Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after FcγRII-mediated uptake

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons. Although human pDCs can induce T cell responses upon viral infection, it remains unclear if pDCs can present exogenous antigens. Here, we show that human pDCs exploit FcγRII (CD32) to internalize antigen–antibody complexes, resulting in the presentation of exogenous antigen to T cells. pDCs isolated from melanoma patients vaccinated with autologous monocyte-derived peptide- and keyhold limpet hemocyanin (KLH)–loaded dendritic cells, but not from nonvaccinated patients or patients that lack a humoral response against KLH, were able to stimulate KLH-specific T cell proliferation. Interestingly, we observed that internalization of KLH by pDCs depended on the presence of serum from vaccinated patients that developed an anti-KLH antibody response. Anti-CD32 antibodies inhibited antigen uptake and presentation, demonstrating that circulating anti-KLH antibodies binding to CD32 mediate KLH internalization. We conclude that CD32 is an antigen uptake receptor on pDCs and that antigen presentation by pDCs is of particular relevance when circulating antibodies are present. Antigen presentation by pDCs may thus modulate the strength and quality of the secondary phase of an immune response

Murine Macrophage Cell Line AP284 Presents Antigen to Cloned MT4+, Lyt-2− T Cells in vitro and in vivo

A murine macrophage cell line AP284 that appeared to be mature in phenotype was isolated. After repeated cloning, the cell line expressed the markers Mac-1, Mac-2, Mac-3, 2.4G2, F4/80 as well as Ia antigens. Moreover, it was positive for the enzymes nonspecific esterase and acid phosphatase, negative for alkaline phosphatase and was able to phagocytize latex beads. We studied whether this cell line was able to present antigen to cloned MT4+, Lyt-2− T cells specific for methylated bovine serum albumin (mBSA) or ovalbumin (OVA). The in vitro proliferative response of the cloned T cells specific for mBSA or OVA was found to be effectively supported by AP284. This proliferation could be blocked by monoclonal antibodies against Ia determinants. AP284 also effectively presented antigen in vivo as was shown in a foot swelling assay measuring delayed type hypersensitivity (DTH) to mBSA caused by specific cloned T cells with the helper phenotype. This offers a unique model system for studying the process of antigen presentation in which both the antigen presenting cells and the T cells are monoclonal

Decreased renal excretion of soluble interleukin-2 receptor α after treatment with daclizumab

Decreased renal excretion of soluble interleukin-2 receptor α after treatment with daclizumab.BackgroundDaclizumab (±150 kD), a humanized monoclonal antibody (mAb) against the alpha-chain of the membrane-bound interleukin-2 (IL-2) receptor (IL-2R) also binds soluble interleukin-2R α (sIL-2Rα; ±45 kD), and thus may influence the glomerular filtration of sIL-2Rα.MethodsWe have studied the influence of daclizumab on the renal excretion of sIL-2Rα in 38 recipients of a renal transplant (32 treated with daclizumab and six controls). sIL-2Rα was measured every 2weeks after transplantation in serum and urine with Immulite® IL-2R, a solid-phase enzyme-linked immunosorbent assay (ELISA).ResultsIn the control population, the fractional excretion of sIL-2Rα was relatively constant with a median value of 1.7%± 0.5%. In daclizumab-treated patients, sIL-2Rα was not detectable in the urine immediately after the administration of daclizumab. sIL-2Rα became detectable in the urine at a mean of 8 ± 3weeks after transplantation. In additional experiments, serum compounds were separated by size-exclusion chromatography and sIL-2Rα was measured in the collected fractions. In the control patients, sIL-2Rα was only present in the low-molecular-weight fractions of serum. In contrast, in daclizumab-treated patients evaluated several weeks after transplantation, sIL-2Rα was merely detected in the high-molecular-weight fractions of serum. During follow-up there was a relative shift of sIL-2Rα from the high- to the low-molecular-weight fractions and this coincided with normalization of sIL-2Rα excretion.ConclusionDaclizumab inhibits the renal excretion of sIL-2Rα by the formation of a complex with sIL-2Rα in serum, which is too large for glomerular filtration. Measurement of urinary sIL-2Rα may provide information on the concentration of anti-IL-2Rα mAb in serum

Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.

Contains fulltext : 88281.pdf (publisher's version ) (Closed access)PURPOSE: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody-mediated depletion of CD25(high) regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines. EXPERIMENTAL DESIGN: Thirty HLA-A2.1(+) metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor alpha-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined. Results : Daclizumab efficiently depleted all CD25(high) immune cells, including CD4(+)FoxP3(+)CD25(high) cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25(+) cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25(+) T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group. CONCLUSIONS: Although daclizumab depleted the CD4(+)FoxP3(+)CD25(high) Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25(+) effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important

The Forward Physics Facility at the High-Luminosity LHC

International audienceHigh energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe Standard Model (SM) processes and search for physics beyond the Standard Model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

The Forward Physics Facility at the High-Luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe Standard Model (SM) processes and search for physics beyond the Standard Model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

The Forward Physics Facility at the High-Luminosity LHC

International audienceHigh energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe Standard Model (SM) processes and search for physics beyond the Standard Model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential

The Forward Physics Facility at the High-Luminosity LHC

High energy collisions at the High-Luminosity Large Hadron Collider (LHC) produce a large number of particles along the beam collision axis, outside of the acceptance of existing LHC experiments. The proposed Forward Physics Facility (FPF), to be located several hundred meters from the ATLAS interaction point and shielded by concrete and rock, will host a suite of experiments to probe standard model (SM) processes and search for physics beyond the standard model (BSM). In this report, we review the status of the civil engineering plans and the experiments to explore the diverse physics signals that can be uniquely probed in the forward region. FPF experiments will be sensitive to a broad range of BSM physics through searches for new particle scattering or decay signatures and deviations from SM expectations in high statistics analyses with TeV neutrinos in this low-background environment. High statistics neutrino detection will also provide valuable data for fundamental topics in perturbative and non-perturbative QCD and in weak interactions. Experiments at the FPF will enable synergies between forward particle production at the LHC and astroparticle physics to be exploited. We report here on these physics topics, on infrastructure, detector, and simulation studies, and on future directions to realize the FPF's physics potential