AbstractsBiology & Animal Science

Impact of immunosenescence and donor age on alloimmunity and transplant outcome

by Timm Heinbokel

Institution: Freie Universität Berlin
Degree: PhD
Year: 2015
Record ID: 1110403
Full text PDF: http://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000099142


Continuous and complex modifications of the immune system in parallel to aging are major factors impacting transplant outcome and organ quality. Increasing numbers of elderly transplant recipients and a growing utilization of organs from older donors thus pose pressing challenges for transplantation medicine. In clinical practice, transplantation of old donor organs has been associated with reduced patient and graft survival, more frequent episodes of acute rejection and delayed graft function. To elucidate the mechanisms underlying these clinical findings, a fully MHC-mismatched murine model of vascularized heterotopic cardiac transplantation with young (8 to 12 weeks) DBA/2 recipients and either young or old (18 months) C57BL/6 donors was used. Cardiac allografts procured from old donor mice were subject to significantly accelerated graft rejection compared to young allografts. This difference in graft survival was associated with higher ISHLT rejection scores and increased intragraft infiltration by CD4+ and CD8+ T cells. Futhermore, organ age impacted characteristics of systemic alloimmune responses of the recipients, with increased frequencies of splenic CD8+ effector T cells and CD8+IFN-γ+ T cells in recipients of old allografts, in addition to higher frequencies of alloreactive IFN-γ and IL-6-producing splenocytes and more potent proliferative responses upon restimulation with donor-type antigen. To discriminate between differential effects of parenchymal tissue and intragraft passenger leukocytes in this context, chimeric donor animals were generated by transplanting young syngeneic bone marrow into old and young prospective donor mice six weeks prior to organ procurement. When transplanting these chimeric allografts (young tissue/young leukocytes or old tissue/young leukocytes) comparable graft survival, rejection scores and systemic immune responses were observed, thus revealing a crucial role of intragraft passenger leukocytes in mediating augmented immune responses when transplanting old allografts. Focusing on dendritic cells as one subset of passenger leukocytes, prospective cardiac allografts were then depleted of intragraft DCs by donor pretreatment with liposomal clodronate. Differences in graft survival and rejection scores where abolished when using hearts depleted of intragraft DCs, and systemic alloimmune responses remained independent of donor age. Furthermore, in-vitro characterization of allostimulatory priming capabilities of DCs showed significantly higher frequencies of IFN-γ-producing cells and higher proliferative responses among allogeneic splenocytes when stimulated by old DCs, as well as increased expression of MHC-II and costimulatory molecules on old DCs. Dendritic cells as a cellular substrate mediating donor-age-dependent acceleration and exacerbation of allograft rejection may thus represent a potential target for donor pretreatment strategies. Kontinuierliche und komplexe Veränderungen des Immunsystems mit zunehmendem Alter haben entscheidenen Einfluss auf den klinischen…