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Proliferation-inducing Ligand (proliferation-inducing + ligand)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

APRIL (TNFSF13) regulates collagen-induced arthritis, IL-17 production and Th2 response

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008
Yanping Xiao
Abstract A proliferation-inducing ligand (APRIL or TNFSF13) shares receptors with B-cell activation factor of the TNF family (BAFF) on B and T cells. Although much is known about the function of APRIL in B cells, its role in T cells remains unclear. Blocking both BAFF and APRIL suggested that BAFF and/or APRIL contributed to collagen-induced arthritis (CIA); however, the role of APRIL alone in CIA remained unresolved. We show here that, in vitro, our newly generated APRIL,/, mice exhibited increased T-cell proliferation, enhanced Th2 cytokine production under non-polarizing conditions, and augmented IL-13 and IL-17 production under Th2 polarizing conditions. Upon immunization with OVA and aluminum potassium sulfate, APRIL,/, mice responded with an increased antigen-specific IgG1 response. We also show that in APRIL,/, mice, the incidence of CIA was significantly reduced compared with WT mice in parallel with diminished levels of antigen-specific IgG2a autoantibody and IL-17 production. Our data indicate that APRIL plays an important role in the regulation of cytokine production and that APRIL-triggered signals contribute to arthritis. Blockade of APRIL thus may be a valuable adjunct in the treatment of rheumatoid arthritis. [source]

The immunological basis of B-cell therapy in systemic lupus erythematosus

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 1 2010
Mo Yin MOK
Abstract Loss of B-cell tolerance is a hallmark feature of the pathogenesis in systemic lupus erythematosus (SLE), an autoimmune disease that is characterized by hypergammaglobulinemia and autoantibody production. These autoantibodies lead to formation of immune-complex deposition in internal organs causing inflammation and damage. Autoreactive B-cells are believed to be central in the pathophysiology of SLE. Other than its role in the production of antibodies that mediate humoral immune response, B-cells also function as antigen-presenting cells and are capable of activating T-cells. Activated B-cells may also produce pro-inflammatory cytokines that aggravate local inflammation. Abnormal B-cell homeostasis has been described in SLE patients. This may occur as a result of intrinsic B-cell defect or from aberrant regulation by maturation and survival signals. B-cell-based therapy is the current mainstream of research and development of novel therapies in SLE patients with severe and refractory disease. Potential cellular and molecular targets for B-cell therapies include cell surface molecules such as CD20 (rituximab) and CD22 (epratuzumab); co-stimulatory molecules involved in B-cell,T-cell interaction such as CTLA4 and B7 molecules (abatacept); maturation and growth factors such as B-cell activating factor and a proliferation-inducing ligand (belimumab, briobacept, atacicept) and B-cell tolerogen (abetimus). This article provides an overview on normal B-cell physiology and abnormal B-cell biology in SLE that form the immunological basis of B-cell-targeted therapy in the treatment of these patients with refractory diseases. [source]

Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma

BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2007
Iris Breitkreutz
Summary Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased ,V,3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1,), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM. [source]

BAFF: a local and systemic target in autoimmune diseases

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2009
I. Moisini
Summary BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF-R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation-inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)-6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress. [source]