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  • 1.
    Cheng, Xiaoxiao
    et al.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Veverka, Vaclav
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom, the Institute of Organic Chemistry and Biochemistry, Flemingovo Namesti 2, 166 10 Prague 6, Czech Republic.
    Radhakrishnan, Anand
    Department of Biochemistry and Molecular Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
    Waters, Lorna C.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Muskett, Frederick W.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Morgan, Sara H.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Huo, Jiandong
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Yu, Chao
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Evans, Edward J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Leslie, Alasdair J.
    Radcliffe Department of Medicine [Oxford].
    Griffiths, Meryn
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Stubberfield, Colin
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Griffin, Robert
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Henry, Alistair J.
    UCB Pharma, Slough SL1 4EN, United Kingdom.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Ladbury, John E.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Ikemizu, Shinji
    Division of Structural Biology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862 0973, Japan.
    Carr, Mark D.
    Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom.
    Davis, Simon J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Structure and Interactions of the Human Programmed Cell Death 1 Receptor2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 17, p. 11771-11785Article in journal (Refereed)
    Abstract [en]

    PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C '' strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1.ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

  • 2.
    Elgbratt, Kristina
    et al.
    Univ Örebro, Sch Hlth & Med Sci, Orebro, Sweden.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Hultgren-Hornquist, Elisabeth
    Univ Örebro, Sch Hlth & Med Sci, Orebro, Sweden.
    A Quantitative Study of the Mechanisms behind Thymic Atrophy in G alpha i2-Deficient Mice during Colitis Development2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36726-Article in journal (Refereed)
    Abstract [en]

    Mice deficient for the G protein subunit G alpha i2 spontaneously develop colitis, a chronic inflammatory disease associated with dysregulated T cell responses. We and others have previously demonstrated a thymic involution in these mice and an aberrant thymocyte dynamics. The G alpha i2(-/-) mice have a dramatically reduced fraction of double positive thymocytes and an increased fraction of single positive (SP) thymocytes. In this study, we quantify a number of critical parameters in order to narrow down the underlying mechanisms that cause the dynamical changes of the thymocyte development in the G alpha i2(-/-) mice. Our data suggest that the increased fraction of SP thymocytes results only from a decreased number of DP thymocytes, since the number of SP thymocytes in the Gai2(-/-) mice is comparable to the control littermates. By measuring the frequency of T cell receptor excision circles (TRECs) in the thymocytes, we demonstrate that the number of cell divisions the G alpha i2(-/-) SP thymocytes undergo is comparable to SP thymocytes from control littermates. In addition, our data show that the mature SP CD4(+) and CD8(+) thymocytes divide to the same extent before they egress from the thymus. By estimating the number of peripheral TREC+ T lymphocytes and their death rate, we could calculate the daily egression of thymocytes. G alpha i2(-/-) mice with no/mild and moderate colitis were found to have a slower export rate in comparison to the control littermates. The quantitative measurements in this study suggest a number of dynamical changes in the thymocyte development during the progression of colitis.

  • 3.
    Fagerlind, Magnus G.
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Webb, Jeremy S.
    Univ Southampton, Sch Biol Sci, Southampton SO16 7PX, Hants, England .
    Barraud, Nicolas
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia .
    McDougald, Diane
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Adv Environm Biotechnol Ctr, Singapore 639798, Singapore .
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Harlen, Mikael
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Kjelleberg, Staffan
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore 639798, Singapore .
    Rice, Scott A.
    Univ New S Wales, Ctr Marine Bioinnovat, Sydney, NSW 2052, Australia / Univ New S Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia / Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore 639798, Singapore .
    Dynamic modelling of cell death during biofilm development2012In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 295, p. 23-36Article in journal (Refereed)
    Abstract [en]

    Biofilms are currently recognised as the predominant bacterial life-style and it has been suggested that biofilm development is influenced by a number of different processes such as adhesion, detachment, mass transport, quorum sensing, cell death and active dispersal. One of the least understood processes and its effects on biofilm development is cell death. However, experimental studies suggest that bacterial death is an important process during biofilm development and many studies show a relationship between cell death and dispersal in microbial biofilms. We present a model of the process of cell death during biofilm development, with a particular focus on the spatial localisation of cell death or cell damage. Three rules governing cell death or cell damage were evaluated which compared the effects of starvation, damage accumulation, and viability during biofilm development and were also used to design laboratory based experiments to test the model. Results from model simulations show that actively growing biofilms develop steep nutrient gradients within the interior of the biofilm that affect neighbouring microcolonies resulting in cell death and detachment. Two of the rules indicated that high substrate concentrations lead to accelerated cell death, in contrast to the third rule, based on the accumulation of damage, which predicted earlier cell death for biofilms grown with low substrate concentrations. Comparison of the modelling results with experimental results suggests that cell death is favoured under low nutrient conditions and that the accumulation of damage may be the main cause of cell death during biofilm development. (C) 2011 Elsevier Ltd. All rights reserved.

  • 4.
    Holmén, Jonathan
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Jansson, Andreas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Larsson, Dennis
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    A Kinetic Overview of the Receptors Involved in 1,25-Dihydroxyvitamin D3 and 24,25-Dihydroxyvitamin D3 Signaling: A Systems Biology Approach2009In: Critical Reviews in Eukaryotic Gene Expression, ISSN 1045-4403, E-ISSN 2162-6502, Vol. 19, no 3, p. 181-196Article, review/survey (Refereed)
    Abstract [en]

    The vitamin D endocrine system modulates an arsenal of important biological functions in more than 30 different tissues in short- and long-term perspectives. Two membrane receptors and one nuclear receptor are suggested to be involved in the vitamin D signaling system, but the function and physiological relevance of the receptors are debated. The complexity of the vitamin D endocrine system makes it necessary to combine experimental data with in silico simulations to get a holistic view of vitamin D-dependent regulation of tissue and cell physiology. This review focus on binding characteristics for the three putative vitamin D receptors and proposes a future systems biology approach including mathematical modeling that will be helpful together with experimental methods in depicting antitumoral and other biological effects promoted by the vitamin D endocrine system.

  • 5.
    James, John R.
    et al.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    McColl, James
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Oliveira, Marta I.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Dunne, Paul D.
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Huang, Elizabeth
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sleep, David L.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Goncalves, Carine M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Morgan, Sara H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Felce, James H.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Mahen, Robert
    Hutchison MRC Res Ctr, Med Res Council Canc Cell Unit, Cambridge CB2 0XZ, England.
    Fernandes, Ricardo A.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    Carmo, Alexandre M.
    Univ Porto, Inst Biol Mol & Celular, Grp Cell Activat & Gene Express, P-4150180 Oporto, Portugal / Univ Porto, Inst Ciencias Biomed Abel Salazar, P-4099003 Oporto, Portugal .
    Klenerman, David
    Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England .
    Davis, Simon J.
    Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, Weatherall Inst Mol Med, Med Res Council Human Immunol Unit, Oxford OX3 9DS, England .
    The T Cell Receptor Triggering Apparatus Is Composed of Monovalent or Monomeric Proteins2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, no 37, p. 31993-32001Article in journal (Refereed)
    Abstract [en]

    Understanding the component stoichiometry of the T cell antigen receptor (TCR) triggering apparatus is essential for building realistic models of signal initiation. Recent studies suggesting that the TCR and other signaling-associated proteins are preclustered on resting T cells relied on measurements of the behavior of membrane proteins at interfaces with functionalized glass surfaces. Using fluorescence recovery after photo-bleaching, we show that, compared with the apical surface, the mobility of TCRs is significantly reduced at Jurkat T cell/glass interfaces, in a signaling-sensitive manner. Using two biophysical approaches that mitigate these effects, bioluminescence resonance energy transfer and two-color coincidence detection microscopy, we show that, within the uncertainty of the methods, the membrane components of the TCR triggering apparatus, i.e. the TCR complex, MHC molecules, CD4/Lck and CD45, are exclusively monovalent or monomeric in human T cell lines, implying that TCR triggering depends only on the kinetics of TCR/pMHC interactions. These analyses also showed that constraining proteins to two dimensions at the cell surface greatly enhances random interactions versus those between the membrane and the cytoplasm. Simulations of TCR-pMHC complex formation based on these findings suggest how unclustered TCR triggering-associated proteins might nevertheless be capable of generating complex signaling outputs via the differential recruitment of cytosolic effectors to the cell membrane.

  • 6.
    Jansson, Andreas
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    A Mathematical Framework for Analyzing T Cell Receptor Scanning of Peptides2010In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 99, no 9, p. 2717-2725Article in journal (Refereed)
    Abstract [en]

    T cells continuously search for antigenic peptides presented on major histocompatibility complexes expressed on nearly all nucleated cells. Because only a few antigenic peptides are presented in a sea of thousands of self-peptides, the T cells have a critical task in discriminating between self- and nonself-peptides. This search process for antigens must be performed with sufficient speed in order to induce a fast response against invading pathogens. This study presents a mathematical framework for analyzing the scanning process of peptides. The framework includes analytic expressions for calculating the sampling rate as well as continuous-systems- and stochastic-agent-based models. The results show that the scanning of self-peptides is a very fast process due to fast off-rates. The simulations also predict the existence of an optimal sampling rate for a certain range of on-rates based on the recently proposed confinement time model. Calculations reveal that most of the self-peptides located within a microdomain are scanned within just a few seconds, and that the T cell receptors have kinetics for self-peptides, facilitating fast scanning. The derived mathematical expressions within this study provide conceptual calculations for further investigations of how the T cell discriminates between self- and nonself-peptides.

  • 7.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Kinetic proofreading and the search for nonself-peptides2011In: Self/Nonself, ISSN 1938-2049, Vol. 2, no 1, p. 1-3Article in journal (Refereed)
    Abstract [en]

    The T cells scan the surface of antigen-presenting cells with their T cell receptors (TCR) in order to find and respond to specific peptide-major histocompatibility complexes (pMHC). Since mainly self-peptides are expressed on antigen-presenting cells, the T cells must utilize sensible mechanisms in order to quickly discriminate between self and nonself-peptides. A range of different models have been proposed to account for this process. Due to the experimental inconsistency of how T cells respond to altered peptides it has been difficult to validate the competing models. Recent models, based on the kinetic proofreading model, propose that a short life-time of the TCR/pMHC complexes may be compensated by fast rebinding of the individual molecules. Hence, both the on- and off-rate involved in the interaction between pMHCs and TCRs will determine the fate of the T cell discrimination. I here briefly review some of the proposed models on T cell discrimination and scanning, and discuss the significance of determining self-peptide kinetics to validate the different models.

  • 8.
    Jansson, Andreas
    University of Skövde, School of Life Sciences.
    Modelling T helper cell activation and development2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    T helper (Th) cell activation and development is one of the most critical events in regulating the adaptive immune response. Understanding its regulation could be of great therapeutical value as many severe diseases are associated with failure in controlling T cell activation and development. However, the regulation of T cell activation appears to be one of the most complex set of cellular and molecular interactions known in the immune system. There is therefore an urgent need for tools to unravel this complexity, and to make use of the quantitative experimental data. To address this issue, mathematical and computational models, based on rigorous biophysical and kinetic data, were developed to study the specific role of some of the major costimulatory molecules involved in Th cell activation, and others developed to investigate proposed theories about mechanisms involved in Th cell differentiation. The simulations of costimulation reveal new implications for the function of the costimulatory molecules CD28 and CTLA-4, and their ligands B7-1 and B7-2, and show how binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects, all profoundly influence complex formation at the immunological synapse. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be, as has been previously proposed, due to the different binding properties of B7-1 and B7-2. Simulations of Th cell development reveal that both instructive and selective processes are likely to be involved in Th cell differentiation. In addition, further simulations indicate that Th2 cells are more likely to become dominant by inhibiting Th1 cells (negative selection), rather than selecting their own growth (positive selection). This thesis also includes an experimental work in which the immunomodulatory role of the bacterial signalling molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) was analysed. This study strongly suggests that OdDHL suppresses Th cell activation and development, and that it is likely targeting the intracellular signalling events involved in the early stages of Th cell activation.

  • 9.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Barnes, Eleanor
    Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
    Klenerman, Paul
    Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Sørensen, Poul
    LEO Pharma, Ballerup, Denmark.
    Davis, Simon J.
    Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom / Medical Research Council Human Immunology Unit and Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    A Theoretical Framework for Quantitative Analysis of the Molecular Basis of Costimulation2005In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 175, no 3, p. 1575-1585Article in journal (Refereed)
    Abstract [en]

    We present a theoretical framework for simulating the synaptic accumulation of the costimulatory molecules CD28, CTLA-4, B7-1, and B7-2, based on a system of mean-field, ordinary differential equations, and rigorous biophysical and expression data. The simulations show that binding affinity, stoichiometric properties, expression levels, and, in particular, competition effects all profoundly influence complex formation at cellular interfaces. B7-2 engages 33-fold more CD28 than CTLA-4 at the synapse in contrast to B7-1, which ligates ~7-fold more CTLA-4 than CD28. Although B7-1 completely dominates interactions with CTLA-4, forming linear arrays of 7-18 receptor-ligand pairs, CTLA-4 is fully engaged by B7-2 when B7-1 is absent. Additional simulations reveal the sensitivity of CD28 interactions to modeled transport processes. The results support the concept that B7-2 and B7-1 are the dominant ligands of CD28 and CTLA-4, respectively, and indicate that the inability of B7-2 to recruit CTLA-4 to the synapse cannot be due to the differential binding properties of B7-1 and B7-2 only. We discuss the apparent redundancy of B7-1 in the context of a potentially dynamic synaptic microenvironment, and in light of functions other than the direct enhancement of T cell inhibition by CTLA-4.

  • 10.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Davis, Simon J.
    Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DS, England / Univ Oxford, John Radcliffe Hosp, Med Res Council Human Immunol Unit, Weatherall Inst Mol Med, Oxford OX3 9DS, England.
    Quantitative analysis predicts the relative therapeutic efficacy of different forms of CTLA4Ig2011In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 49, no 3, p. 527-536Article in journal (Refereed)
    Abstract [en]

    Modulating the activities of costimulatory molecules controlling immune responses holds considerable promise for immunotherapy. CTLA4Ig (abatacept), a soluble version of the T cell-expressed membrane receptor CTLA-4, is approved for the treatment of rheumatoid arthritis. Like natural CTLA-4 molecules, CTLA4Ig ligates B7-1 and B7-2 on antigen presenting cells, preventing CD28-mediated costimulation of T cells. However. CTLA4Ig can also prevent ligation of CTLA-4, potentially blocking vital inhibitory signals, thereby augmenting immunity. There have been no quantitative analyses of the likely effects of CTLA4Ig on costimulatory interactions at the immunological synapse. We present a mathematical model, based on rigorous biophysical and expression data, for simulating the effects of abatacept and a mutated derivative, LEA29Y, on the synaptic interactions of CD28 and CTLA-4. The simulations reveal an unexpectedly large window within which CD28, but not CTLA-4, ligation is blocked by CTLA4Ig, perhaps explaining the efficacy of abatacept at the recommended therapeutic dose (10 mg/kg) and its relative safety. However, the simulations suggest that the present dosing regimen is close to the maximum theoretically safe dose. The simulations also show that, within the therapeutic window, LEA29Y enhances the interaction of CTLA-4 with the more potent of its two native ligands, B7-1. They also suggest that CTLA-4 ligation by B7-1 could, in principle, be enhanced by further decreasing the off-rate of CTLA4Ig for binding to B7-2. Our findings therefore offer molecular explanations for why LEA29Y might prove to be more effective than abatacept in a clinical setting, and suggest ways in which its therapeutic efficacy could be further optimised. (C) 2011 Elsevier Ltd. All rights reserved.

  • 11.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Fagerlind, Magnus
    University of Skövde, School of Life Sciences.
    Karlsson, Diana
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
    In silico simulations suggest that Th-cell development is regulated by both selective and instructive mechanisms2006In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 84, no 2, p. 218-226Article in journal (Refereed)
    Abstract [en]

    Th-cell differentiation is highly influenced by the local cytokine environment. Although cytokines such as IL-12 and IL-4 are known to polarize the Th-cell response towards Th1 or Th2, respectively, it is not known whether these cytokines instruct the developmental fate of uncommitted Th cells or select cells that have already been committed through a stochastic process. We present an individual based model that accommodates both stochastic and deterministic processes to simulate the dynamic behaviour of selective versus instructive Th-cell development. The predictions made by each model show distinct behaviours, which are compared with experimental observations. The simulations show that the instructive model generates an exclusive Th1 or Th2 response in the absence of an external cytokine source, whereas the selective model favours coexistence of the phenotypes. A hybrid model, including both instructive and selective development, shows behaviour similar to either the selective or the instructive model dependent on the strength of activation. The hybrid model shows the closest qualitative agreement with a number of well-established experimental observations. The predictions by each model suggest that neither pure selective nor instructive Th development is likely to be functional as exclusive mechanisms in Th1/Th2 development.

  • 12.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences.
    Harlén, Mikael
    University of Skövde, School of Life Sciences.
    Karlsson, Stefan
    University of Skövde, School of Life Sciences.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Cooley, Margaret
    School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2033, Australia.
    3D computation modelling of the influence of cytokine secretion on Th-cell development suggests that negative selection (inhibition of Th1 cells) is more effective than positive selection by IL-4 for Th2 cell dominance2007In: Immunology and Cell Biology, ISSN 0818-9641, E-ISSN 1440-1711, Vol. 85, no 3, p. 189-196Article in journal (Refereed)
    Abstract [en]

    Th-cell development has been suggested to include selective mechanisms in which certain cytokines select either Th1 or Th2 cells to proliferate and grow. The selective theory is based on the observation that Th2 cells secrete IL-4, a cytokine that promotes Th2 development, whereas Th1 cells secrete interferon-gamma (IFN-italic gamma) that favours Th1 development, and both positive and negative selective influences have been suggested to operate. In this study, we investigate the role of autocrine secretion and utilization of IL-4 by Th2 cells and address the question of whether an activated Th2 cell can be positively selected by IL-4 secreted from other Th2 cells. We present a spatial three dimensional (3D) modelling approach to simulate the interaction between the IL-4 ligand and its IL-4 receptors expressed on discrete IL-4 secreting cells. The simulations, based on existing experimental data on the IL-4 receptor–ligand system, illustrate how Th-cell development is highly dependent on the distance between cells that are communicating. The model suggests that a single Th2 cell is likely to communicate with possible target cells within a range of approximately 100 mum and that an activated Th2 cell manages to fill most of its own IL-4 receptors, even at a low secretion rate. The predictions made by the model suggest that negative selection against Th1 cells is more effective than positive selection by IL-4 for promoting Th2 dominance.

  • 13.
    Jansson, Andreas
    et al.
    University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
    Jirstrand, Mats
    Chalmers Science Park.
    Biochemical modeling with Systems Biology Graphical Notation2010In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 15, no 9-10, p. 365-370Article, review/survey (Refereed)
    Abstract [en]

    The Systems Biology Graphical Notation (SBGN) is an emerging standard for graphical notation developed by an international systems biology community. Standardized graphical notation is crucial for efficient and accutate communication of biological knowledge between researchers with various backgrounds in the expanding field of systems biology. Here, we highlight SBGN from a practical point of view and describe how the user can build and simulate SBGN models from a simple drag-and drop graphical user interface in PathwayLab.

  • 14.
    Jansson, Andreas
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Pernestig, Anna-Karin
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Nilsson, Patric
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Jirstrand, Mats
    Fraunhofer-Chalmers Research Centre for Industrial Mathematics, Gothenburg, Sweden.
    Hornquist, Elisabeth Hultgren
    Univ Örebro, Sch Hlth & Med Sci, Dept Biomed, Örebro, Sweden.
    Toward Quantifying the Thymic Dysfunctional State in Mouse Models of Inflammatory Bowel Disease2013In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 19, no 4, p. 881-888Article, review/survey (Refereed)
    Abstract [en]

    Inflammatory bowel disease is characterized by a number of immunological alterations, not the least in the T-cell compartment. Numerous animal models of colitis have revealed aberrant thymocyte dynamics associated with skewed thymocyte development. The recent advancements in quantitative methods have proposed critical kinetic alterations in the thymocyte development during the progression of colitis. This review focuses on the aberrant thymocyte dynamics in G alpha i2-deficient mice as this mouse model provides most quantitative data of the thymocyte development associated with colitis. Herein, we discuss several dynamic changes during the progression of colitis and propose a hypothesis for the underlying causes for the skewed proportions of the thymocyte populations seen in the G alpha i2-deficient mice and in other mouse models of colitis. (Inflamm Bowel Dis 2013; 19: 881-888)

  • 15.
    Karlsson, Diana
    et al.
    University of Skövde, School of Life Sciences.
    Jansson, Andreas
    University of Skövde, School of Life Sciences.
    Normark, Birgitta Henriques
    Karolinska Inst, Swedish Inst Infect Dis Control, Dept Bacteriol, SE-17182 Solna, Sweden / Karolinska Inst, Dept Microbiol Tumor Biol & Cell Biol, SE-17177 Stockholm, Sweden.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    An individual-based network model to evaluate interventions for controlling pneumococcal transmission2008In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 8, p. 83-Article in journal (Refereed)
    Abstract [en]

    Background: Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, but also a common colonizer of the upper respiratory tract. The emergence and spread of antibiotic resistant pneumococcal strains has threatened effective therapy. The long-term effects of measures aiming to limit pneumococcal spread are poorly understood. Computational modeling makes it possible to conduct virtual experiments that are impractical to perform in real life and thereby allows a more full understanding of pneumococcal epidemiology and control efforts. Methods: We have developed a contact network model to evaluate the efficacy of interventions aiming to control pneumococcal transmission. Demographic data from Sweden during the mid-2000s were employed. Analyses of the model's parameters were conducted to elucidate key determinants of pneumococcal spread. Also, scenario simulations were performed to assess candidate control measures. Results: The model made good predictions of previous findings where a correlation has been found between age and pneumococcal carriage. Of the parameters tested, group size in day-care centers was shown to be one of the most important factors for pneumococcal transmission. Consistent results were generated from the scenario simulations. Conclusion: We recommend, based on the model predictions, that strategies to control pneumococcal disease and organism transmission should include reducing the group size in day-care centers.

  • 16.
    Li, Kaitao
    et al.
    Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, USA.
    Cheng, Xiaoxiao
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Davis, Simon J.
    Radcliffe Department of Medicine and Medical Research Council Human Immunology Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
    Zhu, Cheng
    Coulter Department of Biomedical Engineering, Woodruff School of Mechanical Engineering, Institute for Bioengineering and Bioscience, Georgia Institute of Technology, USA.
    In situ and in silico kinetic analyses of programmed cell death-1 (PD-1) receptor, programmed cell death ligands, and B7-1 protein interaction network2017In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 292, no 16, p. 6799-6809Article in journal (Refereed)
    Abstract [en]

    Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance and is among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1 requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the T cell receptor for agonist pMHC and of LFA-1 (lymphocyte function-associated antigen 1) for ICAM-1 (intercellular adhesion molecule 1) but significantly lower than that of the B7-1/CTLA-4 interaction, suggesting a distinct basis for PD-1- versus CTLA-4-mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1/PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

  • 17.
    Ritchie, A. J.
    et al.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Jansson, Andreas
    University of Skövde, School of Life Sciences.
    Stallberg, J.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Nilsson, Patric
    University of Skövde, School of Life Sciences.
    Lysaght, P.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    Cooley, M. A.
    Sch. of Biotech. and Biomol. Sci., University of New South Wales, Sydney, NSW 2052, Australia.
    The Pseudomonas aeruginosa Quorum-Sensing Molecule N-3-(Oxododecanoyl)-L-Homoserine Lactone Inhibits T-Cell Differentiation and Cytokine Production by a Mechanism Involving an Early Step in T-Cell Activation2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 3, p. 1648-1655Article in journal (Refereed)
    Abstract [en]

    The Pseudomonas aeruginosa quorum-sensing molecule N-3-(oxododecanoyl)-L-homoserine lactone (OdDHL) has been reported to have immunomodulatory activity in several systems, although the mechanism of that activity remains to be fully characterized. We demonstrate here, using a defined in vitro model of antigen responses by T-cell receptor (TCR)-transgenic mouse splenic CD4 T cells, that the effect of OdDHL on activation and cytokine production is complete within 4 h of antigen or mitogen stimulation and does not depend on the insertion of OdDHL in the cell membrane, despite a previous report that immunosuppression by homoserine lactones required a minimum acyl chain length of 11 carbons (S. R. Chhabra, C. Harty, D. S. W. Hooi, M. Daykin, B. W. Bycroft, P. Williams, and D. Pritchard, J. Med. Chem. 46:97-104, 2003). We also demonstrate that while OdDHL can have toxic effects on nonlymphoid leukocytes, it does not induce significant cell death in T cells at the concentrations (≤10 µM) used in these experiments. In addition, we show that primary and secondary antigen-specific cytokine responses are equally susceptible to inhibition by OdDHL and that the compound inhibits the differentiation of both Th1 and Th2 cells. However, the precise balance of cytokine production by CD4 T cells stimulated in the presence of OdDHL varies with both the antigen concentration and its affinity for the transgenic TCR. Thus, conflicting reports of the nature of the immunosuppression by OdDHL may be due in part to the differences in antigen affinity and concentration in different models.

  • 18.
    Synnergren, Jane
    et al.
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Department of Clinical Chemistry/Transfusion Medicine, Sahlgrenska University Hospital.
    Ameen, Caroline
    Cellartis, Göteborg, Sweden.
    Jansson, Andreas
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre.
    Sartipy, Peter
    Cellartis, Göteborg, Sweden.
    Global transcriptional profiling reveals similarities and differences between human stem cell-derived cardiomyocyte clusters and heart tissue2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 4, p. 245-258Article in journal (Refereed)
    Abstract [en]

    It is now well documented that human embryonic stem cells (hESCs) can differentiate into functional cardiomyocytes. These cells constitute a promising source of material for use in drug development, toxicity testing, and regenerative medicine. To assess their utility as replacement or complement to existing models, extensive phenotypic characterization of the cells is required. In the present study, we used microarrays and analyzed the global transcription of hESC-derived cardiomyocyte clusters (CMCs) and determined similarities as well as differences compared with reference samples from fetal and adult heart tissue. In addition, we performed a focused analysis of the expression of cardiac ion channels and genes involved in the Ca2+-handling machinery, which in previous studies have been shown to be immature in stem cell-derived cardiomyocytes. Our results show that hESC-derived CMCs, on a global level, have a highly similar gene expression profile compared with human heart tissue, and their transcriptional phenotype was more similar to fetal than to adult heart. Despite the high similarity to heart tissue, a number of significantly differentially expressed genes were identified, providing some clues toward understanding the molecular difference between in vivo sourced tissue and stem cell derivatives generated in vitro. Interestingly, some of the cardiacrelated ion channels and Ca2+-handling genes showed differential expression between the CMCs and heart tissues. These genes may represent candidates for future genetic engineering to create hESC-derived CMCs that better mimic the phenotype of the cardiomyocytes present in the adult human heart.

  • 19.
    Wallner, Fredrik K.
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Redoxis AB/ProNoxis AB, Lund, Sweden / Wallner Medicinal Chemistry AB, Göteborg, Sweden.
    Hultquist Hopkins, Malin
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Woodworth, Nina
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Lindvall Bark, Therese
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB/ProNoxis AB, Lund, Sweden.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Correlation and cluster analysis of immunomodulatory drugs based on cytokine profiles2018In: Pharmacological Research, ISSN 1043-6618, E-ISSN 1096-1186, Vol. 128, p. 244-251Article in journal (Refereed)
    Abstract [en]

    Drug discovery is a constant struggle to overcome hurdles posed by the complexity of biological systems. One of these hurdles is to find and understand the molecular target and the biological mechanism of action. Although the molecular target has been determined, the true biological effect may be unforeseen also for well-established drugs. Hence, there is a need for novel ways to increase the knowledge of the biological effects of drugs in the developmental process. In this study, we have determined cytokine profiles for 26 non-biological immunomodulatory drugs or drug candidates and used these profiles to cluster the compounds according to their effect in a preclinical ex vivo culture model of arthritis. This allows for prediction of functions and drug target of a novel drug candidate based on profiles obtained in this study. Results from the study showed that the JAK inhibitors tofacitinib and ruxolitinib formed a robust cluster and were found to have a distinct cytokine profile compared to the other drugs. Another robust cluster included the calcineurin inhibitors cyclosporine A and tacrolimus and the protein kinase inhibitors fostamatinib disodium and sotrastaurin acetate, which caused a strong overall inhibition of the cytokine production. The results of this methodology indicate that cytokine profiles can be used to provide a fingerprint-like identification of a drug as a tool to benchmark novel drugs and to improve descriptions of mode of action.

  • 20.
    Wallner, Fredrik K.
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Redoxis AB, Lund, Sweden.
    Hultqvist Hopkins, Malin
    Redoxis AB, Lund, Sweden.
    Lindvall, Therese
    Redoxis AB, Lund, Sweden.
    Olofsson, Peter
    Redoxis AB, Lund, Sweden.
    Tilevik, Andreas
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Cytokine correlation analysis based on drug perturbation2017In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 90, p. 73-79Article in journal (Refereed)
    Abstract [en]

    Cytokines and chemokines play a crucial role in regulating the immune system. Understanding how these molecules are co-regulated is important to understand general immunology, and particularly their role in clinical applications such as development and evaluation of novel drug therapies. Cytokines are today widely used as therapeutic targets and as biomarkers to monitor effects of drug therapies and for prognosis and diagnosis of diseases. Therapies that target a specific cytokine are also likely to affect the production of other cytokines due to their cross-regulatory functions and because the cytokines are produced by common cell types. In this study, we have perturbated the production of 17 different cytokines in a preclinical rat model of autoimmune arthritis, using 55 commercially available immunomodulatory drugs and clinical candidates. The majority of the studied drugs was selected for their anti-inflammatory role and was confirmed to inhibit the production of IL-2 and IFN-γ in this model but was also found to increase the production of other cytokines compared to the untreated control. Correlation analysis identified 58 significant pairwise correlations between the cytokines. The strongest correlations found in this study were between IL-2 and IFN-γ (r=0.87) and between IL-18 and EPO (r=0.84). Cluster analysis identified two robust clusters: (1) IL-7, IL-18 and EPO, and (2) IL-2, IL-17 and IFN-γ. The results show that cytokines are highly co-regulated, which provide valuable information for how a therapeutic drug might affect clusters of cytokines. In addition, a cytokine that is used as a therapeutic biomarker could be combined with its related cytokines into a biomarker panel to improve diagnostic accuracy.

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