Antitumor Abs are promising therapeutics for cancer. Currently, most Ab-based therapies focus on IgG Ab, which interact with IgG FcR (FcγR) on effector cells. In this study, we examined human and mouse neutrophil-mediated tumor cell lysis via targeting the IgA FcR, FcαRI (CD89), in more detail. FcαRI was the most effective FcR in triggering tumor cell killing, and initiated enhanced migration of neutrophils into tumor colonies. Importantly, immature neutrophils that are mobilized from the bone marrow upon G-CSF treatment efficiently triggered tumor cell lysis via FcαRI, but proved incapable of initiating tumor cell killing via FcγR. This may provide a rationale for the disappointing results observed in some earlier clinical trials in which patients were treated with G-CSF and antitumor Ab-targeting FcγR.
Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcαRI (CD89), than by FcγRI (CD64). This difference is most evident in immature neutrophils in which FcγRI-mediated tumor cell lysis is absent. In this study, we show that FcR γ-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 FcαRI, but not via FcγRI, in immature neutrophils. Internalization, an FcR γ-chain-independent function, was, however, effectively initiated via both receptors. These data suggest an impaired functional association between FcγRI and the FcR γ-chain, which prompted us to perform coimmunoprecipitation experiments. As a weaker association was observed between FcγRI and FcR γ-chain, compared with FcαRI and FcR γ-chain, our data support that differences between FcαRI- and FcγRI-mediated functions are attributable to dissimilarities in association with the FcR γ-chain.
Regulation of angiogenesis occurs in the context of particular microenvironments and is governed by a sensitive balance between angiogenic and anti-angiogenic mediators. Under normal physiologic conditions, the expansion of existing blood vessels is held in check suggesting that homeostasis is maintained by a predominance of angiostatic factors. In the rheumatoid arthritis joint, it is probable that the expansive and tumor-like synovial pannus that invades cartilage requires additional nutrients and oxygen. In the face of these demands, there is likely a shift in the balance such that angiogenic mediators predominate leading to neovascularization, a hallmark of rheumatoid arthritis. Chemokines are a subset of cytokines that primarily mediate physiologic and pathophysiologic leukocyte trafficking during inflammation and immune cell differentiation. Chemokines are also fundamental participants, along with a variety of other factors, which regulate angiogenesis. Within the CXC family of chemokines, there is functional discrepancy, where some family members are angiogenic and others are angiostatic. Moreover, the expression of several chemokines has been well documented in rheumatoid arthritis synovial tissues and fluids. This review will discuss what is known about the role of specific chemokines in the regulation of angiogenesis with particular emphasis on those chemokines likely to participate in rheumatoid arthritis.
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