James Andrus

Ontogeny of γδ T Cells in Humans

T cell receptors consist either of an α-chain combined with a β-chain or a γ-chain combined with a δ-chain. αβ T cells constitute the majority of T cells in human blood throughout life. Flow cytometric analyses presented in this study, which focus on the representation of the developmental (naive and memory) subsets of γδ T cells, show by function and phenotype that this lineage contains both naive and memory cells. In addition, we show that the representation of naive T cells is higher among αβ than γδ T cells in adults and that the low frequency of naive γδ T cells in adults reflects ontological differences between the two major γδ subsets, which are distinguished by expression of Vδ1 vs Vδ2 δ-chains. Vδ1 cells, which mirror αβ cells with respect to naive representation, predominate during fetal and early life, but represent the minority of γδ cells in healthy adults. In contrast, Vδ2 cells, which constitute the majority of adult γδ cells, show lower frequencies of naive cells than Vδ1 early in life and show vanishingly small naive frequencies in adults. In essence, nearly all naive Vδ2 cells disappear from blood by 1 year of life. Importantly, even in children less than 1 year old, most of the nonnaive Vδ2 cells stain for perforin and produce IFN-γ after short-term in vitro stimulation. This represents the earliest immunological maturation of any lymphocyte compartment in humans and most likely indicates the importance of these cells in controlling pathology due to common environmental challenges.

Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity

Preclinical Research

Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease

Glutathione (GSH) deficiency may play a pivotal role in a variety of apparently unrelated clinical conditions and diseases. Orally administered N-acetylcysteine (NAC), which replenishes the cysteine required for GSH synthesis, has been tested in a large number of randomized placebo-controlled trials involving these diseases and conditions. This chapter focused on developing a base of evidence suggesting that NAC administration improves disease by increasing cysteine and/or GSH in a variety of diseases, thereby implying a significant role for GSH deficiency in the clinical basis of many diseases. To develop this base of evidence, we systematically selected studies which considered the hypothesis that the therapeutic efficacy for NAC is an indication that cysteine and/or GSH deficiency is a pathophysiological part of the diseases studied. In this manner we focus this chapter on explaining the biological mechanisms of NAC therapy in a wide variety of disorders and demonstrate its ubiquitous role in improving disease that involves disrupted GSH and/or cysteine metabolism. Electronic supplementary material The online version of this article (10.1007/978-981-10-5311-5_20) contains supplementary material, which is available to authorized users.