Hailing Hsu

Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation

The ligand for osteoprotegerin has been identified, and it is a TNF-related cytokine that replaces the requirement for stromal cells, vitamin D3, and glucocorticoids in the coculture model of in vitro osteoclastogenesis. OPG ligand (OPGL) binds to a unique hematopoeitic progenitor cell that is committed to the osteoclast lineage and stimulates the rapid induction of genes that typify osteoclast development. OPGL directly activates isolated mature osteoclasts in vitro, and short-term administration into normal adult mice results in osteoclast activation associated with systemic hypercalcemia. These data suggest that OPGL is an osteoclast differentiation and activation factor. The effects of OPGL are blocked in vitro and in vivo by OPG, suggesting that OPGL and OPG are key extracellular regulators of osteoclast development.

APRIL and TALL-1 and receptors BCMA and TACI: system for regulating humoralimmunity

We report that the tumor neurosis factor homolog APRIL (a proliferation-inducing ligand) stimulates in vitro proliferation of primary B and T cells and increases spleen weight due to accumulation of B cells in vivo. APRIL functions via binding to BCMA (B cell maturation antigen) and TACI (transmembrane activator and CAML-interactor) and competes with TALL-1 (also called BLyS or BAFF) for receptor binding. Soluble BCMA and TACI specifically prevent binding of APRIL and block APRIL-stimulated proliferation of primary B cells. BCMA-Fc also inhibits production of antibodies against keyhole limpet hemocyanin and Pneumovax in mice, indicating that APRIL and/or TALL-1 signaling via BCMA and/or TACI are required for generation of humoral immunity. Thus, APRIL–TALL-1 and BCMA-TACI form a two ligands–two receptors pathway involved in stimulation of B and T cell function.

Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway.

LIGHT was recently described as a member of the tumor necrosis factor (TNF) ‘superfamily’. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte–macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.

Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin‐21 (IL‐21) or IL‐21 receptor (IL‐21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL‐21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL‐21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB × NZW)F1 (NZB/NZW) mouse model of SLE.

Mo2012 Augmentation of Colonic Inflammation by TL1A is Most Severe in the Presence of a Genetic Susceptibility and Bacterial Trigger

TL1A (TNFSF15) is a costimulatory molecule in the TNF superfamily that binds to the receptor DR3 (TNFRSF25). TL1A has been genetically associated with susceptibility to Crohns disease and ulcerative colitis in humans. Mice overexpressing TL1A develop small intestinal pathology and fibrotic responses somewhat akin to Crohns disease. In this study, we used Helicobacter bilis infected mdr1a-/mice as a model of colitis to investigate the relevance of TL1A to disease. Blockade of TL1A with a monoclonal antibody delayed disease development, but did not reduce intestinal signs of disease. However, qPCR analysis of mRNA isolated from the colon of diseased control mice demonstrated minimal upregulation of TL1A in this model. In contrast to the blocking study, dosing of H. bilis infected mdr1a-/mice with TL1A-Fc, an agonist reagent, significantly accelerated disease development and mortality. Disease exacerbation was also observed in uninfected mdr1a-/mice, although disease was much milder. No disease was observed in uninfected wild type FVB mice. These data suggest that TL1A signaling can augment intestinal inflammation, but that on its own, it is not enough to induce inflammation. In the presence of a genetic susceptibility and triggering factor, TL1A can significantly accelerate intestinal pathology.