research highlights

■ autoimmunity immunotherapy Defects in DC tolerance A safety switch for immunotherapy Dendritic cells (DCs) have previously been Cellular therapies—such as implicated in the pathogenesis of the autoim- adoptive T cell transfer—are increasingly used to treat mune disease lupus. Blimp-1, a known regu- hematological malignancies, lator of B cells and T cells, is now shown to with encouraging results. But as also regulate the immune tolerance function progress is made in increasing of DCs, providing new insights into the role of the persistence and activity of these key immune cells in lupus (J. Exp. Med. the transferred T cells, the risk of 208, 2193–2199). serious graft-versus-host disease A polymorphism in Blimp-1 was previously (GVHD) also increases. Antonio identified as risk variant for systemic lupus ery- Di Stasi et al. now report their thematosus (SLE), indicating that this factor clinical test of a ‘suicide gene’ might be important in SLE pathogenesis. By method to delete transferred cells

investigating mice in which Blimp-1 had been Jim Dowdalls / Photo Researchers, Inc. and resolve GVHD in individuals selectively knocked out in DCs, Sun Jung Kim receiving genetically modified T cells for the treatment of leukemia (N. Engl. J. Med. 365, showed that Blimp-1 expression in DCs is et al. 1673–1683). required for immune tolerance in female mice, Although suicide genes such as the herpes simplex virus thymidine kinase have been but not in males. DCs lacking Blimp-1 from previously tested as a safety strategy for adoptive T cell therapies, a faster-acting alternative female mice showed increased production of would be desirable. Therefore, the researchers engineered human T cells to express an the proinflammatory cytokine interleukin-6, inducible suicide protein consisting of human caspase 9 linked to the FK506-binding promoted the induction of follicular T helper protein, FKBP12. Cells expressing this transgene are viable but rapidly undergo apoptosis cells and enhanced germinal center responses. when treated with the dimerizing molecule AP1903. These mice also developed autoreactive anti- To test the ability of the suicide gene product to deplete engineered cells in humans, bodies that carried multiple mutations, consis- the researchers treated five individuals with leukemia with donor T cells that expressed the tent with a germinal center response. fusion protein. Four of the patients developed GVHD in the skin within 42 days after the Together, these gender-dependent responses transplant, and one of these individuals also developed liver GVHD. The four patients were to Blimp-1 knockout in DCs are reminiscent of given one dose of AP1903, and, within 30 minutes, more than 90% of the transferred the human lupus phenotype. It will therefore T cells were eliminated from the peripheral blood, and their GVHD symptoms disappeared be interesting to investigate how the Blimp-1 by 48 hours. And although some transgenic T cells persisted in the treated individuals and polymorphism identified in genome-wide asso- expanded after clearance of the dimerizing drug, GVHD did not recur within up to one year ciation studies influences Blimp-1 expression of monitoring, and three of the four individuals showed no leukemia relapse. and DC function in human studies. —MS The results show that an inducible caspase 9 is an effective tool for the rapid and safe elimination of most transferred T cells in the advent of GVHD. The impact of such deletion of adoptively transferred T cells on cancer relapse will now require further study. —AF ■ addiction Analyzing epidemiological data, Levine biosynthesis. These mutations loosen the © 2011 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2011 One thing leads to et al. showed that cocaine use often occurs substrate specificity of the enzyme, allowing another in smokers. Moreover, people who initiate it to use alanine or glycine rather than serine. Addiction to alcohol or nicotine often pre- cocaine use after they become smokers are This change in substrate results in the pro- cedes the use of cocaine and other illegal sub- most likely to develop cocaine dependence. duction of deoxysphingolipids, which may be stances. A recent study points to the possible Decreasing smoking rates might therefore lead neurotoxic. Proceeding from this mechanistic neural basis of this phenomenon (Sci. Trans. to a decrease in cocaine addiction. —JCL framework, the researchers hypothesized that Med. 3, 107ra109). increasing serine levels might be beneficial. Amir Levine et al. pretreated mice with nic- Indeed, dietary supplementation with l-serine otine and found that it increased addiction- ■ neurological disorders in a mouse model of HSAN1 decreased plasma related behaviors such as conditioned place S erine to the rescue deoxysphingolipid levels and decreased neu- preference in response to cocaine. This effect ropathic symptoms. In 14 individuals with was unidirectional; exposing the mice first to No effective treatments exist for individuals HSAN1, l-serine dietary supplementation also cocaine did not affect responses to nicotine. with hereditary neuropathies. On the basis of reduced plasma deoxysphingolipid levels. Mechanistically, the authors found that recent progress in understanding the cause of In view of the short 10-week course of l-ser- nicotine enhanced the ability of cocaine to one such disorder, hereditary sensory and auto- ine supplementation, neurological symptoms inhibit histone deacetylase, promoting histone nomic neuropathy type 1 (HSAN1), K. Garofalo were not examined in the treated individuals acetylation in the nucleus accumbens, a key et al. provide initial promising results for a with HSAN1. A larger and longer-term clinical component of the brain reward system. This mechanism-based therapy for this rare disease: trial will now be needed to test the safety and priming magnified the effect of cocaine on dietary supplementation with l-serine (J. Clin. efficacy of this therapy.—MB synaptic plasticity in the accumbens. Indeed, Invest. doi:10.1172/JCI57549). pharmacologically or genetically manipulating HSAN1 is caused by mutations in genes that histone acetylation correspondingly modified encode subunits of serine palmitoyltransferase, Written by Michael Basson, Alison Farrell, the effects of cocaine on plasticity. which catalyzes the first step in sphingolipid Juan Carlos López and Meera Swami.

1566 volume 17 | number 12 | december 2011 nature medicine