Th17 pathways in age-dependent alloimmune responses: mechanisms and therapeutic approaches
Cardiac and Vascular Surgery
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.
(See online at https://doi.org/10.1111/ajt.14087) - 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.
(See online at https://doi.org/10.1016/j.jaci.2018.01.038) - 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.
(See online at https://doi.org/10.1097/TP.0000000000001902)
