We read with great interest the article in HEPATOLOGY by Wang et al.,1 which characterized blood chimerism in liver transplant (LT) patients and showed that multipotent hematopoietic stem/progenitor cells (HSPCs) reside in adult human livers. The authors concluded that there are two types of chimerism after LT: transient chimerism resulting from migration of mature donor leukocytes from the liver graft, which usually disappears within 3 weeks after LT, and long-term chimerism derived from putative donor HSPCs in the liver graft. Finally, the authors asked whether donor HSPCs generate mature leukocytes inside the grafted liver or circulate to recipient bone marrow for hematopoiesis.
In a previous study on liver natural killer (NK) cell precursors,2 we observed that mature NK cells of donor origin were detectable in liver grafts up to 2 years after LT, while all donor-derived NK-cell precursors were replaced by recipient-derived precursors within 1 week after LT. To study whether other types of mature donor leukocytes remain present in liver grafts after LT, we now determined intragraft chimerism of CD3+ T cells, CD56+ T cells, and CD14+ monocytes/Kupffer cells in leukocytes isolated from first liver grafts of five LT patients undergoing re-LT. We selected recipient/donor pairs that were mismatched for human leukocyte antigen (HLA)-A2 or HLA-Bw4 during the first transplantation. Using flow-cytometry with monoclonal antibody (mAb) for HLA-A2 or HLA-Bw4 we could differentiate donor from recipient cells. In all five patients we detected considerable percentages of donor-derived mature leukocytes in the first graft, even up to 2 years after transplantation (Table 1). These data are not consistent with the hypothesis of Wang et al.1 that donor-derived leukocytes disappear within 3 weeks after LT, at least within the grafted liver, but demonstrate the possible existence of long-lived donor-derived leukocytes resident in the liver graft.
|% of Total Intragraft Leukocytes (% of Donor-Derived Within Each Subset)|
|Patient 1 (7 days)||Patient 2 (16 days)||Patient 3 (1 year)||Patient 4 (2 years)||Patient 5 (2 years)|
|CD56+ T cells||7.5 (6.8)||1.7 (18.2)||5.7 (1.6)||5.1 (3.7)||6.6 (16.3)|
|CD3+ T cells||12.5 (2.1)||76.5 (6.6)||22.8 (0.8)||10.5 (16)||8.8 (18.6)|
|CD14+ cells||15.4 (63.3)||15.9 (90.5)||7.8 (27.5)||7.2 (37.0)||22.2 (46.0)|
|Lin−CD34+HSPCs||0.5 (0)||0.2 (0)||0.1 (0)||0.3 (0)||0.1 (0)|
We also measured chimerism in lineage−CD34+ HSPCs (at least 2 × 106 events were recorded), which contain the multipotent lin−CD34+CD38−CD90+ HSPCs described in the article.1 We found that all five explanted liver grafts contained only recipient-derived, but no donor-derived, HSPCs (Table 1), indicating that donor-derived hepatic HSPCs are replaced by circulating HSPCs of recipient origin within the first week after transplantation.
Our data suggest that the long-term chimerism described in the Wang et al. article is probably caused by long-lived donor leukocytes resident in liver grafts, and/or hematopoiesis of relocated donor HSPCs. The latter concept is supported by a study of Massberg et al.,3 which describes the liver as one of the peripheral organs in which HSPCs reside shortly before returning to the blood and remigrating to the bone marrow. The relocation of HSPCs from transplanted liver remains to be investigated.