Th17 pathways in age-dependent alloimmune responses: mechanisms and therapeutic approaches

• Applicant: Dr. Timm Heinbokel
• Subject Area: General and Visceral Surgery ; Cardiac and Vascular Surgery
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 275782478

Aging has a complex and far-reaching impact on all compartments of innate and adaptive immunity, posing pressing challenges on transplantation medicine with numbers of elderly transplant recipients and organ donors continually rising. While less vigorous alloimmune responses in elderly transplant recipients have been linked mechanistically to impaired effector T cell responses and preserved regulatory T cell (Treg) functions, IL-17A-driven alloimmune responses have recently been described to be crucial in mediating more frequent acute rejection episodes following transplantation of old donor organs.Although costimulation blockade with CTLA4-Ig is currently used widely for immunosuppressive management, costimulatory interaction has been shown to be necessary in blocking Th17 responses and maintaining Treg homeostasis. In preliminary experiments, administration of CTLA4-Ig dramatically decreased graft survival in old recipient mice compared to young recipient mice, indicating that CTLA4-Ig may promote existing Th17 responses in old mice and modify Th17/Treg balances. We thus aim to define cellular and molecular responses associated with CTLA4-Ig treatment with aging in a murine model of heterotopic cardiac transplantation, additionally using FOXP3-GFP reporter mice and adoptive transfer into RAG1-/- mice to assess conversion of effector T cells into Th17 cells and regulatory T cells in-vitro and in-vivo.Increasing evidence has been challenging the concept of IL-17A-producing cells as being strictly pathogenic, as a recent study was able to show that Th17 cells were non-pathogenic in the presence of TGFb1. In addition, nicotinamide adenine dinucleotide (NAD+) has recently emerged as a new potent regulator of T helper cell differentiation. Intriguingly, NAD+ was able to promote the conversion of regulatory T cells into IL-17A producing cells that co-express TGFb1, thus collectively suggesting that in the presence of NAD+, CD4+IL-17A+ cells may be non-pathogenic due to their capacity to co-express TGFb1. Having observed significantly prolonged allograft survival in mice treated with NAD+ in preliminary experiments, we therefore aim to assess immunosuppressive properties of NAD+-induced CD4+IL-17A+TGFb1 cells in alloimmunity as a novel immunosuppressive approach independent of naïve CD4+ T cells.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Stefan Tullius, Ph.D.