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Editor's Highlight: This paper reports an in vitro cell culture system from human donors for the prediction of the allergic potential of drugs. Naive T cells were cultured in the presence of a drug and tested for transformation of the naive phenotype into a memory phenotype. These results demonstrate a system that can predict possible drug allergy resulting in serious adverse effects in a system that does not utilize experimental animals.Adverse drug reactions represent a major stumbling block to drug development and those with an immune etiology are the most difficult to predict. We have developed an in vitro T-cell priming culture method using peripheral blood from healthy volunteers to assess the allergenic potential of drugs. The drug metabolite nitroso sulfamethoxazole (SMX-NO) was used as a model drug allergen to establish optimum assay conditions. Naive T cells were cocultured with monocyte-derived dendritic cells at a ratio of 25:1 in the presence of the drug for a period of 8 days, to expand the number of drug-responsive T cells. The T cells were then incubated with fresh dendritic cells, and drug and their antigen responsiveness analyzed using readouts for proliferation, cytokine secretion, and cell phenotype. All five volunteers showed dose-dependent proliferation as measured by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester content and by 3H-thymidine uptake. CD4 T cells that had divided in the presence of SMX-NO had changed from a naive phenotype (CD45RA+) to a memory phenotype (CD45RO+). These memory T cells expressed the chemokine receptors CCR2, CCR4, and CXCR3 suggesting a mixture of TH1 and TH2 cells in the responding population, with a propensity for homing to the skin. Drug stimulation was also associated with the secretion of a mixture of TH1 cytokines (interferon γ) and TH2 cytokines (interleukin [IL]-5 and IL-13) as detected by ELISpot. We are currently developing this approach to investigate the allergenic potential of other drugs, including those where an association between specific human leucocyte antigen alleles and susceptibility to an immunological reaction has been established. [ABSTRACT FROM PUBLISHER]

Occupational exposure to metals such as cobalt and beryllium represents a risk factor for respiratory health and can cause immune-mediated diseases. However, the way they act may be different. We show here that the two metals have a divergent effect on peripheral T lymphocytes and monocytes: BeSO4 induces cell death in monocytes but not in T lymphocytes, which instead respond by producing Interferon gamma (IFN-γ); conversely, CoCl2 induces apoptosis in T lymphocytes but not in monocytes. Interestingly, both metals induce p53 overexpression but with a dramatic different outcome. This is because the effect of p53 in CoCl2-treated monocytes is counteracted by the antiapoptotic activity of cytoplasmic p21Cip1/WAF1, the activation of nuclear factor κB, and the inflammasome danger signaling pathway leading to the production of proinflammatory cytokines. However, CoCl2-treated monocytes do not fully differentiate into macrophage or dendritic cells, as inferred by the lack of expression of CD16 and CD83, respectively. Furthermore, the expression of HLA-class II molecules, as well as the capability of capturing and presenting the antigens, decreased with time. In conclusion, cobalt keeps monocytes in a partially activated, proinflammatory state that can contribute to some of the pathologies associated with the exposure to this metal. [ABSTRACT FROM PUBLISHER]

The induction by chemicals of allergic sensitization and allergic disease is an important and challenging branch of toxicology. Skin sensitization resulting in allergic contact dermatitis represents the most common manifestation of immunotoxicity in humans, and many hundreds of chemicals have been implicated as skin sensitizers. There are far fewer chemicals that have been shown to cause sensitization of the respiratory tract and asthma, but the issue is no less important because hazard identification remains a significant challenge, and occupational asthma can be fatal. In all areas of chemical allergy, there have been, and remain still, intriguing challenges where progress has required a close and productive alignment between immunology, toxicology, and clinical medicine. What the authors have sought to do here is to exemplify, within the framework of chemical allergy, how an investment in fundamental research and an improved understanding of relevant biological and biochemical mechanisms can pay important dividends in driving new innovations in hazard identification, hazard characterization, and risk assessment. Here we will consider in turn three specific areas of research in chemical allergy: (1) the role of epidermal Langerhans cells in the development of skin sensitization, (2) T lymphocytes and skin sensitization, and (3) sensitization of the respiratory tract. In each area, the aim is to identify what has been achieved and how that progress has impacted on the development of new approaches to toxicological evaluation. Success has been patchy, and there is still much to be achieved, but the journey has been fascinating and there have been some very important developments. The conclusion drawn is that continued investment in research, if coupled with an appetite for translating the fruits of that research into imaginative new tools for toxicology, should continue to better equip us for tackling the important challenges that remain to be addressed. [ABSTRACT FROM AUTHOR]