Ein theoretischer Rahmen für die Analyse der Immuntoleranzinduktion in Thymus und Peripherie

A beneficial immune response must hold a balance between activation against internal/external disturbances and suppression to avoid damage to healthy tissues. Among numerous factors that control the immune balance, conventional T cells (Tconv), natural regulatory T cells (nTreg) and their interplay are the key factors. Tconvs and nTregs are selected from precursor cells which express randomly generated T cell receptors (TCR). Upon activation by antigen presenting cells (APC), Tconvs boost the immune response via the production of pro-inflammatory cytokines, while nTregs suppress Tconvs in a cell-contact or cytokine-dependent manner. In this study, induction and maintenance of the immune balance in different stages are analyzed by mathematical models. An agent-based modeling approach, which is suitable to consider heterogeneity among cells, is employed to identify the critical factors that affect the outcome of thymic selection. After thymic selection, quality and interplay of selected nTregs and Tconvs determines whether a major immune response can be initiated in periphery. Proliferation of T cells in addition to suppression of Tconvs by nTregs result in a nonlinear interplay between these two repertoires that demands a mathematical analysis. By constructing a set of hierarchical models based on ordinary differential equations (ODE), interplay of activated Tconvs and nTregs is studied. In addition to a direct pathway, nTregs indirectly suppress Tconvs via down-regulation of stimulatory capacity of APCs. By using a series of ODE-based mathematical models that represent the experimental protocols, Treg-associated regulation of immune stimulation is quantified. By targeting different interdependent immunological stages, this theoretical study presents a multi-stage view on the induction and maintenance of immune balance, which cannot be gained solely by experimental studies.Eine erfolgreiche Immunantwort muss die Balance zwischen Abwehr interner und externer Beedrohungen und ihrer Unterdrückung zur Vermeidung von Schäden an gesundem Gewebe halten. Unter den zahlreichen Faktoren, welche die Balance des Immunsystems kontrollieren, nehmen konventionelle T-Zellen (Tconv), natürliche regulatorische T-Zellen (nTreg) und deren Wechselwirkungen eine Schlüsselposition ein. Tconvs und nTregs werden aus Vorläuferzellen selektiert, die zufällig generierte T-Zell Rezeptoren (TCR) exprimieren. Bei Aktivierung durch antigenpräsentierende Zellen (APC) verstärken Tconvs die Immunreaktion durch die Produktion proinflammatorischer Zytokine, während Tconvs von nTregs mittels Zellkontakt oder Zytokinen gehemmt werde. In dieser Studie werden Herstellung des Immungleichgewichts und dessen Aufrechterhaltung in unterschiedlichen Stadien durch mathematische Modelle untersucht. Es wird ein agentbasierter Modellierungsansatz verwendet, der eine Berücksichtigung der Heterogenität der Zellen ermöglicht, um Faktoren zu identifizieren, die kritisch für das Ergebnis der Selektion im Thymus sind. Nach der Selektion im Thymus entscheiden Qualität und Zusammenspiel der selektierten nTregs und Tconvs darüber, ob eine Immunantwort in der Peripherie ausgelöst wird. Proliferation von T-Zellen in Verbindung mit der Unterdrückung von Tconvs durch nTregs führt zu nichtlinearen Wechselwirkungen zwischen den beiden Repertoires, die eine mathematische Analyse nötig machen. Dieses Wechselspiel zwischen Tconvs und nTregs wird anhand eines Satzes hierarchischer Modelle auf der Basis von gewöhnlichen Differentialgleichungen (ODE) untersucht. Neben dem direkten Weg unterdrücken nTregs Tconvs durch das Herunterregulieren der stimulatorischen Kapazität von APCs. Mit Hilfe einer Reihe von ODE basierten mathematischen Modellen, welche die jeweiligen experimentellen Verfahren repräsentieren, wird die durch Tregs vermittelte Regulation von Immunstimuli quantifiziert. Diese Studie ermöglicht durch die Untersuchung verschiedener voneinander abhängiger immunologischer Stadien einen Blick auf verschiedene Stadien der Herstellung und Aufrechterhaltung der Balance des Immunsystems, der nicht allein durch experimentelle Studien möglich ist

Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation

The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates

An Adaptive Control Scheme for Interleukin-2 Therapy.

Regulatory T cells (Treg) are suppressor cells that control self-reactive and excessive effector conventional T helper cell (Tconv) responses. Breakdown of the balance between Tregs and Tconvs is a hallmark of autoimmune and inflammatory diseases. Interleukin-2 (IL-2) is a growth factor for both populations and subtle leverage to restore the healthy immune balance in IL-2 therapy. By using a mechanistic mathematical model, we introduced an adaptive control strategy to design the minimal therapeutic IL-2 dosage required to increase and stabilize Treg population and restrict inflammatory response. This adaptive protocol allows for dose adjustments based on the feedback of the immune kinetics of the patient. Our simulation results showed that a minimal Treg population was required to restrict the transient side effect of IL-2 injections on the effector Tconv response. In silico results suggested that a combination of IL-2 and adoptive Treg transfer therapies can limit this side effect

Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization.

Deposition of amyloid-β (Aβ) fibers in the extracellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). Although many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and intercellular levels in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale despite the presence of mechanisms dedicated to Aβ clearance is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in the sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long timescale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of sAβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of the sleep-wake cycle, thereby indicating the importance of good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate

Improving Public Health Policy by Comparing the Public Response during the Start of COVID-19 and Monkeypox on Twitter in Germany: A Mixed Methods Study

Little is known about monkeypox public concerns since its widespread emergence in many countries. Tweets in Germany were examined in the first three months of COVID-19 and monkeypox to examine concerns and issues raised by the public. Understanding views and positions of the public could help to shape future public health campaigns. Few qualitative studies reviewed large datasets, and the results provide the first instance of the public thinking comparing COVID-19 and monkeypox. We retrieved 15,936 tweets from Germany using query words related to both epidemics in the first three months of each one. A sequential explanatory mixed methods research joined a machine learning approach with thematic analysis using a novel rapid tweet analysis protocol. In COVID-19 tweets, there was the selfing construct or feeling part of the emerging narrative of the spread and response. In contrast, during monkeypox, the public considered othering after the fatigue of the COVID-19 response, or an impersonal feeling toward the disease. During monkeypox, coherence and reconceptualization of new and competing information produced a customer rather than a consumer/producer model. Public healthcare policy should reconsider a one-size-fits-all model during information campaigns and produce a strategic approach embedded within a customer model to educate the public about preventative measures and updates. A multidisciplinary approach could prevent and minimize mis/disinformation

Development of the reproduction number from coronavirus SARS-CoV-2 case data in Germany and implications for political measures.

Background: SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression. Methods: We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute. Results: The time-varying reproduction number (Rt) in Germany decreased to <1 in early April 2020, 2-3 weeks after the implementation of NPIs. Partial release of NPIs both nationally and on federal state level correlated with moderate increases in Rt until August 2020. Implications of state-specific Rt on other states and on national level are characterized. Retrospective evaluation of the model shows excellent agreement with the data and usage of inpatient facilities well within the healthcare limit. While short-term predictions may work for a few weeks, long-term projections are complicated by unpredictable structural changes. Conclusions: The estimated fraction of immunized population by August 2020 warns of a renewed outbreak upon release of measures. A low detection rate prolongs the delay reaching a low case incidence number upon release, showing the importance of an effective testing-quarantine strategy. We show that real-time monitoring of transmission dynamics is important to evaluate the extent of the outbreak, short-term projections for the burden on the healthcare system, and their response to policy changes

Das gemeinsame Interesse von Gesundheit und Wirtschaft: Eine Szenarienrechnung zur Eindämmung der Corona- Pandemie

In der öffentlichen Diskussion über den weiteren Kurs in der Bekämpfung der Corona-Pandemie werden die Interessen des Gesundheitsschutzes oft als Gegensatz zu den Interessen der Wirtschaft dargestellt. Das wird der Problemlage nicht gerecht. Wenn vorzeitige Lockerungen der Beschränkungen zu einer zweiten Infektionswelle führten, würde das Vertrauen von Konsumenten und Investoren beschädigt. Viele Unternehmen müssten unabhängig von staatlichen Vorgaben ihre Geschäftstätigkeit wieder herunterfahren, die Kosten wären erheblich. Umgekehrt führt eine Verlängerung der Beschränkungen jedoch auch zu gesundheitlichen Belastungen in anderen Bereichen. Das Ziel sollte deshalb darin bestehen, die weitere Bekämpfung der Pandemie tragfähig zu gestalten und ökonomische mit gesundheitlichen Zielen bestmöglich in Einklang zu bringen

The Common Interests of Health Protection and the Economy: Evidence from Scenario Calculations of Covid-19 Containment Policies

We develop a novel approach integrating epidemiological and economic models that allows databased simulations during a pandemic. We examine the economically optimal opening strategy that can be reconciled with the containment of a pandemic. The empirical evidence is based on data from Germany during the Sars-Cov-2 pandemic. Our empirical findings reject the view that there is necessarily a conflict between health protection and economic interests and suggest a non-linear U-shape relationship: it is in the interest of public health and the economy to balance non-pharmaceutical interventions in a manner that further reduces the incidence of infections. Our simulations suggest that a prudent strategy that leads to a reproduction number of around 0.75 is economically optimal. Too restrictive policies cause massive economic costs. Conversely, policies that are too loose lead to higher deaths tolls and higher economic costs in the long run. We suggest this finding as a guide for policymakers in balancing interests of public health and the economy during a pandemic