Apoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells

BACKGROUND: Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. PRINCIPAL FINDINGS: Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. CONCLUSION: In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism

Synchronization of discrete-time multi-agent systems on graphs using H2-Riccati design

In this paper design methods are given for synchronization control of discrete-time multi-agent systems on directed communication graphs. The graph properties complicate the design of synchronization controllers due to the interplay between the eigenvalues of the graph Laplacian matrix and the required stabilizing gains. A method is given herein, based on an H2 type Riccati equation, that decouples the design of the synchronizing gains from the detailed graph properties. A condition for synchronization is given based on the relation of the graph eigenvalues to a bounded circular region in the complex plane that depends on the agent dynamics and the Riccati solution. This condition relates the Mahler measure of the node dynamics system matrix to the connectivity properties of the communication graph. The notion of `synchronizing region' is used. An example shows the effectiveness of these design methods for achieving synchronization in cooperative discrete-time systems

Cooperative control of multi-agent systems: optimal and adaptive design approaches

Task complexity, communication constraints, flexibility and energy-saving concerns are all factors that may require a group of autonomous agents to work together in a cooperative manner. Applications involving such complications include mobile robots, wireless sensor networks, unmanned aerial vehicles (UAVs), spacecraft, and so on. In such networked multi-agent scenarios, the restrictions imposed by the communication graph topology can pose severe problems in the design of cooperative feedback control systems.  Cooperative control of multi-agent systems is a challenging topic for both control theorists and practitioners and has been the subject of significant recent research. Cooperative Control of Multi-Agent Systems extends optimal control and adaptive control design methods to multi-agent systems on communication graphs.  It develops Riccati design techniques for general linear dynamics for cooperative state feedback design, cooperative observer design, and cooperative dynamic output feedback design.  Both continuous-time and discrete-time dynamical multi-agent systems are treated. Optimal cooperative control is introduced and neural adaptive design techniques for multi-agent nonlinear  systems with unknown dynamics, which are rarely treated in literature are developed. Results spanning systems with first-, second- and on up to general high-order nonlinear dynamics are presented. Each control methodology proposed is developed by rigorous proofs. All algorithms are justified by simulation examples. The text is self-contained and will serve as an excellent comprehensive source of information for researchers and graduate students working with multi-agent systems. The Communications and Control Engineering series reports major technological advances which have potential for great impact in the fields of communication and control. It reflects research in industrial and academic institutions around the world so that the readership can exploit new possibilities as they become available

Differential graphical games for H-infinity control of linear heterogeneous multiagent systems

Differential graphical games have been introduced in the literature to solve state synchronization problem for linear homogeneous agents. When the agents are heterogeneous, the previous notion of graphical games cannot be used anymore and a new definition is required. In this paper, we define a novel concept of differential graphical games for linear heterogeneous agents subject to external unmodeled disturbances, which contain the previously introduced graphical game for homogeneous agents as a special case. Using our new formulation, we can solve both the output regulation and H-infinity output regulation problems. Our graphical game framework yields coupled Hamilton-Jacobi-Bellman equations, which are, in general, impossible to solve analytically. Therefore, we propose a new actor-critic algorithm to solve these coupled equations numerically in real time. Moreover, we find an explicit upper bound for the overall L2-gain of the output synchronization error with respect to disturbance. We demonstrate our developments by a simulation example.Funding Agencies|Vinnova Competence Center LINK-SIC; Wallenberg Artificial Intelligence, Autonomous Systems and Software Program (WASP); GACR [16-25493Y]; ONR [N00014-17-1-2239, N00014-18-1-2221]; NSF [ECCS-1839804]; China NSFC [61633007]; NRF BCA GBIC grant on Scalable and Smart Building Energy Management [NRF2015ENC-GBICRD001-057]; MoE Academic Research on Secure and Privacy Preserving Multi-Agent Cooperation [RG94/17-(S)-SU RONG (VP)]</p

H∞-output regulation of linear heterogeneous multiagent systems over switching graphs

In this paper, we analyze H∞-output regulation of linear heterogeneous multiagent systems. The agents are subject to modeled and unmodeled disturbances and communicate over a switching graph. We derive a sufficient condition that guarantees H∞ output regulation for the mentioned setup. This sufficient condition places requirements on both the single-agent systems and the switching graph. The requirement on the single-agent systems is an H∞-criterion that should be satisfied by a proper design of the controller. Meanwhile, the switching graph needs to be maximally connected. Moreover, we derive an upper bound for the overall (Formula presented.) -gain of the output synchronization error with respect to the unmodeled disturbances over a fixed communication graph. We illustrate our technical developments by a simulation example

Successful transplantation of human islets in recipients bearing a kidney graft

Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable. Methods. Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy. Results. C-peptide after transplantation was higher than 0.17 nmol/l in all 15 recipients, reflecting the absence of primary non-function. Insulin requirement was reduced by over 50 % in all but one patient, and insulin independence was achieved in 10 (66%) recipients, five of whom now have stable, prolonged insulin independence, well controlled fasting glycaemia, a substantial first-phase and normal second-phase response to glucose, normal insulin sensitivity (HOMA analyses) and HbA(1e) of under 6.2% (33, 26, 18, 13 and 12 months after transplantation respectively). Of importance for patient management, an assessment of fasting blood glucose and proinsulin values following overnight withdrawal of insulin administration one month after transplantation was a potent predictor of insulin independence, and could be used to decide patients who should have further islet preparations. Conclusion/interpretation. These findings support the use of islet transplantation as a cure for Type I diabetes in patients with severe complications