimulation with ffLVS or ffSchu S4 for five days.

<p>Cytokine concentrations were measured in cell culture supernatants using multiplex analysis. Median values ± SEM from PBMC samples of 14–16 individuals per donor group are shown (black bars indicate convalescent patients; grey bars indicate LVS vaccinees; white bars indicate naïve donors). Statistically significant differences between immune and naïve donors are marked by asterisks (<i>P</i><0.05). For IL-7, 36 out of 40 values were below the detection limit and therefore not included in the data analysis.</p

Heat map of Spearman correlation coefficients for iMFI values in various cell populations after intra-individual comparison for all donors.

<p>Integrated MFI values were obtained for all three functional markers (IFN-γ, MIP-1β, CD107a) in all mono-, bi- and trifunctional T-cell subsets and for all donors using <i>Clust</i> semi-automated gating. The iMFI values (24 values per PBMC sample, identified by numbers 1–24) from recall stimulation with 0.1 cfu ffLVS/PBMC were compared and lined up in a two-dimensional matrix. Correlated data are marked by shades of grey depending on the strength of the correlation coefficients; a coefficient above 0.7 is considered to indicate very strong correlation.</p

Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens

PurposeThe IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental design and resultsFirst, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.ConclusionsThese results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases

B7-H4–deficient mice display augmented neutrophil-mediated innate immunity

B7-H4 is an immunoglobulin superfamily molecule and shown to be inhibitory for T-cell responses. To explore physiologic roles of B7-H4, we created B7-H4–deficient (KO) mice by genetic targeting. B7-H4KO mice are healthy and their T- and B-cell responses to polyclonal antigens are in normal range. However, B7-H4KO mice are more resistant to infection by Listeria monocytogenes than their littermates. Within 3 days after infection, bacterial colonies in livers and spleens are significantly lower than the controls, suggesting a role of B7-H4 in enhancing innate immunity. Further studies demonstrate that neutrophils increase in peripheral organs of B7-H4KO mice more so than their littermates but their bactericidal functions remain unchanged. Augmented innate resistance is completely dependent on neutrophils, even in the absence of adaptive immunity. In vitro B7-H4 inhibits the growth of bone marrow–derived neutrophil progenitors, suggesting an inhibitory function of B7-H4 in neutrophil expansion. Our results identify B7-H4 as a negative regulator of the neutrophil response to infection and provide a new target for manipulation of innate immunity