Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

International audienceInterference with immune cell proliferation represents a successful treatment strategy in T cell-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis (MS). One prominent example is pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), which mediates de novo pyrimidine synthesis in actively proliferating T and B lymphocytes. Within the TERIDYNAMIC clinical study, we observed that the DHODH inhibitor teriflunomide caused selective changes in T cell subset composition and T cell receptor repertoire diversity in patients with relapsing-remitting MS (RRMS). In a preclinical antigen-specific setup, DHODH inhibition preferentially suppressed the proliferation of high-affinity T cells. Mechanistically, DHODH inhibition interferes with oxidative phosphorylation (OXPHOS) and aerobic glycolysis in activated T cells via functional inhibition of complex III of the respiratory chain. The affinity-dependent effects of DHODH inhibition were closely linked to differences in T cell metabolism. High-affinity T cells preferentially use OXPHOS during early activation, which explains their increased susceptibility toward DHODH inhibition. In a mouse model of MS, DHODH inhibitory treatment resulted in preferential inhibition of high-affinity autoreactive T cell clones. Compared to T cells from healthy controls, T cells from patients with RRMS exhibited increased OXPHOS and glycolysis, which were reduced with teriflunomide treatment. Together, these data point to a mechanism of action where DHODH inhibition corrects metabolic disturbances in T cells, which primarily affects profoundly metabolically active high-affinity T cell clones. Hence, DHODH inhibition may promote recovery of an altered T cell receptor repertoire in autoimmunity

Associations Between Nutrition, Gut Microbiome, and Health in A Novel Nonhuman Primate Model.

Red-shanked doucs (Pygathrix nemaeus) are endangered, foregut-fermenting colobine primates which are difficult to maintain in captivity. There are critical gaps in our understanding of their natural lifestyle, including dietary habits such as consumption of leaves, unripe fruit, flowers, seeds, and other plant parts. There is also a lack of understanding of enteric adaptations, including their unique microflora. To address these knowledge gaps, we used the douc as a model to study relationships between gastrointestinal microbial community structure and lifestyle. We analyzed published fecal samples as well as detailed dietary history from doucs with four distinct lifestyles (wild, semi-wild, semi-captive, and captive) and determined gastrointestinal bacterial microbiome composition using 16S rRNA sequencing. A clear gradient of microbiome composition was revealed along an axis of natural lifestyle disruption, including significant associations with diet, biodiversity, and microbial function. We also identified potential microbial biomarkers of douc dysbiosis, including Bacteroides and Prevotella, which may be related to health. Our results suggest a gradient-like shift in captivity causes an attendant shift to severe gut dysbiosis, thereby resulting in gastrointestinal issues

Education and the mass media: The origins of mass communications research in the United States, 1939-1955

This study examines the development of mass communications research as an area of study at United States universities during World War II and the Cold War. By mid-century mass communications researchers became recognized experts in describing the effects of the mass media on learning and other social behavior. This study analyzes the ideological and historical forces which gave rise to, and shaped, their research.The growth of the various technologies of mass communication in the early part of the twentieth century was a source of great concern, as well as a source of great optimism, among educators. Between World War I and World War II educators engaged in a wide ranging debate about the role of these mass media, centered largely around the issue of propaganda and its relationship to democracy and education. The dissertation presents an overview of this debate and argues that the debate subsided with the outbreak of World War II.The United States involvement in World War II required the creation of propaganda agencies whose primary goal was the development of techniques of mass persuasion. Scholars who went to work for these agencies sharpened their expertise in these areas, and made important personal contacts which facilitated the development of the field. Since the term "propaganda" had come to possess negative connotations, these researchers orchestrated a semantic shift away from "propaganda" to "mass communications."The field was enhanced by the large governmental research contracts which were awarded to university-based mass communications researchers during the Cold War. The work of several key figures in this research is discussed, including Berelson, Stanton, Hovland, Cantril, and Dodd.The work of Paul Lazarsfeld and Wilbur Schramm is reviewed, based on archival records. Lazarsfeld's early interest in this research is located in his adherence to socialism as a youth in Vienna. Schramm's interest in persuasion stems from his education in the neo-humanist tradition of Norman Foerster.The conclusion argues that ideological commitments of key researchers in the field, as well as other historical forces, had a major impact on the way in which these researchers came to view the mass media.U of I OnlyETDs are only available to UIUC Users without author permissio