Scott E. Strome

The antiinflammatory effects of i.v. Ig (IVIG) in the treatment of autoimmune disease are due, in part, to the Fc fragments of Ig aggregates. In order to capitalize on the known antiinflammatory and tolerogenic properties of Ig Fc aggregates, we created a recombinant human IgG1 Fc multimer, GL-2045. In vitro, GL-2045 demonstrated high-avidity binding to Fc receptors, blocked the binding of circulating immune complexes from patients with rheumatoid arthritis to human Fcγ receptors (FcγRs), and inhibited antibody-mediated phagocytosis at log order–lower concentrations than IVIG. In vivo, administration of GL-2045 conferred partial protection against antibody-mediated platelet loss in a murine immune thrombocytopenic purpura (ITP) model. GL-2045 also suppressed disease activity in a therapeutic model of murine collagen-induced arthritis (CIA), which was associated with reduced circulating levels of IL-6. Furthermore, GL-2045 administration to nonhuman primates (NHPs) transiently increased systemic levels of the antiinflammatory cytokines IL-10 and IL-1RA, reduced the proinflammatory cytokine IL-8, and decreased surface expression of CD14 and HLA-DR on monocytes. These findings demonstrate the immunomodulatory properties of GL-2045 and suggest that it has potential as a treatment for autoimmune and inflammatory diseases, as a recombinant alternative to IVIG.

Monoclonal antibodies (mAbs) that target immune co‐signaling pathways have the potential to enable immune mediated tumor eradication. While early adoption of these agents for the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) has produced some astounding clinical successes, the majority of patients fail to respond to therapy. The purpose of this review is to first provide a broad overview of the immuno‐oncology (I‐O) landscape and to then focus on the current status of mAb‐based I‐O (mAb:I‐O) for the treatment of SCCHN, with particular attention to the development of strategies for improving treatment responses.

Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27+IgD− memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40–CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27+IgD− memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death.

Erythropoiesis, the production of red blood cells, must be tightly controlled to ensure adequate oxygen delivery to tissues without causing thrombosis or stroke. Control of physiologic and pathologic erythropoiesis is dependent predominantly on erythropoietin (EPO), the expression of which is regulated by hypoxia-inducible factor (HIF) activity in response to low oxygen tension. Accumulating evidence indicates that oxygen-independent mediators, including inflammatory stimuli, cytokines, and growth factors, also upregulate HIF activity, but it is unclear whether these signals also result in EPO production and erythropoiesis in vivo. Here, we found that signaling through herpesvirus entry mediator (HVEM), a molecule of the TNF receptor superfamily, promoted HIF-1α activity in the kidney and subsequently facilitated renal Epo production and erythropoiesis in vivo under normoxic conditions. This Epo upregulation was mediated by increased production of NO by renal macrophages. Hvem-deficient mice displayed impaired Epo expression and aggravated anemia in response to erythropoietic stress. These data reveal that HVEM signaling functions to promote HIF-1α activity and Epo production, and thus to regulate erythropoiesis. Furthermore, our findings suggest that this molecular mechanism could represent a therapeutic target for Epo-responsive diseases, including anemia.

Objectives: Total maxillectomy creates a significant defect in the supporting framework of the orbit. Successful reconstruction of the deficit requires repair of the orbital floor to prevent early and late complications. This paper describes the recreation of the orbital floor using a coronoid‐temporalis sling.Study Design: Retrospective review of two patients who underwent total maxillectomy and subsequent coronoid‐temporalis sling reconstruction of the surgical defect.Methods: The charts of two patients who underwent coronoid‐temporalis reconstruction of the orbital floor were retrospectively reviewed. The outcomes were evaluated. The authors present a method for reconstruction of the orbital floor and discuss the advantages and disadvantages of this method.Results: Two patients underwent successful reconstruction of the orbital floor with a coronoid‐temporalis sling procedure. Both patients display acceptable functional and cosmetic results.Conclusion: Coronoid‐temporalis sling is a readily available and easily modified tissue for reconstruction of the orbital floor. It offers similar results to those previously described techniques in this area without need for further extensive surgery.

Squamous cell carcinoma of the head and neck (SCCHN) is an important source of cancerrelated morbidity and mortality worldwide. Current treatment options are founded on various combinations of surgery, radiation therapy, and chemotherapy, with implementation largely based on patient/disease-specific factors and provider/institutional bias. Despite improvements in surgical techniques and the development of novel chemoradiotherapy strategies for organ preservation, survival has remained relatively unchanged in the past 30 years. Additionally, the impact of these novel treatment approaches on the quality of life of patients remains largely unknown. Improvements in survival and the quality of life for patients with SCCHN will likely require the development of new therapeutic alternatives based on the improved understanding of the molecular pathogenesis of SCCHN and associated changes in the immune response.