Treatment related adverse events have been a serious issue
Treatment-related adverse events have been a serious issue in clinical application. Severe toxicity has been reported in clinical trials using antibody blockade of CSF-1R (20 mg/kg), PD-1, and CTLA-4.29, 30, 31 However, apparent side effects were not observed in our study with PLX3397 treatment alone or in combination. This might be due to the lower dose (20 mg/kg) used in our study compared to the previous reports that used 40–275 mg/kg in mice.52, 53, 54 Furthermore, a clinical trial has reported that an oral dose of 1,000 mg/day is well tolerated. The different drug properties between Pyridoxine HCl mg and the small-molecule inhibitors might be another reason for this diversity. Meanwhile, the dose of anti-PD-1 used in this study was also lower than previous studies, with 200 μg per mouse.14, 24, 49 As a consequence, our triple combination strategy demonstrated significant anti-tumor ability with fewer side effects.
Materials and Methods
Conflicts of Interest
Acknowledgments This study was supported by a National Key R&D Program of China grant (2017YFA0105702) and National Natural Science Foundation of China Program grants (81772939, 81472195, and 81372445). We are grateful to Xiaogang Wang (PerkinElmer) for helping offering access to the multispectral scanner Vectra and InForm software.
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that typically affects multiple organ systems. Kidney involvement, or lupus nephritis (LN), appears in 40–60% of individuals with SLE, and is one of the leading causes of morbidity and mortality in these patients . Additionally, about 40% of SLE patients will display central nervous system (CNS) manifestations, known as neuropsychiatric lupus (NPSLE) . Diffuse NPSLE manifests with a diverse array of symptoms that include headaches, cognitive dysfunction, and depression, all of which negatively affect patients' quality of life . The exact pathogenesis of LN and NPSLE are not yet known, although cytokines, immune cell infiltrates, and autoantibodies are believed to play an important role in both of these common end organ pathologies. Macrophages are an important cellular component of the innate immune system. Present in nearly every tissue, macrophages can assume a myriad of phenotypes allowing them to perform various functional roles ranging from contributing to inflammation, to trophic scavenging and even aiding in the resolution of inflammation , . The phenotype of a macrophage is dependent upon its microenvironment, which with it can interact through its large repertoire of surface receptors . Within the brain, the resident macrophage population is known as microglia. Microglia are the predominant immune cell in the central nervous system (CNS), and are potent cytokine producers. An important receptor in regulating both macrophage and microglia function is the colony stimulating factor 1 receptor (CSF-1R). Signaling through the CSF-1R (by either CSF-1 or IL-34) is crucial for macrophage and microglia development, survival, function, and activation . Additionally, CSF-1R signaling is important for migration and proliferation of macrophages . Macrophages are thought to be important in the pathogenesis of LN. In both LN patients and mouse models of SLE, elevated levels of CSF-1 are found in the serum, urine, and kidneys, with urine and serum levels correlating with LN disease activity , , , . An influx of macrophages with a unique activated phenotype can be seen in both murine ,  and human LN , , with macrophages accumulating both periglomerularly and intraglomerularly , , . However, while the presence of macrophages within kidneys displaying active LN is consistent with a role of macrophages in disease pathogenesis, it does not prove that they are necessary to cause disease. Within the brain, cytokines such as TWEAK, IL-6, IP-10, TNF, MCP-1, and G-CSF are significantly upregulated in the cerebral spinal fluid (CSF) of NPSLE patients, and may be directly linked to disease pathogenesis. These cytokines can all be released by activated microglia, and additionally may modulate microglia activity. Activated microglia can be found in both human and murine lupus brains , . As the major immune effector cell in the brain, it has been surmised that microglia may be relevant to NPSLE pathogenesis.