Thorac Cardiovasc Surg 2015; 63 - OP226
DOI: 10.1055/s-0035-1544478

Indoleamine 2,3-Dioxygenase (IDO) Mediates Immune Tolerance through Catabolism of Platelet-Derived Serotonin

I. Schmitt-Knosalla 1, A. Kühl 2, I. Lahdou 3, C. Bhagat 4, K. Wassilew 5, S. Brösel 1, K. Kotnik 4, R. Hetzer 5, H.-D. Volk 1, M. Bader 4, C. Knosalla 5
  • 1Charité - Universitätsmedizin Berlin, Institute of Medical Immunology, Berlin, Germany
  • 2Department of Gastroenterology, Infeciology and Rheumatology, Charité - Universitätsmedizin Berlin, Berlin, Germany
  • 3Department of Transplantation Immunology, Institut für Immunologie, Universität Heidelberg, Heidelberg, Germany
  • 4Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
  • 5Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany

Objectives: A recently established paradigm in immunology indicates that dendritic cells (DCs) expressing IDO are able to suppress T cell responses and promote immunological tolerance. Using the competitive pharmacological inhibitor of IDO, 1-MT, mechanistic studies from a range of mouse models have supported the hypothesis that rapid and selective degradation of the essential amino acid tryptophan is the means by which IDO-dependent suppression of T cell responses functions.

Methods and Results: Based on a model of heterotopic murine heart transplantation in mice we found that CD40-CD154 and CD28:B7 pathway blockade induces functional IDO activity in mouse cardiac endothelial cells. Using the stringent model of tryptophan hydroxylase-1 deficient (Tph1 −/−) mice, which have normal concentrations of tryptophan but lack the rate-limiting enzyme in peripheral serotonin biosynthesis, we investigated the role of serotonin[5-hydroxytryptamine(5-HT)], which has been suggested to be an important cofactor in T cell activation. Using the models of tryptophan hydroxylase-1 deficient (Tph1 −/−), IDO1-deficent (IDO-1−/−) and platelet depleted mice, we report the novel finding that platelet-derived serotonin mediates the suppression of T cell responses and the promotion of immune tolerance that results from intragraft expression of the immunoregulatory enzyme IDO. Further, we showed that IDO mediated prolonged allograft survival acts through 5-HT1A and 5-HT2, but not through 5-HT1B receptor signaling.

Conclusions: As serotonin-induced signaling is an integral part of T cell activation, these studies provide a broader understanding of the regulatory controls driving the immune response and of serotoninergic functions. The findings have clinical implications, since targeting of serotoninergic pathways may offer novel therapeutic options in the prevention of rejection after organ allotransplantation.