Donor brain death (BD) and its pathophysiological changes have been shown to influence graft quality, therefore accelerating the immune response post transplantation. However, detailed information regarding immune activation of distinct lymphocyte subsets in the periphery and in BD donor organs is still missing in order to explain enhanced immunogenicity. For this purpose, C57BL/6 mice underwent BD induction and were followed for 3 hrs under continuous ventilation, whereas ventilated mice were used as sham group (SH) (n=5). By cell isolation and flow cytometry, we observed a strong induction of activated CD25+CD3+CD4+ T cells in BD donor derived hearts and kidneys compared with SH (p<0.01). Contrarily, an infiltration of cytotoxic CD3+CD8+ T cells was exclusively induced in hearts as a consequence of BD (p<0.01). Moreover, we detected enhanced levels of CD3-NKp46+ NK cells in BD donor hearts, livers and kidneys which appeared significantly activated reflected by their CD69 expression. The latter observation is in sharp contrast to CD3+CD4+ T helper or CD3+CD8+ cytotoxic T cells, which did not show induction of CD69 in all investigated organs (spleen, liver, heart, kidney, peripheral blood). Interestingly, an induction of co-stimulatory molecules including CTLA-4 and CD28 on all lymphocytes isolated from peripheral blood and kidneys as a consequence of BD was obvious (p<0.01). In addition, all investigated organs displayed higher frequencies of CTLA-4+CD11c+ conventional dendritic (mDCs) cells compared with the SH, whereas the kidney displayed the highest level of MHC class II+ mDCs (p<0.05 versus spleen, lymphnodes and liver, respectively). Strikingly, CTLA-4+MHC class II+ PDCA1+ plasmacytoid cells were highly induced indicating their massive infiltration especially in liver, kidney and lymphnodes due to BD (p<0.05 compared to SH, respectively). Among B cells, CD19+CD220 mature B cells were clearly diminished, whereas BD results in an induction of CD19+CD220- immature B cells in all organs. In summary, our results gain novel insights into the pathophysiology of BD induced immune activation revealing significant differences between various organs and the periphery. This indicates distinct mechanisms of activation which needs consideration for future treatment strategies.

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