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

• Final Report Year: 2018

Final Report Abstract

This project was able to delineate age-specific effects of immunosuppressive drugs on the clinical outcome after alloimmune transplantation. Costimulatory blockade-based treatment with CTLA4-Ig caused significant perturbation in the Treg compartment of old mice with reduced frequencies and compromised proliferation of CD4+CD25+Foxp3+ cells and reduced suppressor activity of old Tregs, thus leading to detrimental effects on graft survival in old recipient mice. Rapamycin, on the other hand, led to significantly prolonged graft survival in old recipients through induction of regulatory type 1 cells. Lastly, tacrolimus was shown to specifically affect intracellular calcium signaling and IL-2 production in an age-dependent manner. These results are significant contributions to the debate on age-specific immunosuppression for the growing population of elderly transplant recipients, since all of these drugs are routinely used in clinical practice. With its second specific aim, this project was able to significantly advance the mechanistic understanding of how a novel immunosuppressive agent, nicotinamide adenine dinucleotide (NAD+), is able to affect the differentiation of T helper cells in such a way that prolonged transplant outcome is achieved. By using various transgenic mouse strains and disease models as well as advanced in-vitro techniques, it was shown that, surprisingly, mast cells play a pivotal role in mediating NAD+-mediated T helper cell differentiation, in absence of antigen-presenting cells or other antigen-specific stimuli. This specific aim thus unraveled a novel cellular and molecular pathway in T helper cell differentiation that is relevant far beyond the field of transplant immunology.

Publications

• Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus. Am J Transplant. 2017;17(5):1242–54
  Krenzien F, Quante M, Heinbokel T, Seyda M, Minami K, Uehara H, et al.
  
• Mast cells regulate CD4+ T-cell differentiation in the absence of antigen presentation. J Allergy Clin Immunol. 2018 Feb 20
  Rodriguez Cetina Biefer H, Heinbokel T, Uehara H, Camacho V, Minami K, Nian Y, et al.
  
• Rapamycin Prolongs Graft Survival and Induces CD4+IFN-γ+IL-10+ Regulatory Type 1 Cells in Old Recipient Mice. Transplantation. 2018 Jan 2;102(1):59–69
  Quante M, Heinbokel T, Edtinger K, Minami K, Uehara H, Nian Y, et al.