The effect of aging on the efficacy of immunosuppressants in organ transplantation

Schuitenmaker, J.M. (Jeroen) (2016) The effect of aging on the efficacy of immunosuppressants in organ transplantation. thesis, Medicine.

Text SchuitenmakerJM.pdf Restricted to Registered users only Download (2MB)

Abstract

Background Immunosenescence, the progressive dysfunction of the immune system with aging, has a major impact on transplant outcomes. In the majority of all mortalities in older transplant recipients, there is a link between age and complications that are exacerbated by immunosuppressive therapies. However, studies on age-specific effects of immunosuppressants are scarce. With the increasing number of older transplant donors and recipients, an age-adapted immunosuppression regime may be required. In this study we elucidate the effect of aging on the efficacy of Rapamycin, CTLA-4-Ig and Tacrolimus. Material & Methods Skin grafts of young DBA/2 mice were transplanted onto young (2 months) and old (18 months) C57BL/6 mice. Mice were treated with Rapamycin (1 mg per kg per day, i.p.), CTLA-4-Ig (0,2 mg per day i.p.) or PBS. Alloimmune response was assessed by flow cytometry. For our in vitro experiments young (2 months) and old (18 months) naïve CD4+ T cells were isolated and cultured in Th1 polarizing conditions without or with Rapamycin (100ng/ml) and analyzed by flow cytometry. For the calcineurin/calcium experiments, naïve CD4+ T cells from 2 and 18 months old mice were cultured in α-CD3/α-CD28 polarizing conditions and treated with or without Tacrolimus (5ng/ml). Calcineurin concentration was measured by ELISA and calcium influx was assessed by a fluorescent Ca2+ indicator and analyzed with a fluorescence reader. Graft survivals were compared by Log-rank and differences between groups were analyzed by Student´s t-test. A p-value < 0.05 was considered significant. Results Grafts in older, untreated recipients survived significantly longer (7 vs. 9 days; p=0,006), indicating that immunosenescence promotes allograft survival. Of particular relevance, Rapamycin prolonged graft survival in an age-specific fashion: while the median graft survival was only modestly extended in young recipients (12 days), graft survival was significantly prolonged in old recipients (19 days; p=0,008). These age-specific effects of Rapamycin were linked to an increase in the frequency of IL-10+ producing CD4+ T cells. Of additional relevance, reduced calcineurin levels and suppression of calcium influx were observed in old CD4+ T cells after treatment with Tacrolimus. Conclusion These results demonstrate the age-specific effects of immunosuppressants on the alloimmune responses and transplant outcomes, thus emphasizing on the need for age-adapted immunosuppression with a necessity to design immunosuppressive trials in the elderly patient.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervisors Groningen, the Netherlands: and Leuvenink, Prof. Henri Ph.D. and Professor of Experimental Transplant Surgery and Department of Surgery/Surgical Research Lab and University Medical Center Groningen and University of Groningen and Son, Prof. Willem van M.D. and Professor of internal medicine and nephrology and University Medical Center Groningen and University of Groningen
Supervisor name:	Tullius, Prof. Stefan G. M.D. and Chief, Division of Transplant Surgery and Director, Transplant Surgery Research Laboratory and Brigham and Women’s Hospital and Professor of Surgery, Harvard Medical School
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:46
Last Modified:	25 Jun 2020 10:46
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/730

Actions (login required)

View Item