CSF1R blockade improves clinical parameters in prediabetic rhesus macaques

Abstract

Abstract It is unknown whether dysregulated CSF1R himonocytes/macrophages drive the progression to diabetes and if their removal and endogenous replacement with fresh macrophages resolves disease. Therefore, we hypothesize that depletion of activated CSF1R+ tissue macrophages using a monoclonal antibody against CSF1R and replacement with freshly differentiated macrophages will alleviate inflammation in tissues and ameliorate diabetes-associated disease in prediabetic rhesus macaques. We identified 6 aged Indian rhesus macaques with heightened fasting blood glucose as well as higher area-under-the-curve in an intravenous glucose tolerance test (IVGTT), indicating prediabetes. Three animals were treated with a rhesus IgG1 recombinantanti-CSF1R antibody administered i.v. (15 mg/kg) once every two weeks for 6 weeks. An IgG1 control was administered to the remaining 3 animals. Clinical parameters such as blood pressure, plasma levels of total cholesterol, glucose, insulin, adiponectin, colony stimulating factor 1 (CSF1), IL1β, monocyte chemoattractant protein 1 (MCP-1) were monitored throughout treatment and up to 8 weeks after the 3 rdinjection. A 27-color flow cytometry panel were used to monitor changes in immune cell populations throughout the study. Treatment with anti-CSF1R resulted in decreased total cholesterol, increased adiponectin, increased CSF1, and increased IL1β levels in the blood throughout the study. Flow cytometry experiments confirmed the depletion of CD16+ monocytes (known to be CSF1R +) in treated animals. Treatment with anti-CSF1R resulted in improvement in multiple clinical parameters associated with the progression to type-2 diabetes mellitus.