Important role of haematopoietic chimerism following Immunosuppressive drug withdrawal in a porcine lung transplantation model

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.

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, i.e. pigs with acute rejection before postoperative day 178 (n=16) were randomized into one group, long term surviving animals (n=11) into the other. Peripheral blood chimerism was monitored by flow cytometry and real time PCR. Intragraft chimerism was detected from bronchoalveolar lavage fluid by fluorescent in situ hybridization. Blood chimerism peaked one 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 completely, but remained detectable for up to 36 postoperative months in tolerant animals. In bronchoalveolar lavage fluid, the percentage of male nuclei was equally high under immunosuppression in both groups. Rejecting animals showed a rapid decrease of Y-bearing cells in bronchoalveolar lavage fluid after drug withdrawal and an almost complete loss when acute rejection occurred. In tolerant pigs intragraft chimerism remained detectable throughout the follow-up.

This study demonstrates a clear correlation of donor leukocyte chimerism with long term allograft survival in a porcine allogeneic lung transplantation model.