Langerhans Cell Homeostasis and Turnover After Nonmyeloablative and Myeloablative Allogeneic Hematopoietic Cell Transplantation

Abstract

Background Langerhans cells (LCs) are self-renewing epidermal myeloid cells that can migrate and mature into dendritic cells. Recipient LCs that survive cytotoxic therapy given in preparation for allogeneic hematopoietic cell transplantation may prime donor T cells to mediate cutaneous graft-versus-host disease (GVHD). This possible association, however, has not been investigated in the setting of nonmyeloablative allografting. Methods We prospectively studied the kinetics of LC-chimerism after sex-mismatched allogeneic hematopoietic cell transplantation with nonmyeloablative (n=23) or myeloablative (n=25) conditioning. Combined XY-FISH and Langerin-staining was used to assess donor LC-chimerism in skin biopsies obtained on days 28, 56 and 84 after transplant. The degree of donor LC-chimerism was correlated with the development of skin GVHD. Results We observed significantly delayed donor LC-engraftment after nonmyeloablative transplantation compared with other hematopoietic compartments and compared with LC-engraftment after myeloablative conditioning. In most recipients of nonmyeloablative transplants, recipient LCs proliferated in situ, recruitment of donor-LCs was delayed by two months, and full donor LC-chimerism was only reached by day 84 after transplant. Although persistence of host LCs on day-28 after transplant was not predictive for acute or chronic skin GVHD, the recruitment of donor-derived LCs was associated with non-specific inflammatory infiltrates (p=0.009). Conclusions These results show that LCs can self-renew locally but are replaced by circulating precursors even after minimally toxic nonmyeloablative transplant conditioning. Cutaneous inflammation accompanies donor LC-engraftment, but differences in LC conversion-kinetics do not predict clinical or histopathological GVHD.

Regulation of macrophage development and function in peripheral tissues

“…More recently, several other tissue-resident macrophages, including alveolar macrophages, spleen red pulp macrophages and Kupffer cells 13–17 , were also shown to be maintained independently of circulating precursors either through longevity or self-renewal. Several studies in humans were consistent with a circulation-independent maintenance of tissue-resident macrophages: patients with severe monocytopenia have normal numbers of Langerhans cells in the epidermis 18,19 ; donor Langerhans cells can be detected for years in a recipient of a human limb graft 20 ; and host Langerhans cells remained in patients that received sex-mismatched allogeneic bone marrow transplants 21,22 . Similarly to Langerhans cells, numerous tissue-resident macrophages are present in patients with severe monocytopenia 18,19 and in patients who received a sex-mismatched allogeneic bone marrow transplant 22 .…”

Cell(s) of Origin of Langerhans Cell Histiocytosis

“…While fetal-derived LCs are self-renewing in epidermis during steady-state, bone marrow-derived precursors are recruited during inflammation, such as graft versus host disease after human stem cell transplantation 51;52 . In mice, the epidermis is initially infiltrated by classical monocytes 53 , but a second wave of more long-lived LC precursors has recently been described 54;55 .…”

CD1c+ blood dendritic cells have Langerhans cell potential

“…[2][3][4] Observations in humans also confirm that LCs can be self-maintained [5][6][7] or replaced by bone marrow-derived cells in the context of transplantation and inflammation. [7][8][9][10] The nature of bone marrow-derived LC precursors that repopulate the epidermis after inflammation is incompletely defined. Experiments in mice with clodronate depletion and bead-labeling suggest a monocyte origin but do not completely exclude other precursors.…”