• Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm?

      Marschall, Andrea L J; Dübel, Stefan; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016)
      Challenges posed by complex diseases such as cancer, chronic viral infections, neurodegenerative disorders and many others have forced researchers to think beyond classic small molecule drugs, exploring new therapeutic strategies such as therapy with RNAi, CRISPR/Cas9 or antibody therapies as single or as combination therapies with existing drugs. While classic antibody therapies based on parenteral application can only reach extracellular targets, intracellular application of antibodies could provide specific advantages but is so far little recognized in translational research. Intrabodies allow high specificity and targeting of splice variants or post translational modifications. At the same time off target effects can be minimized by thorough biochemical characterization. Knockdown of cellular proteins by intrabodies has been reported for a significant number of disease-relevant targets, including ErbB-2, EGFR, VEGFR-2, Metalloproteinase MMP2 and MMP9, β-amyloid protein, α-synuclein, HIV gp120, HCV core and many others. This review outlines the recent advances in ER intrabody technology and their potential use in therapy.
    • The biology and mathematical modelling of glioma invasion: a review.

      Alfonso, J C L; Talkenberger, K; Seifert, M; Klink, B; Hawkins-Daarud, A; Swanson, K R; Hatzikirou, H; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-11)
      Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion.
    • Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions.

      Hatzikirou, H; Alfonso, J C L; Mühle, S; Stern, C; Weiss, S; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38124 Braunschweig, Germany. (2015-11-06)
      Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
    • Cellular automaton models for time-correlated random walks: derivation and analysis.

      Nava-Sedeño, J M; Hatzikirou, H; Klages, R; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-12-05)
      Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is "data-driven". Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous diffusion for the dynamics of interacting cell populations, like confluent cell monolayers and cell clustering.
    • Commentary: "Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?".

      Robert, Philippe A; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2015)
    • Computational Study to Determine When to Initiate and Alternate Therapy in HIV Infection.

      Haering, Matthias; Hördt, Andreas; Müller, A; Hernandez-Vargas, Esteban Abelardo (2014)
      HIV is a widespread viral infection without cure. Drug treatment has transformed HIV disease into a treatable long-term infection. However, the appearance of mutations within the viral genome reduces the susceptibility of HIV to drugs. Therefore, a key goal is to extend the time until patients exhibit resistance to all existing drugs. Current HIV treatment guidelines seem poorly supported as practitioners have not achieved a consensus on the optimal time to initiate and to switch antiretroviral treatments. We contribute to this discussion with predictions derived from a mathematical model of HIV dynamics. Our results indicate that early therapy initiation (within 2 years postinfection) is critical to delay AIDS progression. For patients who have not received any therapy during the first 3 years postinfection, switch in response to virological failure may outperform proactive switching strategies. In case that proactive switching is opted, the switching time between therapies should not be larger than 100 days. Further clinical trials are needed to either confirm or falsify these predictions.
    • Computer Simulation of Multi-Color Brainbow Staining and Clonal Evolution of B Cells in Germinal Centers.

      Meyer-Hermann, Michael; Binder, Sebastian C; Mesin, Luka; Victora, Gabriel D; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (2018-01-01)
      Clonal evolution of B cells in germinal centers (GCs) is central to affinity maturation of antibodies in response to pathogens. Permanent or tamoxifen-induced multi-color recombination of B cells based on the brainbow allele allows monitoring the degree of color dominance in the course of the GC reaction. Here, we use computer simulations of GC reactions in order to replicate the evolution of color dominance
    • Deceleration of fusion-fission cycles improves mitochondrial quality control during aging.

      Figge, Marc Thilo; Reichert, Andreas S; Meyer-Hermann, Michael; Osiewacz, Heinz D; Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany. (2012-06)
      Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span.
    • Discrete-time neural observer for HIV infection dynamic

      Hernandez-Vargas, Esteban A.; Alanis, Alma Y.; Sanchez, Edgar N.; Systems Immunology, Helmholtz-Zentrum für Infecktionsforschung, Inhoffenstraße 7, D-38124, Braunschweig, Germany (Institute of Electrical and Electronics Engineers, 2013-04-19)
    • The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response.

      He, Jin-Shu; Meyer-Hermann, Michael; Xiangying, Deng; Zuan, Lim Yok; Jones, Leigh Ann; Ramakrishna, Lakshmi; de Vries, Victor C; Dolpady, Jayashree; Aina, Hoi; Joseph, Sabrina; et al. (2013-11-18)
      The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE(+) cells in memory responses is particularly unclear. IgE(+) B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE(+) GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE(+) GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE(+) GC cells, whereas sequential switching gives rise to IgE(+) PCs. We propose a comprehensive model for the generation and memory of IgE responses.
    • Diversity of coupled oscillators can enhance their synchronization.

      Montaseri, Ghazal; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016-10)
      The heterogeneity of coupled oscillators is important for the degree of their synchronization. According to the classical Kuramoto model, larger heterogeneity reduces synchronization. Here, we show that in a model for coupled pancreatic β-cells, higher diversity of the cells induces higher synchrony. We find that any system of coupled oscillators that oscillates on two time scales and in which heterogeneity causes a transition from chaotic to damped oscillations on the fast time scale exhibits this property. Thus, synchronization of a subset of oscillating systems can be enhanced by increasing the heterogeneity of the system constituents.
    • Ebola virus infection modeling and identifiability problems.

      Nguyen, Van Kinh; Binder, Sebastian C; Boianelli, Alessandro; Müller, A; Hernandez-Vargas, Esteban Abelardo; Helmholtz Center for Infection Research (2015)
      The recent outbreaks of Ebola virus (EBOV) infections have underlined the impact of the virus as a major threat for human health. Due to the high biosafety classification of EBOV (level 4), basic research is very limited. Therefore, the development of new avenues of thinking to advance quantitative comprehension of the virus and its interaction with the host cells is urgently needed to tackle this lethal disease. Mathematical modeling of the EBOV dynamics can be instrumental to interpret Ebola infection kinetics on quantitative grounds. To the best of our knowledge, a mathematical modeling approach to unravel the interaction between EBOV and the host cells is still missing. In this paper, a mathematical model based on differential equations is used to represent the basic interactions between EBOV and wild-type Vero cells in vitro. Parameter sets that represent infectivity of pathogens are estimated for EBOV infection and compared with influenza virus infection kinetics. The average infecting time of wild-type Vero cells by EBOV is slower than in influenza infection. Simulation results suggest that the slow infecting time of EBOV could be compensated by its efficient replication. This study reveals several identifiability problems and what kind of experiments are necessary to advance the quantification of EBOV infection. A first mathematical approach of EBOV dynamics and the estimation of standard parameters in viral infections kinetics is the key contribution of this work, paving the way for future modeling works on EBOV infection.
    • Estimation of the cancer risk induced by therapies targeting stem cell replication and treatment recommendations.

      Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2018-08-06)
      Rejuvenation of stem cell activity might increase life expectancy by prolonging functionality of organs. Higher stem cell replication rates also bear the risk of cancer. The extent of this risk is not known. While it is difficult to evaluate this cancer risk in experiments, it can be estimated using a mathematical model for tissue homeostasis by stem cell replication and associated cancer risk. The model recapitulates the observation that treatments targeting stem cell replication can induce a substantial delay of organ failure. The model predicts that the cancer risk is minor under particular conditions. It depends on the assumed implications for cell damage repair during treatment. The benefit of rejuvenation therapy and its impact on cancer risk depend on the biological age at the time of treatment and on the overall cell turnover rate of the organs. Different organs have to be considered separately in the planning of systemic treatments. In recent years, the transfer of blood from young to old individuals was shown to bear the potential of rejuvenation of stem cell activity. In this context, the model predicts that the treatment schedule is critical for success and that schedules successful in animal experiments are not transferable to humans. Guidelines for successful protocols are proposed. The model presented here may be used as a guidance for the development of stem cell rejuvenation treatment protocols and the identification of critical parameters for cancer risk.
    • Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.

      Jain, Harsh Vardhan; Richardson, Alan; Müller, A; Byrne, Helen M (2014)
      Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.
    • F-Actin-Driven CD28-CD80 Localization in the Immune Synapse.

      Siokis, Anastasios; Robert, Philippe A; Demetriou, Philippos; Dustin, Michael L; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier, 2018-07-31)
      During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.
    • Functional modules of sigma factor regulons guarantee adaptability and evolvability.

      Binder, Sebastian C; Eckweiler, Denitsa; Schulz, Sebastian; Bielecka, Agata; Nicolai, Tanja; Franke, Raimo; Häussler, Susanne; Müller, A; Helmholtz Centre for infection research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany. (2016)
      The focus of modern molecular biology turns from assigning functions to individual genes towards understanding the expression and regulation of complex sets of molecules. Here, we provide evidence that alternative sigma factor regulons in the pathogen Pseudomonas aeruginosa largely represent insulated functional modules which provide a critical level of biological organization involved in general adaptation and survival processes. Analysis of the operational state of the sigma factor network revealed that transcription factors functionally couple the sigma factor regulons and significantly modulate the transcription levels in the face of challenging environments. The threshold quality of newly evolved transcription factors was reached faster and more robustly in in silico testing when the structural organization of sigma factor networks was taken into account. These results indicate that the modular structures of alternative sigma factor regulons provide P. aeruginosa with a robust framework to function adequately in its environment and at the same time facilitate evolutionary change. Our data support the view that widespread modularity guarantees robustness of biological networks and is a key driver of evolvability.
    • IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.

      Prajeeth, Chittappen K; Dittrich-Breiholz, Oliver; Talbot, Steven R; Robert, Philippe A; Huehn, Jochen; Stangel, Martin; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (2018-01-01)
      Autoreactive T cells that infiltrate into the central nervous system (CNS) are believed to have a significant role in mediating the pathology of neuroinflammatory diseases like multiple sclerosis. Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes. Our previous work demonstrated that effectors secreted by Th1 and Th17 cells have different capacities to influence the phenotype and function of glial cells. We have shown that Th1-derived effectors altered the phenotype and function of both microglia and astrocytes whereas Th17-derived effectors induced direct effects only on astrocytes but not on microglia. Here we investigated if effector molecules associated with IFN-γ producing Th1 cells induced different gene expression profiles in microglia and astrocytes. We performed a microarray analysis of RNA isolated from microglia and astrocytes treated with medium and Th-derived culture supernatants and compared the gene expression data. By using the criteria of 2-fold change and a false discovery rate of 0.01 (corrected
    • Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis.

      Schaadt, Nadine S; Alfonso, Juan Carlos López; Schönmeyer, Ralf; Grote, Anne; Forestier, Germain; Wemmert, Cédric; Krönke, Nicole; Stoeckelhuber, Mechthild; Kreipe, Hans H; Hatzikirou, Haralampos; et al. (Springer, 2017-07-01)
      Purpose: To improve microscopic evaluation of immune cells relevant in breast cancer oncoimmunology, we aim at distinguishing normal infiltration patterns from lymphocytic lobulitis by advanced image analysis. We consider potential immune cell variations due to the menstrual cycle and oral contraceptives in non-neoplastic mammary gland tissue. METHODS: Lymphocyte and macrophage distributions were analyzed in the anatomical context of the resting mammary gland in immunohistochemically stained digital whole slide images obtained from 53 reduction mammoplasty specimens. Our image analysis workflow included automated regions of interest detection, immune cell recognition, and co-registration of regions of interest. RESULTS: In normal lobular epithelium, seven CD8[Formula: see text] lymphocytes per 100 epithelial cells were present on average and about 70% of this T-lymphocyte population was lined up along the basal cell layer in close proximity to the epithelium. The density of CD8[Formula: see text] T-cell was 1.6 fold higher in the luteal than in the follicular phase in spontaneous menstrual cycles and 1.4 fold increased under the influence of oral contraceptives, and not co-localized with epithelial proliferation. CD4[Formula: see text] T-cells were infrequent. Abundant CD163[Formula: see text] macrophages were widely spread, including the interstitial compartment, with minor variation during the menstrual cycle. CONCLUSIONS: Spatial patterns of different immune cell subtypes determine the range of normal, as opposed to inflammatory conditions of the breast tissue microenvironment. Advanced image analysis enables quantification of hormonal effects, refines lymphocytic lobulitis, and shows potential for comprehensive biopsy evaluation in oncoimmunolog
    • Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery.

      López Alfonso, Juan Carlos; Poleszczuk, Jan; Walker, Rachel; Kim, Sungjune; Pilon-Thomas, Shari; Conejo-Garcia, Jose J; Soliman, Hatem; Czerniecki, Brian; Harrison, Louis B; Enderling, Heiko; et al. (American Society of Clinical Oncology, 2019-01-01)
      PURPOSE Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and diseasefree survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced antitumor immunity contributing to outcomes. MATERIALS AND METHODS We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus, esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR, RS, and radiotherapy alone in a mathematical model of tumor-immune interactions. RESULTS RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046) and improved DFS for cancers with higher survival (breast: HR = 0.64; P , .001). For rectal cancer, with intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04). Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter combinations. This could create an immune memory that may explain increased DFS after RS for certain cancers. CONCLUSION Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune activation of RS versus SR in controlled clinical studies
    • Immunology. Antigen feast or famine.

      Dustin, Michael L; Müller, A; Skirball Institute for Molecular Medicine, New York University School of Medicine, New York, NY 10016, USA. michael.dustin@med.nyu.edu (2012-01-27)