Mechanisms in Induction of Immunological Tolerance

• Applicant: Privatdozentin Dr. Wiebke Sommer
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315564180

Aim of this research proposal is to study mechanisms leading to a stable immunological tolerance in recipients of combined heart- and kidney transplantation. In a porcine model, heterotopic transplanted hearts were accepted when a kidney co-transplantation from the same donor was performed. All recipients developed stable tolerance toward both grafts.This phenomenon was termed kidney-induced cardiac allograft tolerance (KICAT). The underlying mechanisms leading to this long-term success of tolerance induction remain unclear. For the planned studies, heterotopic heart- and kidney transplantations will be performed in nonhuman primates (NHP).Foxp3+CD25+CD4+ regulatory T cells (Treg) seem to have a distinct role in the process of allograft acceptance. First, the role of Tregs within the tolerance induction process will be studied. In order to proof the importance of Tregs, a depletion of CD4+CD25highFoxP3+ cells is envisioned by using a novel anti-human CCR4-immunotoxin, which specifically deplete effector Treg in cynomolgus monkeys (NHP). This depletion of Tregs is assumed to prevent tolerance induction of both, heart and kidney allograft, confirming the substantial role of Tregs. Further, a detailed characterization of Tregs within the process of tolerance induction is planned by studying new surface markers, CD49b and LAG-3, which characterize specifically CD4+ type 1 regulatory cells in cynomolgus monkey. Further, the role of plasmacytoid dendritic cells (pDC) will undergo further research. Preliminary data suggests that pDCs actively promote the activation and/or expansion of recipient Tregs and therefore support the induction KICAT. In detail, CCR9+ pDCs are able to convert CD4+ naïve T-cells into Tregs, thereby having pro-tolerogenic function. NHP undergoing combined heart/kidney transplantation will receive a treatment with anti-CD303 mAB, leading to pDC depletion, which potentially inhibits the onset of KICAT.At last, the role of Erythropoetin (EPO) in the development of KICAT will be identified. CD4+CD8+ T cells express Erythropoetin receptor (EPO-R) and a dose-dependent decreasing effect of EPO on allogeneic CD4+ T-cell proliferation was detectable, thus indicating an immunosuppressive effect. In order to determine if high dose EPO treatment will provide similar tolerance induction as kidney co-transplantation, animals will either receive additional erythropoietin perioperatively or in contrast, a pharmacological downregulation of EPO will be achieved by administering a substance which has proven to diminish EPO in vivo, acriflavine. These experiments will provide further insight into mechanisms leading to the development of KICAT.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Joren Madsen, Ph.D.