Hierarchy of CD4 T cell epitopes of the ANRS Lipo5 synthetic vaccine relies on the frequencies of pre-existing peptide-specific T cells in healthy donors.

The Agence National de Recherche sur le SIDA et les hepatitis Lipo5 vaccine is composed by five long fragments of HIV proteins and was recently shown to induce in seronegative volunteers a CD4 T cell response largely dominated by the G2 fragment. To understand this response profile, we submitted the five HIV fragments to HLA-DR-binding assays and evaluated the frequency of naive Lipo5-specific CD4 T lymphocytes in the blood of 22 healthy individuals. We enumerated the Lipo5-specific T cell lines induced in vitro by weekly rounds of specific stimulation.

First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.

Background: IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8+ T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4.

Methods: MBC patients were administered one dose of IMP321 s.

A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma.

Purpose: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II-driven dendritic cell activation.

Experimental Design: Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c.

A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells.

The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II + cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes.

IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: a single-blind phase I study.

sLAG-3 (IMP321), a natural high affinity ligand for MHC class II, was tested for safety, tolerability and its ability to increase Th-1-type T cell responses to a commercial trivalent split influenza vaccine (Agrippal) in a phase I single-blinded, randomized, controlled clinical trial. Twenty healthy volunteers were first injected with increasing doses of IMP321 alone (safety for first-in-man use). Then 40 volunteers were recruited into 4 consecutive cohorts of 10 subjects, who were randomly assigned to receive the flu vaccine plus 3, 10, 30 or 100 microg IMP321 or the flu vaccine plus saline control.

IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study.

Background: LAG-3 (CD223) is a natural high affinity ligand for MHC class II. The soluble form (sLAG-3) induces maturation of monocyte-derived dendritic cells in vitro and is used as a potent Th1-like immune enhancer with many antigens in animal models. To extend this observation to human, a proof of concept study was conducted with a clinical-grade sLAG-3, termed IMP321, coinjected with alum-non-absorbed recombinant hepatitis B surface antigen.

Tetraspan microdomains distinct from lipid rafts enrich select peptide-MHC class II complexes.

Complexes of peptide and major histocompatibility complex (MHC) class II are expressed on the surface of antigen-presenting cells but their molecular organization is unknown. Here we show that subsets of MHC class II molecules localize to membrane microdomains together with tetraspan proteins, the peptide editor HLA-DM and the costimulator CD86. Tetraspan microdomains differ from other membrane areas such as lipid rafts, as they enrich MHC class II molecules carrying a selected set of peptide antigens.

Interleukin 15 stimulates production of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by human peripheral blood mononuclear cells.

In peripheral blood mononuclear cells (PBMC), matrix metalloproteinase (MMP)-9 mediates the extravasation of immune cells and may be involved in tissue destruction during inflammation. We investigated the effect of the pro-inflammatory cytokines interleukin (IL-)12 and 15 on the secretion of MMP-9 in PBMC. IL-15, but not IL-12, induces MMP-9 in PBMC and in T cells.

Matrix metalloproteinase (MMP)-8 and MMP-9 in cerebrospinal fluid during bacterial meningitis: association with blood-brain barrier damage and neurological sequelae.

To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.

Matrix metalloproteinase upregulation in chronic inflammatory demyelinating polyneuropathy and nonsystemic vasculitic neuropathy.

Objective: To determine the expression pattern and cellular source of matrix metalloproteinases (MMPs) in chronic inflammatory demyelinating polyneuropathy (CIDP) and nonsystemic vasculitic neuropathy (NSVN).

Background: MMPs are endopeptidases involved in tissue destruction and infiltration by immune cells in multiple sclerosis and Guillain-Barré syndrome. Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases.

Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis.

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other components of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques and in brain tissue in experimental allergic encephalomyelitis. To measure quantitatively the expression of these MMPs and their endogenous inhibitors (TIMP-1 and -2), we analysed samples from 52 patients with relapsing-remitting and primary progressive multiple sclerosis by ELISA (enzyme-linked immunosorbent assay) and substrate-gel electrophoresis (zymography).