Differential effects of aging to immunosuppressive therapies in organ transplantation

• Applicant: Dr. Felix Krenzien
• Subject Area: General and Visceral Surgery
• Term: from 2013 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236131746

Aging has been associated with a decline of the immune response, its impact in solid organ transplantation remains, however poorly understood. The proposed study will critically examine age-specific immune responses to immunosuppressive therapies in solid organ transplantation and to identify the mechanisms that promote graft survival in elderly recipients.It is well established that aging impacts all aspects of the immune response, however, how aging impacts transplant outcome is not sufficiently understood. Over the past decade, the volume of elderly patients waiting for and receiving transplants has dramatically increased. Older recipients have shown the highest proportional increase of patients receiving organ transplants, thus there is an urgent need to understand how aging affects alloimmune responses after organ transplantation. Furthermore, it is critical to determine whether immunosuppressants need to be adapted in an age-dependent manner. Indeed, whether immunosuppressants have an age-specific mode of action remains unclear and of critical clinical importance. The main overall objective is to characterize age-specific alloimmune responses to immunosuppressants in solid organ transplantation. The long-term goal of the proposed study is to adapt immunosuppressive therapies in an age dependant manner that will improve graft survival in older recipients which constitute a fast growing segment of patients. Rapamycin and CTLA4-Ig are two immunosuppressant drugs routinely used to prevent allograft rejection. Rapamycin and CTLA4-Ig have distinct immunosuppressive mode of action. Rapamycin promotes the outgrowth of Tregs by blocking the mammalian target of rapamycin (mTOR) pathways, while CTLA4-Ig is known to prevent T cell activation by co-stimulation blockade. Using a mouse heart transplant model the group of Tullius were able to show that rapamycin promoted long-term graft acceptance in old recipients but failed to do so in young recipients. In contrast, treatment with the fusion protein CTLA4-Ig resulted in a dramatic decrease of cardiac allografts survival in old recipients while young recipients survived long-term. Taken together, these results suggest strongly that immunosuppressants have age-specific effects and that older recipients may benefit from an immunosuppression with rapamycin. Based on these findings, mTOR inhibition has the potential to promote graft acceptance in aging transplant recipients. The hypothesis will be tested according the following specific aims: Aim 1To elucidate how immunosenscence and rapamycin treatment promote allograft survival by characterizing the alloimmune response in young and old recipients. To compare alloimmune response in young and old recipients to CTLA4-Ig as a treatment that is not promoting graft acceptance in the elderly.Aim 2To identify by which cellular and molecular mechanisms immunosenscence and rapamycin treatment enhance allograft survival in older recipients.

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