Grifols : Award Winners of the 9th Annual Martín Villar Haemostasis Awards

• Created in 2007, the awards recognize the progress made in the field of Hemostasis. The awards are endowed with 20,000 euros for each of the two prizes: Basic Research and Clinical Research.
• The Basic Research category was awarded to Dr. Nimesh Gupta for presenting the antigen-specific tolerance in the administration of missing antigens during fetal development.
• The Clinical Research category was awarded to the cross-sectional study, led by Davide Matino, in patients with severe hemophilia A. The study found a strong correlation between IDO1 functionality (a regulatory enzyme that supports peripheral tolerance in adult life) and inhibitor status.

Barcelona, June 30, 2016.- For the ninth consecutive year, Grifols presents the Martín Villar Awards for Research on Hemostasis, through which the company promotes and reinforces its commitment to scientific research. These awards recognize the work of scientists and researchers that conduct their studies in the field of blood coagulation disorders. The awards ceremony was held at the symposium organized by Grifols at the WFH World Congress in Orlando on July 26, 2016. For this edition, the awarded studies are:

Basic Research Award

'Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance' (Science Translational Medicine 2015; 7(275): 275ra21) authored by: Nimesh Gupta, Slobodan Culina,Yann Meslier, Jordan Dimitrov, Christophe Arnoult, Sandrine Delignat, Bagirath Gangadharan, Maxime Lecerf, Sune Justesen Valérie Gouilleux-Gruart, Benoit L. Salomon, David W. Scott, Srinivas V. Kaveri, Roberto Mallone, Sébastien Lacroix-Desmazes.

The authors studied whether the administration of missing antigens during fetal development confers antigen-specific tolerance. Using the physiological pathway by which maternal immunoglobulins (Igs) are transferred to fetuses through the neonatal Fc receptor (FcRn), they demonstrated Ag-specific immune tolerant progeny in an animal model. Firstly, it was revealed that after the administration of Fc-fused antigens (Fc-fused hemagglutinin [Fc-fused HA]) to pregnant mice (HA-specific T Cell Receptor transgenic mouse model), the progeny generated peripheral antigen-specific regulatory T cells (Tregs), as result of the transplacental delivery of the Fc-fused antigen to the fetal circulation. When this strategy was applied to a preclinical animal model of severe hemophilia A, the transplacental delivery of the Fc-fused immunodominant FVIII domains provided long-lasting tolerance upon FVIII replacement therapy. This study provides a strategy to modulate the T cell repertoire in an Ag-specific manner and generate Tregs that are crucial to achieve immune tolerance. The approach was successfully translated into a mouse model of severe hemophilia A, which may be applicable to other genetic deficiencies. This strategy may provide a development opportunity toward an antigen-specific tolerance in patients with hemophilia A.

Clinical Research Award

'IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII' (J Clin Invest. 2015;125(10):3766-81) authored by: Davide Matino, Marco Gargaro, Elena Santagostino, Matteo N.D. Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria E. Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo N. Talesa,Claudia Volpi, Carmine Vacca,Ciriana Orabona, Rossana Iannitti, Maria G. Mazzucconi, Cristina Santoro, Antonella Tosti, Sara Chiappalupi, Guglielmo Sorci, Giuseppe Tagariello, Donata Belvini, Paolo Radossi, Raffaele Landolfi, Dietmar Fuchs, Louis Boon, Matteo Pirro, Emanuela Marchesini, Ursula Grohmann, Paolo Puccetti, Alfonso Iorio, and Francesca Fallarino.

The authors performed a cross-sectional study in patients with severe hemophilia A, and found a strong correlation between IDO1 functionality (a regulatory enzyme that supports peripheral tolerance in adult life) and inhibitor status. They investigated IDO1 expression and function in response to CpG-ODN (a prototypical danger signal) in patients with F8 mutations, who were either inhibitor positive (n=50) or negative (n=50). The results showed that in a cohort of 100 severe hemophilia A patients, with and without inhibitors -but with F8 mutations resulting in complete absence of endogenous FVIII- there was a strong and statistically significant association between failure to activate IDO1 in response to CpG-ODN and the presence of inhibitors. Thus, 3 6/50 (72%) inhibitor-free patients upregulated IDO1 expression and function in response to CpG-ODN stimulation, whereas only 18/50 (36%) inhibitor-positive patients were capable of upregulating IDO1 under the same stimulation conditions. It was also found that tryptophan metabolites, which resulted from ID01 activity, prevented generation of anti-FVIII antibodies. Additionally, hemophilic mice with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involved ID01-dependent induction of regulatory T cells (Treg). This data shows that danger signals sensed by TLRs have an impact on the immune system of hemophilic patients, which, in turn, could affect their ability to regulate immunity through acquired tolerance mechanisms. These findings indicate that a strategy that improves ID01 function might be an option to prevent or eradicate inhibitors in hemophilic patients treated with FVIII proteins.

The application process for the 2017 cycle begins September 1, 2016 and will remain open until May 15, 2017.
More information regarding the Martin Villar Awards at http://www.martinvillar-awards.com