News & Articles

The Euro-Thymaide FP6 Integrated Project was launched in January 2004 and gathers 20 academic laboratories with excellent expertise in the exploration of thymus functions, and 4 biotechnology companies.

The final objective of this IP is the design of innovative approaches for the diagnosis and treatment of autoimmune diseases based on new knowledge of thymus-dependent self-tolerance.

Type 1 diabetes (T1D) has been selected as the prototype autoimmune disease that will be tackled by this project.

The Euro-Thymaide Consortium held its first annual assembly in Barcelona on 28-29 January 2005 in presence of Members of the Scientific Advisory Board (SAB), Prof. Jean-Charles Cerottini (Ludwig Institute for Cancer Research, Lausanne, Switzerland) and Prof. Christian Boitard (INSERM Unit 561, Hôpital Cochin, Paris, France).
Representative of  the Juvenile Diabetes Research Foundation (New York) , Dr. Teodora Staeva-Vieira attended the Euro-Thymaide First Annual Assembly.

Important development have been discussed at the meeting with experts and the scientific officer of the European Commission, Dr. Torbjörn Ingemansson.

Before reporting on the work progress during the first year of Euro-Thymaide existence, it is important to briefly summarize the state of knowledge at the initiation of the project.

The thymus occupies a prominent place in the physiology of the immune system. In parallel with T-cell development and generation (thymopoiesis), this major lymphoid organ is responsible for the establishment of central self-tolerance, i.e. the inability of the immune system to aggress the host that it protects from infectious and cancer agents.

The thymus assumes this essential function by two ways:

1) Deletion of self-reactive T lymphocytes emerging during the
    intrathymic random recombination of gene segments encoding the
    variable parts of the T-cell receptor for the antigen (TCR);
2) Generation of CD4+ CD25+ regulatory T cells (Treg) able to inhibit in
    periphery self-reactive T cells that have escaped the thymic censorship.
  
The discovery of the intrathymic transcription of genes encoding most of the peripheral tissue-specific and neuroendocrine-related antigens has radically changed the common scientific view about the establishment of tolerance to peripheral tissues.

Before that discovery, the immunologists thought peripheral antigens were sequestered from developing T cells in the thymus and that tolerance to peripheral tissues/cells was primarily due to peripheral tolerogenic mechanisms.

Consequently, “Back to central tolerance” became a leitmotiv in the field of immunology to understand the pathogenesis of autoimmunity, i.e. diseases secondary to a failure of immune tolerance to host tissue components.

The AutoImmune REgulator gene and protein (AIRE) had been identified as the gene several mutations of which are responsible for the APECED or autoimmune polyglandular syndrome (APS-I), a rare monogenic disorder characterized by several endocrine deficiencies in the newborn.

The AIRE protein shares several features of a transcription factor and Aire invalidation was shown to promote peripheral autoimmune processes in correlation with a reduction in the thymus transcription of several genes coding for tissue-specific antigens.

Finally, more and more experimental evidence had been accumulated in favor of a thymic dysfunction as a crucial factor in the pathogenesis of organ-specific autoimmune iseases, including T1D.

Such thymic dysfunction includes both a decrease in the intrathymic presentation of self-antigens to developing T cells, as well as a decrease in the generation of self-antigen specific Treg.

The Euro-Thymaide Consortium involves the following contractors:

Contractor 1 – Vincent GEENEN, University of Liege (ULG), B (Coordinator)
Contractor 2 – Bruno KYEWSKI, DKFZ, Heidelberg, D
Contractor 3 – Georg HOLLÄNDER, University of Basel (UBASEL1), CH
Contractor 4 – Ludger KLEIN, Institute of Molecular Pathology (IMP), Vienna, A
Contractor 5 – Philippe NAQUET, CNRS, University of Aix-Marseille II, F
Contractor 6 – Ricardo PUJOL-BORRELL,Autonomous University of Barcelona (UAB1), SP
Contractor 7 – Pärt PETERSON, University of Tartu (UTARTU), EE
Contractor 8 – Alexander MARX, University of Würzburg, D
Contractor 9 – Hamish SCOTT, WEHI, Victoria, AUS
Contractor 10 – Didier HOBER, CHRU-Lille, F
Contractor 11 – Rafick-Pierre SEKALY, University of Montreal, CDN
Contractor 12 – Josef PENNINGER, IMBA, Vienna, A
Contractor 13 – Isabella SCREPANTI, University “La Sapienza”(DMSP), Roma, I
Contractor 14 – Fiona POWRIE, University of Oxford, UK
Contractor 15 – Catherine HAWRYLOWICZ, King’s College London (KCL), UK
Contractor 16 – Dolores JARAQUEMADA,Autonomous University of Barcelona(UAB2), SP
Contractor 17 – Antonius ROLINK, University of Basel (UBASEL2), CH
Contractor 18 – Joost VAN MEERWIJK, INSERM Unit 563, Toulouse, F
Contractor 19 – Thomas BOEHM, Max Planck Institute of Immunbiology (MPI),Freiburg, D
Contractor 20 – Eric JENKINSON, University of Birmingham, UK
Contractor 21 – Kai KROHN, FIT Biotech, Tampere, FIN
Contractor 22 – Future Partner (FP1)
Contractor 23 – Bernhard FISCHER, Apeiron Biologics, Vienna, A
Contractor 24 – Lutz ZEITLMANN, Ingenium Pharmaceuticals, Martinsried, D
Contractor 25 – Alain BOSSELOIR, Zentech, Liege-Sart Tilman, B

The Euro-Thymaide project is constituted by six interacting work packages (WP), each WP tackling a specific objective in the exploration of central tolerance and in the use of central tolerogenic mechanisms for the design of novel approaches in the diagnosis and treatment (peptide and cell therapies) of autoimmune diseases such as T1D.
- WP1: Promiscuous gene expression in the thymus network and use of thymic selfantigens in tolerogenic therapy – WP1 leader: Bruno Kyewski.
- WP2: AIRE as a protein responsible for the expression of self-antigens in the thymus
– WP2 leader: Pärt Peterson.
- WP3: Coxsackievirus B4 (CVB4) and thymus-based pathogenesis of T1D
          – WP3 leader: Didier Hober.
- WP4: Targeting the role of Cbl-family proteins in tolerance,
           autoimmunity, and allergy – WP4 leader: Josef Penninger.
- WP5: Regulatory T cells – WP5 leader: Fiona Powrie.
- WP6: Differentiation of thymus epithelium – WP6 leader: Thomas
           Boehm.

The work performed and results achieved after one year, can be summarized as follows:  

  - Development of a database on intrathymic expression of tissue-
    specific self-antigens.
  - Demonstration of AIRE control on intrathymic promiscuous expression
    of tissue-specific self-antigens.
  - Characterisation of a severe dysfunction of human thymus resulting
    from infection with Coxsackievirus B4 (CVB4).
  - Identification of a novel splice variant of the human p56lck gene,
    expressed in peripheral blood lymphocytes and coding for a protein
    that lacks some but not all SH3-binding partners. Its expression is
    unrelated to type 1 diabetes (T1D).
  - Map of cbl-b SNPs in a cohort of type 1 diabetic and control individuals.
  - The production of a panel of specific anti-FOXP3 monoclonal
    antibodies, and characterisation of FOXP3 protein expression in human
    tissues.
  - Characterisation of the mouse Foxn1 locus, including functional activity
    of Foxn1 promoters.

These progress are relevant for the development of new cures and therapies to autoimmune diseases. Autoimmune diseases are a significant burden for the quality of life and health care cost. Patients with autoimmunity are usually treated with non-specific immunosuppression, which is expensive, in term of drug and laboratory control costs, and accompanied by severe side effects, that in turn may require medical intervention.

Therapeutic interventions directed at specific mechanisms, would represent an important socioeconomic improvement. As an outcome of this first year of activity in the projet, four Euro-Thymaide participants have presented exploitable results and, according to the other participants, we should expect very significant results in 2005.
One channel of exploitation will be readily available with SMEs already involded in the network as active partners.

A licensing procedure is already under current progress for a new antigen against T1D.

For the other results, discussions are presently under way within the consortium to assess the best action plan.