Selective blockade of the inhibitory Fcgamma receptor (FcgammaRIIB) in human dendritic cells and monocytes induces a type I interferon response program.

The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies, we have shown that selective antibody-mediated blockade of inhibitory FcgammaRIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. We show that Fcgamma receptor (FcgammaR)-mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation-associated chemokines, as well as type 1 interferon (IFN) response genes, including the activation of signal transducer and activator of transcription 1 (STAT1). FcgammaR-mediated STAT1 activation is rapid and requires activating FcgammaRs. However, this IFN response is observed without a detectable increase in the expression of type I IFNs themselves or the need to add exogenous IFNs. Induction of IFN response genes plays an important role in FcgammaR-mediated effects on DCs, as suppression of STAT1 by RNA interference inhibited FcgammaR-mediated DC maturation. These data suggest that the balance of activating/inhibitory FcgammaRs may regulate IFN signaling in myeloid cells. Manipulation of FcgammaR balance on DCs and monocytes may provide a novel approach to regulating IFN-mediated pathways in autoimmunity and human cancer.

A 38-Year-Old Man With An Ataxic Gait, Night Sweats, and Weight Loss.

CASE PRESENTATION: A 38-year-old Jamaican man with no medical history presented with worsening right-sided weakness. He developed an ascending hemiparesis that began in the right lower extremity 3 months ago and progressed to the right upper extremity this past month. Over the past 3 months, the patient has had unintentional weight loss and an ataxic gait, and for the past month he has had night sweats. He denied headache, vision changes, numbness, tingling, cough, or chest pain. Social history was significant for 20 smoking pack-years and daily use of marijuana.

A 76-Year-Old Woman With Incidental Right Middle Lobe Atelectasis.

CASE PRESENTATION: A 76-year-old nonsmoking woman visiting from Honduras for the last 6 months with no known medical history originally presented to the ED complaining of abdominal pain. While in the ED, an incidental right middle lobe collapse was found on CT abdomen scan. Review of systems was positive for a chronic productive cough with white sputum for 3 years. She denied association with fevers, chills, night sweats, hemoptysis, appetite changes, or weight loss.

A 48-Year-Old Man With Excessive Drooling and Descending Paralysis Requiring Mechanical Ventilation.

CASE PRESENTATION: A 48-year-old man presented with a chief report of worsening dysphagia for 5 days. Initially, he had difficulty swallowing solids, but it has progressed to difficulty with liquids. There was associated sialorrhea, hypophonia, slurring of speech, hoarseness of voice, cough, and prominent upper extremity weakness. Of note, 2 weeks ago, the patient had an upper respiratory tract infection (including otitis media) that was treated with amoxicillin-clavulanate. His wife and son were also recently sick with an upper respiratory tract infection. His medical history included hypertension managed with amlodipine; he denied any history of TB, recent travel, or canned food ingestion. He denied fevers, stridor, dyspnea, rash, odynophagia, nausea, vomiting, or diarrhea.

Enhanced T-cell responses to glioma cells coated with the anti-EGF receptor antibody and targeted to activating FcgammaRs on human dendritic cells.

The induction of effective immune responses to tumor vaccines requires the preferential activation of effector T cells relative to regulatory or suppressive T cells. Glial tumors commonly overexpress the epidermal growth factor receptor (EGFR), which can be targeted by monoclonal antibodies. Here we show that the coating of glial tumor cells with a clinical grade anti-EGFR antibody, cetuximab, leads to enhanced tumor-specific, interferon-gamma producing CD8+ T cells by dendritic cells (DCs). The selective targeting of monoclonal antibody coated glioma cells to activating Fcgamma receptors (FcgammaRs) on DCs, which is achieved with a blocking antibody to the inhibitory form of FcgammaR, leads to the induction of antitumor immunity without the need for an exogenous maturation stimulus. Importantly, this approach reduces the concurrent induction of regulatory T cells, which can also be depleted to further enhance immunity. These data suggest that immunity to EGFR expressing tumors, including glioma, can be enhanced through the concerted function of antitumor monoclonal antibodies, activating FcgammaR, and DCs.

Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients.

CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg's) play an important role in the maintenance of immune tolerance. The mechanisms controlling the induction and maintenance of Treg's in humans need to be defined. We find that human myeloid dendritic cells (DCs) are superior to other antigen presenting cells for the maintenance of FOXP3(+) Treg's in culture. Coculture of DCs with autologous T cells leads to an increase in both the number of Treg's, as well as the expression of FOXP3 protein per cell both in healthy donors and myeloma patients. DC-mediated expansion of FOXP3(high) Treg's is enhanced by endogenous but not exogenous interleukin-2 (IL-2), and DC-T-cell contact, including the CD80/CD86 membrane costimulatory molecules. DCs also stimulate the formation of Treg's from CD25(-) T cells. The efficacy of induction of Treg's by DCs depends on the nature of the DC maturation stimulus, with inflammatory cytokine-treated DCs (Cyt-DCs) being the most effective Treg inducers. DC-induced Treg's from both healthy donors and patients with myeloma are functional and effectively suppress T-cell responses. A single injection of cytokine-matured DCs led to rapid enhancement of FOXP3(+) Treg's in vivo in 3 of 3 myeloma patients. These data reveal a role for DCs in increasing the number of functional FOXP3(high) Treg's in humans.