Allogeneic NK cells induce the in vitro activation of monocyte-derived and conventional type-2 dendritic cells and trigger an inflammatory response under cancer-associated conditions.

Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.

Pharmacokinetics and tolerability of a novel long-acting glucagon-like peptide-1 analog, CJC-1131, in healthy and diabetic subjects.

OBJECTIVE: The safety, tolerability, pharmacokinetics and preliminary pharmacodynamics of single rising doses of a novel GLP-1 analog, CJC-1131, was evaluated. METHODS: CJC-1131 was subcutaneously injected in 8 groups (1.5 - 20.5 microg/kg) of healthy subjects (each group of six subjects included 1 placebo per dose level). CJC-1131 was also injected subcutaneously in 6 groups (1.5 - 12 microg/kg) of Type 2 diabetic patients after a 9-day washout period from their own anti-diabetic medication. Each group of 8 patients included 2 placebo-treated patients. Seven blood glucose measurements were taken daily, and meal tolerance tests were performed on the day before dosing and on Day 3. RESULTS: CJC-1131 was quickly absorbed from the subcutaneous space, and a less than dose-proportional increase was found in Cmax. The half-life of CJC-1131 varied from 8.9 - 14.7 days in healthy subjects and from 9.1 - 13.8 days in patients. The maximum tolerated dose in healthy subjects was established at 12 microg/kg with nausea and vomiting being the dose-limiting events. These events occurred generally in the morning after dosing. Blood glucose levels in patients decreased on Day 1 in proportion with dose, with a maximum average decrease of 4.1 mmol/l in the highest dose group. Higher doses appeared to be related to a slight weight loss in patients. CONCLUSIONS: Conjugation to albumin led to a major prolongation of the half-life of GLP-1. The tolerability of this potential antidiabetic drug seems to be limited only by gastrointestinal complaints.

[Corneal pathology in Crohn's disease: electron microscopic study of a case]. / Kératopathie dans la maladie de Crohn. Etude d'un cas au microscope électronique.

Corneal pathology in Crohn's disease is relatively rare. We had the opportunity to take a biopsy of a bullous mass in the cornea of a man with Crohn's disease. Analysis of electronic pictures shows an aberrant structure of the nucleus, a very dense nuclear membrane and fragmented nucleoles. The cytoplasm contains many patches without membrane; the basal membrane is composed of filaments, and the stroma possesses figures of fingerprint-type. This unclassified description of the cornea might be typical for Crohn's disease.