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Correlation of donor leukocyte chimerism with pulmonary allograft survival after immunosuppressive drug withdrawal in a porcine model

: Kruse, B.; Thissen, S.; Warnecke, G.; Avsar, M.; Gottlieb, J.; Hohlfeld, J.M.; Karstens, J.H.; Kaever, V.; Länger, F.; Pabst, B.; Ungefroren, H.; Haverich, A.; Strüber, M.


Transplantation 87 (2009), No. 10, pp.1468-1477
ISSN: 0041-1337
Journal Article
Fraunhofer ITEM ()
drug administration schedule; graft rejection; graft survival; animal model; miniature swine; transplantation tolerance; bronchoalveolar lavage; histocompatibility testing; immunosuppressive agent; lung transplantation; major histocompatibility complex; polymerase chain reaction

BACKGROUND: This study was designed to analyze the role of postoperative donor cell chimerism for the induction and maintenance of transplantation tolerance in a porcine lung transplantation model. METHODS: Left-sided single lung transplantation from major histocompatibility mismatched male donors was performed in 27 female minipigs. All received a 28-day course of pharmacologic immunosuppression using various agents, some in combination with preoperative irradiation. Groups for eventual analysis were strictly defined by outcome, that is, pigs with acute rejection before postoperative day 178 (n=16) were allocated into one group, long-term surviving animals (n=11) into the other. Peripheral blood chimerism was monitored by flow cytometry and real-time polymerase chain reaction. Intragraft chimerism was detected from bronchoalveolar lavage fluid (BALF) by fluorescent in situ hybridization. RESULTS: Blood chimerism peaked 1 hour after transplantation and was significantly higher in the group of long-term survivors at that time. Thereafter chimerism rapidly decreased, but tended to remain higher in long-term survivors. In case of acute rejection donor cells were lost, but remained detectable for up to 36 postoperative months in tolerant animals. In BALF, the percentage of male nuclei was equally high under immunosuppression in both groups. Rejecting animals showed a rapid decrease of Y-bearing cells in BALF after drug withdrawal and an almost complete loss when acute rejection occurred. In tolerant pigs, intragraft chimerism remained detectable throughout the follow-up. CONCLUSIONS: This study demonstrates a clear correlation of donor leukocyte chimerism with long-term allograft survival in a porcine allogeneic lung transplantation model.