For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less
INTRODUCTION: The mode of action of dimethyl fumarate (DMF), an immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS), has not yet been fully elucidated. While in-vitro experime Show more
INTRODUCTION: The mode of action of dimethyl fumarate (DMF), an immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS), has not yet been fully elucidated. While in-vitro experiments and animal studies suggest effects on immune cell survival, proliferation, migration and oxidative stress response, corresponding observations from human studies are lacking. This study aims to characterize ex-vivo and in-vivo effects in a cohort of DMF treated RRMS patients.
METHODS: Blood samples were collected from twenty well-characterized RRMS patients at baseline and after 3, 6 and 12 months of DMF treatment and an age- and gender-matched cohort of 20 healthy individuals at 0 and 3 months. Leukocyte subpopulations, immunoglobulin levels and cytokine secretion were measured. T cells were assessed for their levels of reactive oxygen species (ROS), metabolic status and their proliferative capacity. Levels of antioxidants were determined in serum by mass spectrometry. Responses of monocyte activation markers as well as NFkB and MAPK pathways to DMF were analysed.
RESULTS: Upon DMF treatment, all lymphocyte subpopulations dropped significantly over the course of 12 months with cytotoxic and effector T cells being affected most significantly. DMF induced cell death and inhibited proliferation of T cells in-vitro. Interestingly, this anti-proliferative effect decreased under treatment. In-vivo DMF treatment led to decreased T cell glycolysis and higher turn-over of antioxidants. In line with these results a significant increase of cytosolic ROS levels after 3 months treatment was detected in T cells. In-vitro DMF treatment reduced NFkB (p65) translocation to the nucleus and MAPK (p38) levels decreased upon stimulation with monomethyl fumarate (MMF) in-vitro and ex-vivo. Consequently, the expression of co-stimulatory molecules like CD40 and CD150 was decreased in antigen presenting cells both in-vitro and ex-vivo.
CONCLUSION: This study translates knowledge from in-vitro and animal studies on DMF into the clinical setting. Our data suggest that DMF not only alters lymphocyte composition, but also has profound effects on proliferation and induces oxidative stress in T cells. It also acts on innate immunity by reducing the activation status of antigen presenting cells (APCs) via NFkB and MAPK inactivation. Show less