Differential effects of aging to immunosuppressive therapies in organ transplantation
Final Report Abstract
The DFG research fellowship allowed Dr. Felix Krenzien and his collaborates to bring evidence for an ageadapted immunosuppression in organ transplantation and shed light into mechanism of immunology of aging. Four innovative projects were conducted and realized as follows: 1. We investigate the impact of aging on CD8+ T cells and demonstrated that aged CD8+ T cells delay allograft rejection. CD8+ T cells played a critical role linked to a compromised production of IFNγ in addition to a defective IL-2 receptor signaling machinery and a defective communication between CD8+ T cells and dendritic cells. 2. Next, we investigated the impact of aging on T cells when treated with Tacrolimus. Collectively, our study demonstrates age-specific immunosuppressive effects of Tacrolimus with impact of aging on immunosuppression with clinically relevant aspects that will allow us to better understand the use of immunosuppressants in the context of immunosenscence. 3. We investigated the role of older donor organs since they showed inferior transplantation outcomes. These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted. 4. Finally, we investigated the role of therapeutic application of NAD+ on T cells to induce homeostatic immune response and regulatory T cells. Our findings unraveled a new pathway orchestrating CD4+ T cell differentiation and demonstrate that NAD+ may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases. Moreover, those finding might be crucial as metabolic changes occur with age possibly orchestring the immune system. The research fellowship allowed Dr. Felix Krenzien to continue his research in Germany. The ongoing collaboration with the Transplant Surgery Research Laboratory at the Brigham and Women's Hospital, Harvard Medical School will be greatly beneficial for future research projects and the scientific discourse at his department.
Publications
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Abstossungsprophylaxe nach Organtransplantation: Altersadaptierte Immunsuppression. Deutsches Ärzteblatt. 02/2014
Krenzien F, Edtinger K, Tullius SG
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Early prediction of survival after open surgical repair of ruptured abdominal aortic aneurysms. BioMed Central Surgery. 11/2014
Krenzien F, Matia I, Wiltberger G, Hau HM, Schmelzle M, Jonas S, Kaisers UX, Fellmer PT
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A Rationale for Age-Adapted Immunosuppression in Organ Transplantation. Transplantation. 08/2015
Krenzien F, ElKhal A, Quante M, Biefer HR, Hirofumi U, Gabardi S, Tullius SG
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Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly. Current Opinion in Organ Transplantation. 08/2015
Gabardi S, Tullius SG, Krenzien F
