• An Adaptive Control Scheme for Interleukin-2 Therapy.

      Khailaie, Sahamoddin; Montaseri, Ghazal; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier (Cell Press), 2020-10-12)
      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.
    • Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents.

      Rizzuti, Ilaria Francesca; Mascheroni, Pietro; Arcucci, Silvia; Ben-Mériem, Zacchari; Prunet, Audrey; Barentin, Catherine; Rivière, Charlotte; Delanoë-Ayari, Hélène; Hatzikirou, Haralampos; Guillermet-Guibert, Julie; et al. (American Physical Society, 2020-09-18)
      While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.
    • Agent-Based Modeling of T Cell Receptor Cooperativity.

      Siokis, Anastasios; Robert, Philippe A; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MDPI, 2020-09-04)
      Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR-pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon.
    • B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2.

      Reimer, Dorothea; Meyer-Hermann, Michael; Rakhymzhan, Asylkhan; Steinmetz, Tobit; Tripal, Philipp; Thomas, Jana; Boettcher, Martin; Mougiakakos, Dimitrios; Schulz, Sebastian R; Urbanczyk, Sophia; et al. (Elsevier (CellPress), 2020-08-11)
      Plasma cells secreting affinity-matured antibodies develop in germinal centers (GCs), where B cells migrate persistently and directionally over defined periods of time. How modes of GC B cell migration influence plasma cell development remained unclear. Through genetic deletion of the F-actin bundling protein Swiprosin-1/EF-hand domain family member 2 (EFhd2) and by two-photon microscopy, we show that EFhd2 restrains B cell speed in GCs and hapten-specific plasma cell output. Modeling the GC reaction reveals that increasing GC B cell speed promotes plasma cell generation. Lack of EFhd2 also reduces contacts of GC B cells with follicular dendritic cells in vivo. Computational modeling uncovers that both GC output and antibody affinity depend quantitatively on contacts of GC B cells with follicular dendritic cells when B cells migrate more persistently. Collectively, our data explain how GC B cells integrate speed and persistence of cell migration with B cell receptor affinity.
    • Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.

      Bonifacius, Agnes; Goldmann, Oliver; Floess, Stefan; Holtfreter, Silva; Robert, Philippe A; Nordengrün, Maria; Kruse, Friederike; Lochner, Matthias; Falk, Christine S; Schmitz, Ingo; et al. (Frontiers, 2020-08-07)
      Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
    • Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization.

      Hoore, Masoud; Khailaie, Sahamoddin; Montaseri, Ghazal; Mitra, Tanmay; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Elsevier (CellPress), 2020-07-22)
      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.
    • Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV.

      Theobald, Sebastian J; Kreer, Christoph; Khailaie, Sahamoddin; Bonifacius, Agnes; Eiz-Vesper, Britta; Figueiredo, Constanca; Mach, Michael; Backovic, Marija; Ballmaier, Matthias; Koenig, Johannes; et al. (2020-07-15)
      Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.
    • Solving the nonlinear boundary layer flow equations with pressure gradient and radiation

      Xenos, Michalis A.; Petropoulou, Eugenia N.; Siokis, Anastasios; Mahabaleshwar, U. S.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MDPI, 2020-05-01)
      The physical problem under consideration is the boundary layer problem of an incompressible, laminar flow, taking place over a flat plate in the presence of a pressure gradient and radiation. For the mathematical formulation of the problem, the partial differential equations of continuity, energy, and momentum are taken into consideration with the boundary layer simplifications. Using the dimensionless Falkner–Skan transformation, a nonlinear, nonhomogeneous, coupled system of partial differential equations (PDEs) is obtained, which is solved via the homotopy analysis method. The obtained analytical solution describes radiation and pressure gradient effects on the boundary layer flow. These analytical results reveal that the adverse or favorable pressure gradient influences the dimensionless velocity and the dimensionless temperature of the boundary layer. An adverse pressure gradient causes significant changes on the dimensionless wall shear parameter and the dimensionless wall heat-transfer parameter. Thermal radiation influences the thermal boundary layer. The analytical results are in very good agreement with the corresponding numerical ones obtained using a modification of the Keller’s-box method.
    • Assortative mating by population of origin in a mechanistic model of admixture

      Goldberg, Amy; Rastogi, Ananya; Rosenberg, Noah A.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (Elsevier BV, 2020-04-07)
      Populations whose mating pairs have levels of similarity in phenotypes or genotypes that differ systematically from the level expected under random mating are described as experiencing assortative mating. Excess similarity in mating pairs is termed positive assortative mating, and excess dissimilarity is negative assortative mating. In humans, empirical studies suggest that mating pairs from various admixed populations-whose ancestry derives from two or more source populations-possess correlated ancestry components that indicate the occurrence of positive assortative mating on the basis of ancestry. Generalizing a two-sex mechanistic admixture model, we devise a model of one form of ancestry-assortative mating that occurs through preferential mating based on source population. Under the model, we study the moments of the admixture fraction distribution for different assumptions about mating preferences, including both positive and negative assortative mating by population. We demonstrate that whereas the mean admixture under assortative mating is equivalent to that of a corresponding randomly mating population, the variance of admixture depends on the level and direction of assortative mating. We consider two special cases of assortative mating by population: first, a single admixture event, and second, constant contributions to the admixed population over time In contrast to standard settings in which positive assortment increases variation within a population, certain assortative mating scenarios allow the variance of admixture to decrease relative to a corresponding randomly mating population: with the three populations we consider, the variance-increasing effect of positive assortative mating within a population might be overwhelmed by a variance-decreasing effect emerging from mating preferences involving other pairs of populations. The effect of assortative mating is smaller on the X chromosome than on the autosomes because inheritance of the X in males depends only on the mother's ancestry, not on the mating pair. Because the variance of admixture is informative about the timing of admixture and possibly about sex-biased admixture contributions, the effects of assortative mating are important to consider in inferring features of population history from distributions of admixture values. Our model provides a framework to quantitatively study assortative mating under flexible scenarios of admixture over time.
    • On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

      Alfonso, Juan Carlos L; Papaxenopoulou, Lito A; Mascheroni, Pietro; Meyer-Hermann, Michael; Hatzikirou, Haralampos; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier/Cell Press, 2020-02-11)
      Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests that radiotherapy success depends on the functional tumor vascularity extent and reveals that the pre-treatment tumor size is not a consistent determinant of treatment outcomes. The one-size-fits-all approach of conventionally fractionated radiotherapy is predicted to result in some overtreated patients. In addition, model simulations also suggest that an arbitrary increase in treatment duration does not necessarily result in better tumor control. This study highlights the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential of radiotherapy.
    • Graph-based description of tertiary lymphoid organs at single-cell level.

      Schaadt, Nadine S; Schönmeyer, Ralf; Forestier, Germain; Brieu, Nicolas; Braubach, Peter; Nekolla, Katharina; Meyer-Hermann, Michael; Feuerhake, Friedrich; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (PLOS, 2020-02-01)
      Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions.
    • Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.

      Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier, 2019-10-29)
      Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
    • Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy

      Enderling, Heiko; Alfonso, Juan Carlos López; Moros, Eduardo; Caudell, Jimmy J.; Harrison, Louis B.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier(Cell Press), 2019-08-01)
      In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).
    • Regulatory roles of IL-10-producing human follicular T cells.

      Cañete, Pablo F; Sweet, Rebecca A; Gonzalez-Figueroa, Paula; Papa, Ilenia; Ohkura, Naganari; Bolton, Holly; Roco, Jonathan A; Cuenca, Marta; Bassett, Katharine J; Sayin, Ismail; et al. (Rockefeller University Press, 2019-06-17)
      Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell-derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell-derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10-producing TF cells but not with total T reg cells, TFR, or IL-10-producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.
    • Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy.

      Alfonso, J C L; Berk, L; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (BioMed Central (BMC), 2019-05-30)
      Standard radiobiology theory of radiation response assumes a uniform innate radiosensitivity of tumors. However, experimental data show that there is significant intratumoral heterogeneity of radiosensitivity. Therefore, a model with heterogeneity was developed and tested using existing experimental data to show the potential effects from the presence of an intratumoral distribution of radiosensitivity on radiation therapy response over a protracted radiation therapy treatment course.
    • On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas.

      Mascheroni, Pietro; López Alfonso, Juan Carlos; Kalli, Maria; Stylianopoulos, Triantafyllos; Meyer-Hermann, Michael; Hatzikirou, Haralampos; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MPDI, 2019-05-24)
      Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes. View Full-Text
    • Postprandial Metabolic Effects of Fiber Mixes Revealed by in vivo Stable Isotope Labeling in Humans.

      Schlicker, Lisa; Boers, Hanny M; Dudek, Christian-Alexander; Zhao, Gang; Barua, Arnab; Trezzi, Jean-Pierre; Meyer-Hermann, Michael; Jacobs, Doris M; Hiller, Karsten; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MPDI, 2019-05-07)
      Food supplementation with a fiber mix of guar gum and chickpea flour represents a promising approach to reduce the risk of type 2 diabetes mellitus (T2DM) by attenuating postprandial glycemia. To investigate the effects on postprandial metabolic fluxes of glucose-derived metabolites in response to this fiber mix, a randomized, cross-over study was designed. Twelve healthy, male subjects consumed three different flatbreads either supplemented with 2% guar gum or 4% guar gum and 15% chickpea flour or without supplementation (control). The flatbreads were enriched with ~2% of 13C-labeled wheat flour. Blood was collected at 16 intervals over a period of 360 min after bread intake and plasma samples were analyzed by GC-MS based metabolite profiling combined with stable isotope-assisted metabolomics. Although metabolite levels of the downstream metabolites of glucose, specifically lactate and alanine, were not altered in response to the fiber mix, supplementation of 4% guar gum was shown to significantly delay and reduce the exogenous formation of these metabolites. Metabolic modeling and computation of appearance rates revealed that the effects induced by the fiber mix were strongest for glucose and attenuated downstream of glucose. Further investigations to explore the potential of fiber mix supplementation to counteract the development of metabolic diseases are warranted.
    • 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
    • Synchronous Germinal Center Onset Impacts the Efficiency of Antibody Responses.

      Arulraj, Theinmozhi; Binder, Sebastian C; Robert, Philippe A; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Frontiers, 2019-01-01)
      The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback mechanism termed antibody feedback. By imposing antibody feedback, germinal centers can interact and regulate the output of other germinal centers. Using an agent-based model of the germinal center reaction, we studied the impact of antibody feedback on kinetics and efficiency of a germinal center. Our simulations predict that high feedback of antibodies from germinal centers reduces the production of plasma cells and subsequently the efficiency of the germinal center reaction by promoting earlier termination. Affinity maturation is only weakly improved by increased antibody feedback and ultimately interrupted because of premature termination of the reaction. The model predicts that the asynchronous onset and changes in number of germinal centers could alter the efficiency of antibody response due to changes in feedback by soluble antibodies. Consequently, late initialized germinal centers have a compromised output due to higher antibody feedback from the germinal centers formed earlier. The results demonstrate potential effects of germinal center intercommunication and highlight the importance of understanding germinal center interactions for optimizing the antibody response, in particular, in the elderly and in the context of vaccination.
    • 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.