Immune pathomechanism of drug hypersensitivity reactions

Drug hypersensitivity research has progressed enormously in recent years, and a greater understanding of mechanisms has contributed to improved drug safety. Progress has been made in genetics, enabling personalized medicine for certain drugs, and in understanding drug interactions with the immune system. In a recent meeting in Rome, the clinical, chemical, pharmacologic, immunologic, and genetic aspects of drug hypersensitivity were discussed, and certain aspects are briefly summarized here. Small chemicals, including drugs, can induce immune reactions by binding as a hapten to a carrier protein. Park (Liverpool, England) demonstrated (1) that drug haptens bind to protein in patients in a highly restricted manner and (2) that irreversibly modified carrier proteins are able to stimulate CD4(+) and CD8(+) T cells from hypersensitive patients. Drug haptens might also stimulate cells of the innate immune system, in particular dendritic cells, and thus give rise to a complex and complete immune reaction. Many drugs do not have hapten-like characteristics but might gain them on metabolism (so-called prohaptens). The group of Naisbitt found that the stimulation of dendritic cells and T cells can occur as a consequence of the transformation of a prohapten to a hapten in antigen-presenting cells and as such explain the immune-stimulatory capacity of prohaptens. The striking association between HLA-B alleles and the development of certain drug reactions was discussed in detail. Mallal (Perth, Australia) elegantly described a highly restricted HLA-B∗5701-specific T-cell response in abacavir-hypersensitive patients and healthy volunteers expressing HLA-B∗5701 but not closely related alleles. Expression of HLA-B∗1502 is a marker known to be necessary but not sufficient to predict carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Han Chinese. The group of Chen and Hong (Taiwan) described the possible "missing link" because they showed that the presence of certain T-cell receptor (TCR) clonotypes was necessary to elicit T-cell responses to carbamazepine. The role of TCRs in drug binding was also emphasized by Pichler (Bern, Switzerland). Following up on their "pharmacological interactions of drugs with immune receptors" concept (p-i concept), namely that drugs can bind directly to TCRs, MHC molecules, or both and thereby stimulate T cells, they looked for drug-binding sites for the drug sulfamethoxazole in drug-specific TCRs: modeling revealed up to 7 binding sites on the CDR3 and CDR2 regions of TCR Vα and Vβ. Among many other presentations, the important role of regulatory T cells in drug hypersensitivity was addressed.

Global Change and the World's Mountain. Where are we coming from, and where are we going to?

The history of mountain research is most fascinating. Three names for 3 centuries may give an idea of the growing knowledge about the world's mountains: Horace Bénédict de Saussure, who climbed and studied the Mont Blanc in 1787; Alexander von Humboldt, ever investigating the environment during his attempt to ascend the Chimborazo in 1802; and Carl Troll, who founded the International Geographical Union's Commission on High-altitude Geoecology in 1968. Awareness of the growing impact of human activities on the environment led to scientific and political initiatives at the global level, beginning in the 1970s. The Perth conference in 2010 has offered an opportunity to both look back on these developments and explore the future of the world's mountains in a time of rapidly growing “global change” problems and processes.

MRD's approach: Ideally suited to support Future Earth research agenda in mountains

Both Future Earth and Mountain Research and Development (MRD) aim to support production and dissemination of knowledge for sustainable development. As shown in Future Earth’s Strategic Research Agenda 2014, the global research community has begun to acknowledge its societal role and the need for a new type of research in which scientists link disciplines and coproduce transformation knowledge with stakeholders. Future Earth has defined three research themes that conceptualize the issues to be dealt with at the same time as the way in which this should be done. In many ways, MRD’s policy has made the journal a forerunner of Future Earth’s stipulated “step-change in research”. Indeed, MRD’s section policies aim to support similar contents and ways of producing these forms of knowledge. MRD publishes “systems knowledge” in its MountainResearch section, “target knowledge” in its MountainAgenda section, and “transformation knowledge” in its MountainDevelopment section. Each of these sections has dedicated review criteria to assess and enhance the quality of the knowledge presented in the papers. In this poster, we provide examples from each of the three sections of what the knowledge types look like, how they are assessed, and how they contribute to the three Future Earth themes.