Nerve agents are organophosphorus chemical warfare agents that exert their action through the irreversible inhibition of acetylcholinesterase, with a consequent overstimulation of cholinergic transmission followed by its shutdown. Beyond warfare, they have notoriously been employed in acts of terrorism as well as high profile assassinations. After a brief historical introduction on the development and deployment of nerve agents, this review provides a survey of their chemistry, the way they affect cholinergic transmission, the available treatment options, and the current directions for their improvement. As the review illustrates, despite their merits, the currently available treatment options present several shortcomings. Current research directions involve the search for improved antidotes, antagonists of the nicotinic receptors, small-molecule pretreatment options, as well as bioscavengers as macromolecular pretreatment options. These efforts are making good progress in many different directions and, hopefully, will lead to a lower target susceptibility, thus reducing the appeal of nerve agents as chemical weapons.

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naïve and central memory CD4 T cells and naïve CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.

Summary Phosphatidylinositol 3 kinase (PI3K) inhibitors such as idelalisib have been associated with potentially severe autoimmune toxicity. In the present study, we demonstrate that relapsed refractory patients with chronic lymphocytic leukaemia treated with idelalisib rituximab on the phase III registration trial show uniform decrease in regulatory T cells (Tregs) and increase in CD8 T cells with treatment. Patients who do not develop toxicity show enrichment for T cells expressing multiple chemokine receptors, while those who do develop toxicity have an activated CD8 T cell population with T helper 17 cell differentiation at baseline, which then increases, leading to an increased CD8:Treg ratio that likely triggers autoimmune toxicity.