Enhanced FcαRI-mediated neutrophil migration towards tumour colonies in the presence of endothelial cells.

Neutrophils potently kill tumour cells in the presence of anti-tumour antibodies in vitro. However, for in vivo targeting, the neutrophils need to extravasate from the circulation by passing through endothelial barriers. To study neutrophil migration in the presence of endothelial cells in vitro, we established a three-dimensional collagen culture in which SK-BR-3 tumour colonies were grown in the presence or absence of an endothelial barrier.

CD47-signal regulatory protein-α (SIRPα) interactions form a barrier for antibody-mediated tumor cell destruction.

Monoclonal antibodies are among the most promising therapeutic agents for treating cancer. Therapeutic cancer antibodies bind to tumor cells, turning them into targets for immune-mediated destruction. We show here that this antibody-mediated killing of tumor cells is limited by a mechanism involving the interaction between tumor cell-expressed CD47 and the inhibitory receptor signal regulatory protein-α (SIRPα) on myeloid cells.

Experimentally induced liver metastases from colorectal cancer can be prevented by mononuclear phagocyte-mediated monoclonal antibody therapy.

Background & Aims: Development of liver metastases is a frequent complication in patients with colorectal cancer (CRC), even after successful resection of the primary tumor. As such, post-operative adjuvant therapies that aim to eliminate residual disease after surgery may improve patient outcome.

Methods: We used a colon carcinoma liver metastases model, in which CC531s colon carcinoma cells are injected into the portal circulation by a surgical procedure.

Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes.

Background: Anti-glomerular basement membrane (anti-GBM) disease often results in end-stage renal failure despite therapy with plasma exchange and immunosuppressive drugs. The newly discovered streptococcal enzymes IgG-degrading enzyme of S.pyogenes (IdeS) and endoglycosidase S (EndoS) act with remarkable specificity on circulating IgG.

Both complement and IgG fc receptors are required for development of attenuated antiglomerular basement membrane nephritis in mice.

To elucidate the mechanisms of glomerulonephritis, including Goodpasture's syndrome, mouse models are used that use heterologous Abs against the glomerular basement membrane (GBM) with or without preimmunization with foreign IgG from the same species. These studies have revealed the requirement of either FcgammaR or complement, depending on the experimental model used. In this study, we provide evidence that both FcgammaR and complement are obligatory for a full-blown inflammation in a novel attenuated passive model of anti-GBM disease.

Experimental antibody therapy of liver metastases reveals functional redundancy between Fc gammaRI and Fc gammaRIV.

Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery--although mandatory--paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases.

FcR gamma-chain dependent signaling in immature neutrophils is mediated by FcalphaRI, but not by FcgammaRI.

Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcalphaRI (CD89), than by FcgammaRI (CD64). This difference is most evident in immature neutrophils in which FcgammaRI-mediated tumor cell lysis is absent. In this study, we show that FcR gamma-chain-dependent functions (such as Ab-dependent cellular cytotoxicity and respiratory burst), as well as signaling (calcium mobilization and MAPK phosphorylation), were potently triggered via FcalphaRI, but not via FcgammaRI, in immature neutrophils.

Inefficient antigen presentation via the IgA Fc receptor (FcalphaRI) on dendritic cells.

Dendritic cells (DC) are professional antigen presenting cells that can induce and regulate adaptive immune responses. For that reason, DC are attractive candidates for vaccination strategies. Recently, expression of the IgA Fc receptor (FcalphaRI, CD89) was observed on DC, which activation led to DC maturation.

Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors.

Antitumor Abs are promising therapeutics for cancer. Currently, most Ab-based therapies focus on IgG Ab, which interact with IgG FcR (FcgammaR) on effector cells. In this study, we examined human and mouse neutrophil-mediated tumor cell lysis via targeting the IgA FcR, FcalphaRI (CD89), in more detail.

The Fc receptor for IgA (FcalphaRI, CD89).

Traditionally IgA has been regarded as a non-inflammatory antibody, which inhibits adhesion of micro-organisms to the mucosal wall without initiation of inflammatory responses. Recently, however, a dichotomy has been suggested between the actions of secretory IgA (SIgA), which is present at mucosal sites, and serum IgA. SIgA exerts its function as first line of defence by limiting invasion of pathogens.