Deliverable 9'3:Immunogrid tutorial for conferencesworkshop

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Deliverable 9.3Immunogrid tutorial for
conferences/workshop
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Immunogrid partners

• CINECA, Bologna, Italy (Project coordinator)
• University of Queensland, Australia (Scientific
  coordinator)
• CNR, Rome, Italy
• CNRS, Montpellier, France
• Technical University of Denmark
• Birkbeck College, University of London, UK
• Department of Experimental Pathology, University
  of Bologna, Italy
• University of Catania, Catania, Italy

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• Immunogrid

• A project funded by the European Union which
  will establish an infrastructure for the
  simulation of the immune system that integrates
  processes at molecular, cellular and organ
  levels.
• To be designed for applications that support
  clinical outcomes such as design of vaccines and
  immunotherapies and optimization of immunization
  protocols.

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Immunogrid aims

• Combining data, tools and resources to develop a
  simulator and create models for the human immune
  system
• Pre-clinical testing and validation
• Dissemination to researchers and clinicians

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Immune system

• A complex and adaptive learning system
• Organs (the bone marrow, spleen, thymus, lymph
  nodes etc)
• Specialised cells (T cells, B cells etc)
• Molecules that communicate between these cells,
  giving homing properties to cells and initiating
  the killing of infected cells
• Evolved to defend an individual against foreign
  invaders
• Operates at multiple levels from molecule to
  cell, organ, organism

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Modelling the immune system

• Computer models complement and replace actual
  testing or experiments
• At present we can start from some interesting but
  limited tools (system and molecular level
  simulators) that can run on simple
  computational platforms
• In order to better describe the Human Immune
  System we want to increase the complexity
• Dimensions and dimensionality
• Increase the number of molecule types
• Introduce molecular complexity

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Modelling the immune system

• Grid computing can provide powerful computational
  infrastructure and capacity that can match the
  complexity of the real human immune system.
• Grid
• Integrated, collaborative use of high-end
  computers, networks, databases, and scientific
  instruments owned and managed by multiple
  organisations.' http//globus.org/

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Why model immune system?

• Computer models complement and replace actual
  testing or experiments
• Experimentation is expensive and has limitations
• some experiments cannot be performed
• number of experiments that can be performed
• time-scale (e.g. HIV infection)
• ethical concerns (e.g. there are strict rules as
  what experiments can be performed in humans)

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Available tools

• List of tools and services that we want to use
  in computational immunology
• Peptide Binding Prediction
• NetMHC
• Proteasomal Cleavage Prediction
• NetChop
• Integrated class I antigen presentation
• NetCTL
• Educational Immune System Simulator
• ImmSim
• Setup, upload and run immune simulations using
  the GRID.
• - CimmSim
• - Simtriplex

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• VACCINE
• A suspension of attenuated live or killed
  microorganisms (bacteria, viruses, or
  rickettsiae), or fractions , administered to
  induce immunity and thereby prevent infectious
  disease.

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Types of vaccine

• Vaccines containing killed microorganisms ( flu,
  cholera, bubonic plague, and hepatitis A.)
• Vaccines containing live, attenuated
  microorganisms .Examples include yellow fever,
  measles, rubella, and mumps.

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Types of vaccine

• Toxoids - these are inactivated toxic compounds
  from micro-organisms . Examples of toxoid-based
  vaccines include tetanus and diphtheria.
• Subunit a fragment of an inactived microrganism
  can create an immune response.examples include
  vaccine against HBV ,the virus like particle
  (VLP) vaccine against Human Papillomavirus (HPV)
  .

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Vaccinepratical scenario

• An important application of immunogrid is the
  design of new vaccinations protocols.
• One example of protocol is triplex vaccine which
  has been studied in cancer immunoprevention.

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Triplex vaccine

• Experiments with mouse provide will provide input
  for the improved computational models and be
  used to validate new protocols resulting from
  these models ,comparing with triplex.

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CBS immune-predictors

• NetChop (Proteasomal cleavages (MHC ligands).
• NetCTL (Integrated class I antigen presentation)
• NetMHC (Binding of peptides to different HLA
  alleles).

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NetChop

• The NetChop server produces neural network
  predictions for cleavage sites of the human
  proteasome.
• NetChop has been trained on human data only, and
  will therefore presumably have better performance
  for prediction of the cleavage sites of the human
  proteasome.

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NetChop (contd)?

• The proteasome is an abundant multi-enzyme
  complex that provides the main pathway for
  degradation of intracellular proteins in
  eukaryotic cells.
• The proteasome generates the antigenic peptides
  (epitopes) that are displayed on the cell surface
  in association with Major Histocompatibility
  Complex (MHC) class I molecules.

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Proteasomal Cleavage
Proteasome
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How to use Netchop

• Go to the web site http//www.cbs.dtu.dk/services/
  NetChop/

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How to use Netchop

• Choose one peptide and past the sequence in FAST
  format inside the white field

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How to use Netchop

• Click on submit
• Then you get the following results

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Net CTL

• NetCTL predicts CTL epitopes in protein
  sequences.
• The updated version has been trained on a set of
  886 known MHC class I ligands.

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How to use NetCTL

• Go to website http//www.cbs.dtu.dk/services/NetCT
  L/

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How to use NetCTL

• Research for a MHC class I ligand in the
  database you can find in the web site
• Go to submission and paste the sequence

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How to use NetCTL

• Click on submit
• You will get the epitope prediction

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NetMHC

• NetMHC 3.0 server predicts binding of peptides to
  a number of different HLA alleles using
  artificial neural networks (ANNs) and weight
  matrices.
• Predictions can be obtained for 12 human
  supertypes, and 120 individual human alleles
  using ANNs and weight matrices (ungapped HMMs).
  Furthermore 12 animal (Monkey and Mouse) allele
  predictions are available.

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MHCPeptide Binding
T-cell Receptor
Peptide
MHC
APC
APC Antigen Presenting Cell
MHC Major Histocompatibility Complex
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How to use NetMHC

• Go to the website http//www.cbs.dtu.dk/services/N
  etMHC/

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How to use Net MHC

• Select the allele you want to make predictions
  for. 113 alleles are available currently
• Put your sequence of pepitedes in the white field

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How to use NetMHC

• Click on submit
• You will get the prediction

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ImmSimEducational Immune Simulator

• This resource should be used to learn about the
  immune system and how it responds to certain
  events by allow you to run live simulations and
  view the immune cells and cellular components
  changing with time.
• Presently only the module C-ImmSim is available
  SimTriplex will be available on the same server
  during 2007.
• Link http//igrid-ext.cryst.bbk.ac.uk/educ/

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ImmSim (contd)?

• With ImmSim you can study
• Individual clonotypic antigen-specificity such
  as T-cells and B-cells receptor components.
• The effect that an administered vaccine has on
  the immune system.
• To follow the AIDS pathogenesis after HIV-1
  infection.
• How the immune system responds to various
  pathogens like bacteria and viruses with
  different replicatin rate.

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ImmSim (contd)?

• Selecting Populations section, you can observe
  how immune responses vary throughout a population
  under different conditions.
• The following tho slides will show you cancer and
  HIV cases.

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Educational Immune System Simulator (contd)
This is the first page that appears when you go
to the Educational Immune System Simulator.
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Educational Immune System Simulator (contd)
You can choose multiple type of simulations
(cellular components, Vaccinations, HIV and
Populations). Note that the simulations are
based on pre-defined data.
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Educational Immune System Simulator (contd)

• Below you can find different schedules of
  vaccination based on Triplex vaccinne
• for mammary carcinoma
• Click on run simulation

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Educational Immune System Simulator (contd)

• Here you can run HIV specific simulation

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Educational Immune System Simulator (contd)

• Selecting Populations section, you can observe
  how immune responses
• vary throughout a population under different
  conditions.

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CimmSim v2.0

• CimmSim online v2.0 allows you to setup, upload
  and run immune simulations using the grid. This
  site has been updated to allow submission of
  multiple jobs at once. Additionally, simulations
  are run on the NGS GRID.

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How to use CimmSim Online v2.0

• Go to the web site http//igrid-ext.cryst.bbk.
  ac.uk/immunogrid/cimmsim/

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How to use CimmSim Online v2.0

• Click on Create button (left panel), and edit
  (if you like) the input datafile.
• Then click on create at the end of the datafile
  to build a job.

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How to use CimmSim Online v2.0

• Then click on prepare to submit the job

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How to use CimmSim Online v2.0

• Then click on the right arrow to select the
  job(s).

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How to use CimmSim Online v2.0

• Finally, click on Run these jobs button

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How to use CimmSim Online v2.0

• Clicking on view results allow you to get the
  behavior of various immune system entities.

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Exercises

• Exercise n.1
• Net chop
• Intracellular protein degradation is a major
  source of short antigenic peptides that can be
  presented on the cell surface in the context of
  major histocompatibility class I molecules for
  recognition by cytotoxic T lymphocytes .
• If you use the Net chop server you can predict
  the epitope of MHC 1 ligands

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Exercises

• You have the following antigens
• 1) PLEC1_HUMAN
• 2) FLNA_HUMAN
• Find the sequence of these antigen- ligands in
  SYFPEITHI dataset (http//www.cbs.dtu.dk/suppl/imm
  unology/CTL )
• Put the sequence in the white field you can
  find in the web site http//www.cbs.dtu.dk/servic
  es/NetChop/
• What woud you get?

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Exercises

• Exercise n.2
• Net CTL
• NetCTL 1.2 server predicts CTL epitopes in
  protein sequences
• Use the following MHC1 ligands (HIV antigens)
  1)ENV_HV1RH
• 2) NEF_HV1SC
• 3) ENV_HV1C4

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Exercises

• Search the sequence in FAST format in the
  database HIV dataset (http//www.cbs.dtu.dk/suppl/
  immunology/CTL-1.2/HIV_dataset)
• Paste the sequence in the white field that you
  can find in the web site http//www.cbs.dtu.dk/ser
  vices/NetCTL/
• What would you get?

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Exercises

• Exercise n.3
• Net MHC
• NetMHC 3.0 server predicts binding of peptides to
  a number of different HLA alleles
• Put the sequence of this peptide that is in FAST
  format inside the white field
• ASQKRPSQRHGSKYLATASTMDHARHGFLPRHRDTGILDSIGRFFG
  GDRGAPK NMYKDSHHPARTAHYGSLPQKSHGRTQDENPVVHFFKNIVT
  PRTPPPSQGKGR KSAHKGFKGVDAQGTLSKIFKLGGRDSRSGSPMARR
  ELVISLIVES http//www.cbs.dtu.dk/services/NetMHC
• What would you get?

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Exercises

• Exercise n.4
• CimSim CimmSimonline v2.0 allows you to setup,
  upload and run immune simulations using the grid.
• Go to http//igrid-ext.cryst.bbk.ac.uk/immunogrid/
  cimmsim
• Change the different parameters you can find
  inside the grey window
• Click on create
• What would you get?

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Exercises

• Exercise n.5
• ImmSim educational immune simulator
• Go to Link http//igrid-ext.cryst.bbk.ac.uk/educ/
  
• Try the simulator
• What would you get?