Donor bone marrow infusion reduces the infiltration of recipient-derived CD4 and dendritic cells in lung allograft

Abstract

Aim: Recent studies showed that donor bone marrow (BM) infusion reduced the incidence of obliterative bronchiolitis in lung recipients, however the mechanism(s) responsible for this observation is unknown. We sought to determine whether donor bone marrow infusion at the time of transplantation would have long-term effects on the host response to the lung allograft. Methods: Brown Norway (RT 1An) left lungs were transplanted into Lewis (RT 1A1) recipients. Some recipients (n ≥5 per time point) were given cyclosporine A(CsA, 10 mg/kg/day x 5 days, then 5 mg/kg/every other day until sacrifice), while others (n ≥5) received both CsA and 1.0 × 108 unmodified donor BM cells per rat on the day of transplant (CsA + BM). Animals were sacrificed at two weeks and 6 months posttransplant. Leukocytes from the bronchoalveolar lavage (BAL) fluid of the lung graft, native lung, peripheral blood, BM and thymus were collected. Four-color flow cytometry was used to analyse cell phenotypes. Results: At 6 months after transplant, only 4 of 11 lung grafts (36%) in the control versus 8 of 10 grafts (80%) in the BM-treated animals were accepted (p<0.05). At two weeks, BM infusion increased total donor-derived leukocytes (10.3% vs. 6.6%) and donor-derived dendritic cells (DC, 3.7% vs. 1.0%) in the graft. At 6 months, there was no difference in donor-derived cell numbers or lineages. However, host derived CD4 (15.6% vs. 27.6%; p=0.08) and DC (4.5% vs. 9.1%; p=0.03) were reduced in lung grafts of BM-treated animals. Conclusion: Donor BM infusion increases the trafficking of donor cells to lung grafts in early stage, and decreases the infiltration of host CD4 and DCs in long-surviving grafts. These findings suggest that donor BM infusion has a long-lasting modulatory effect on host alloreactivity, resulting in improved graft survival.