Designing programs for eliminating canine rabies from islands: Bali, Indonesia as a case study

<p>Background: Canine rabies is one of the most important and feared zoonotic diseases in the world. In some regions rabies elimination is being successfully coordinated, whereas in others rabies is endemic and continues to spread to uninfected areas. As epidemics emerge, both accepted and contentious control methods are used, as questions remain over the most effective strategy to eliminate rabies. The Indonesian island of Bali was rabies-free until 2008 when an epidemic in domestic dogs began, resulting in the deaths of over 100 people. Here we analyze data from the epidemic and compare the effectiveness of control methods at eliminating rabies.</p> <p>Methodology/Principal Findings: Using data from Bali, we estimated the basic reproductive number, R0, of rabies in dogs, to be ~1·2, almost identical to that obtained in ten–fold less dense dog populations and suggesting rabies will not be effectively controlled by reducing dog density. We then developed a model to compare options for mass dog vaccination. Comprehensive high coverage was the single most important factor for achieving elimination, with omission of even small areas (<0.5% of the dog population) jeopardizing success. Parameterizing the model with data from the 2010 and 2011 vaccination campaigns, we show that a comprehensive high coverage campaign in 2012 would likely result in elimination, saving ~550 human lives and ~$15 million in prophylaxis costs over the next ten years.</p> <p>Conclusions/Significance: The elimination of rabies from Bali will not be achieved through achievable reductions in dog density. To ensure elimination, concerted high coverage, repeated, mass dog vaccination campaigns are necessary and the cooperation of all regions of the island is critical. Momentum is building towards development of a strategy for the global elimination of canine rabies, and this study offers valuable new insights about the dynamics and control of this disease, with immediate practical relevance.</p&gt

Attenuated IL-2 muteins leverage the TCR signal to enhance regulatory T cell homeostasis and response in vivo

Interleukin-2 (IL-2), along with T-cell receptor (TCR) signaling, are required to control regulatory T cell (Treg) homeostasis and function in vivo. Due to the heightened sensitivity to IL-2, Tregs retain the ability to respond to low-dose or attenuated forms of IL-2, as currently being developed for clinical use to treat inflammatory diseases. While attenuated IL-2 increases Treg selectivity, the question remains as to whether a weakened IL-2 signal sufficiently enhances Treg suppressive function(s) toward disease modification. To understand this question, we characterized the in vivo activity and transcriptomic profiles of two different attenuated IL-2 muteins in comparison with wildtype (WT) IL-2. Our study showed that, in addition to favoring Tregs, the attenuated muteins induced disproportionately robust effects on Treg activation and conversion to effector Treg (eTreg) phenotype. Our data furthermore suggested that Tregs activated by attenuated IL-2 muteins showed reduced dependence on TCR signal, at least in part due to the enhanced ability of IL-2 muteins to amplify the TCR signal in vivo. These results point to a new paradigm wherein IL-2 influences Tregs’ sensitivity to antigenic signal, and that the combination effect may be leveraged for therapeutic use of attenuated IL-2 muteins

Phase Synchrony Rate for the Recognition of Motor Imagery in Brain-Computer Interface

Motor imagery attenuates EEG µ and β rhythms over sensorimotor cortices. These amplitude changes are most successfully captured by the method of Common Spatial Patterns (CSP) and widely used in braincomputer interfaces (BCI). BCI methods based on amplitude information, however, have not incoporated the rich phase dynamics in the EEG rhythm. This study reports on a BCI method based on phase synchrony rate (SR). SR, computed from binarized phase locking value, describes the number of discrete synchronization events within a window. Statistical nonparametric tests show that SRs contain significant differences between 2 types of motor imageries. Classifiers trained on SRs consistently demonstrate satisfactory results for all 5 subjects. It is further observed that, for 3 subjects, phase is more discriminative than amplitude in the first 1.5-2.0 s, which suggests that phase has the potential to boost the information transfer rate in BCIs.

Phase Synchrony Rate for the Recognition of Motor Imagery in BCI

Motor imagery attenuates EEG α and β rhythms over sensorimotor cortices. These amplitude changes are most successfully captured by the method of Common Spatial Patterns (CSP) and widely used in braincomputer interfaces (BCI). BCI methods based on amplitude information, however, have not incoporated the rich phase dynamics in the EEG rhythm. This study reports on a BCI method based on phase synchrony rate (SR). SR, computed from binarized phase locking value, describes the number of discrete synchronization events within a window. Statistical nonparametric tests show that SRs contain significant differences between 2 types of motor imageries. Classifiers trained on SRs consistently demonstrate satisfactory results for all 5 subjects. It is further observed that, for 3 subjects, phase is more discriminative than amplitude in the first 1.5-2.0 s, which suggests that phase has the potential to boost the information transfer rate in BCIs.

TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation

Analogous to the clinical use of recombinant high-affinity antibodies, transfer of T cell receptor genes may be used to create a T cell compartment specific for self-antigens to which the endogenous T cell repertoire is immune tolerant. Here we show in a spontaneous prostate carcinoma model that the combination of vaccination with adoptive transfer of small numbers of T cells that are genetically modified with a tumor-specific TCR results in a marked suppression of tumor development, even though both treatments are by themselves without effect. These results demonstrate the value of TCR gene transfer to target otherwise non-immunogenic tumor-associated self-antigens provided that adoptive transfer occurs under conditions that allow in vivo expansion of the TCR-modified T cells. This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org

Targeting self-antigens through allogeneic TCR gene transfer

Adoptive transfer of T-cell receptor (TCR) genes has been proposed as an attractive approach for immunotherapy in cases where the endogenous T-cell repertoire is insufficient. While there are promising data demonstrating the capacity of TCR-modified T cells to react to foreign antigen encounter, the feasibility of targeting tumor-associated self-antigens has not been addressed. Here we demonstrate that T-cell receptor gene transfer allows the induction of defined self-antigenspecific T-cell responses, even when the endogenous T-cell repertoire is nonreactive. Furthermore, we show that adoptive transfer of T-cell receptor genes can be used to induce strong antigen-specific T-cell responsiveness in partially MHC-mismatched hosts without detectable graft versus host disease. These results demonstrate the feasibility of using a collection of "off the shelf" T-cell receptor genes to target defined tumor-associated self-antigens and thereby form a clear incentive to test this immunotherapeutic approach in a clinical settin