Effective Antigen-Specific Immunotherapy in the Marmoset Model of Multiple Sclerosis

Mature T cells initially respond to Ag by activation and expansion, but high and repeated doses of Ag cause programmed cell death and can suppress T cell-mediated diseases in rodents. We evaluated repeated systemic Ag administration in a marmoset model of experimental allergic encephalomyelitis that closely resembles the human disease multiple sclerosis. We found that treatment with MP4, a chimeric, recombinant polypeptide containing human myelin basic protein and human proteolipid protein epitopes, prevented clinical symptoms and did not exacerbate disease. CNS lesions were also reduced as assessed in vivo by magnetic resonance imaging. Thus, specific Ag-directed therapy can be effective and nontoxic in primates. The Journal of Immunology, 2001, 166: 2116 -2121. M ultiple sclerosis (MS) 4 is a paralytic disease involving destruction of myelin sheaths surrounding axons in the CNS (1, 2). MS affects young adults, most often women residing in northern latitudes. The disease exhibits relapsing and remitting symptoms including disturbances in vision, speech, coordination, and cognition as well as weakness, spasticity, and paralysis (1, 2). Lymphocytic infiltration in the CNS white matter and immune reactions against myelin Ags indicate an autoimmune etiology for MS (1-8). Allergic encephalomyelitis was first observed as a side effect of the rabies vaccine prepared from rabbit brains by Pasteur in the 1880s (see Ref. 3). Rivers and others showed that the CNS inflammation was caused not by the rabies virus but by immune sensitization to the combination of adjuvant and brain tissue contaminating the vaccine (3, 4). Experimental allergic encephalomyelitis (EAE) models in various animal species, typically rodents, were later developed by immunization with myelin proteins in adjuvant or by the adoptive transfer of myelinreactive T cells, causing inflammatory damage to the white matter (1-6). Rodent EAE is the most widely used disease model despite important differences from MS (2). Encephalitogenic CD4 ϩ T cells are believed to initiate and perpetuate EAE and MS and thus constitute a therapeutic target (1-8). Abundant myelin protein Ags, including myelin basic protein (MBP) and proteolipid protein (PLP) as well as the less abundant Ags, myelin oligodendrocyte glycoprotein (MOG) and myelin-associated glycoprotein (MAG), are recognized by T cells in MS patients (9 -11). T cell responses against MBP and PLP may occur at an increased frequency in MS patients compared with controls (1, 2, 11, 12). Ag-specific immunotherapies directed at T cells could avoid the harmful side effects of general immunosuppressive treatments. We have investigated a potential immunotherapy for MS based on our observation that T cells undergo apoptosis both in vitro and in vivo when exposed to high or repeated doses of their cognate Ag (13, To present a broad array of potential epitopes to reactive T cells, we constructed MP4, a protein chimera of the 21.5-kDa isoform of human MBP, and a modified form of human PLP, termed PLP4, that lacks the hydrophobic domains of the protein but includes all of the known T cell epitopes (19 -21). MP4 is processed into multiple determinants and can eliminate rodent EAE by promoting tolerance to different epitopes In a few instances, EAE and Ag treatments have been studied in nonhuman primates. EAE was originally induced in rhesus macaques using CNS homogenates or purified MBP (3, 4, 30 -32). It was also found that repeated injections of MBP could arrest EAE The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact

Decision-Making in Rats is Sensitive to Rare and Extreme Events: the Black Swan Avoidance

In Brief Most studies assessing decision-making under uncertainty use events with probabilities that are above 10-20 %. Here, to study decision-making in radical uncertainty conditions, Degoulet, Willem, Baunez, Luchini and Pintus provide a novel experimental design that aims at measuring the extent to which rats are sensitive - and how they respond - to extremely rare (below 1% of probability) but extreme events in a four-armed bandit task. Gains (sugar pellets) and losses (time-out punishments) are such that large - but rare - values materialize or not depending on the option chosen. The results show that all rats diversify their choices across options. However, most rats exhibit sensitivity to rare and extreme events despite their sparse occurrence, by combining more often options with extreme gains (Jackpots) and/or avoidance of extreme losses (Black Swans). In general, most rats’ choices feature one-sided sensitivity in favor of trying more often to avoid extreme losses than to seek extreme gains - that is, they feature Black Swan Avoidance. Highlights - A novel experiment is proposed to measure whether rats are sensitive - and how they respond - to radical uncertainty materialized by extremely rare and extreme events in a four-armed bandit task; - Most rats exhibit sensitivity to rare and extreme events; - Most rats opt more often to avoid rare and extreme losses than to seek rare and extreme gains: they feature Black Swan avoidance