Donor-derived cells and human graft-versus-host disease of the skin

Abstract

Graft-versus-host disease (GvHD)-induced apoptosis of the skin targets both epidermal keratinocytes and dermal endothelial cells. We studied the donor-versusrecipient origin of GvHD of these target cells in skin of 18 sex-mismatched hematopoietic stem-cell transplant (HSCT) recipients. Combining XY fluorescence in situ hybridization (FISH) and double immunostaining, and further 3D tissue Zstack analysis, we found keratinocytes and endothelial cells of donor origin, but only in patients with GvHD. Using terminal dUTP nick-end labeling (TUNEL) assay on sister sections, we found a correlation between the numbers of chimeric and apoptotic epidermal and endothelial cells. Moreover, donor-derived cells were more numerous and preferentially distributed in the areas of severe GvHD damage in biopsies performed early in the course of GvHD, whereas they were less numerous and found in the whole epidermis in late biopsies. Because donor-derived cells were found at the site and at the time of maximum tissue damage, they could contribute to epidermal and microvessel repair. IntroductionKeratinocyte apoptosis and inflammatory infiltrate are the hallmarks of acute cutaneous graft-versus-host disease (GvHD), but endothelial-cell damage is also found in human 1 and experimental studies. In an animal model we demonstrated that endothelial cells in all organs are targets of GvHD. 2 In humans with acute GvHD we have found disruption of microvessel walls in gut biopsies. 3 Endothelial damage has also been demonstrated at the chronic phase of GVHD in the skin. 4 Studies in animal models, 5 and in human hematopoietic stemcell transplant (HSCT) recipients, have shown that marrow stem cells could differentiate into cell types other than blood cells, particularly in oral mucosa, 6 digestive tract, 7 and liver. 8 A study demonstrated that human bone marrow contributes to vascular endothelium in the skin. 9 However, the donor-versus-recipient origin of endothelium as target in GvHD lesions has not been studied in humans, so far. Patients, materials, and methodsEighteen female patients received an allogeneic, non-T-cell-depleted, marrow transplant from a male sibling donor. Three patients were transplanted for aplastic anemia and 15 for malignant disease, after a myeloablative conditioning regimen (irradiation-based therapy in 10 patients; chemotherapy alone in 8). All patients were full hematopoietic donor chimera, without relapse, at the time of biopsy. A skin rash led to biopsy, and, among the 18 patients, 13 had biopsy-confirmed pathologic acute GvHD. Pathologic grade was grade 3 in 6 patients, grade 2 in 5 patients, and grade 1 in 2 patients. All patients were given steroids which were rapidly tapered in 5 patients in whom pathologic diagnosis was not acute GvHD but suspected drug-induced rash.Biopsies from female patients grafted with a female donor were considered as negative controls (n ϭ 10), and biopsies from male recipients grafted with a male donor were considered as positive controls (n ϭ 8). No significant differences in terms...

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

“…Previous work reported that cells of human or murine origin do home to the skin, such as in graft-versus-host disease in humans (14) and epithelial progenitors in murine bone marrow (15). Our group reported that donor-derived keratinocytes could be identified at wound sites in a BMT model (16).…”

Concise Review: Transplantation of Human Hematopoietic Cells for Extracellular Matrix Protein Deficiency in Epidermolysis Bullosa

“…Malfunction of the local arm (e.g., congenital deficiency of a structural skin protein in genodermatoses) or overwhelming of normal skin repair mechanisms (e.g., burn injury) or the systemic arm (e.g., breakdown of regulatory mechanisms that protect the skin from immune-mediated injury) can result in the loss of skin integrity and increased susceptibility to infections. In addition to endogenous repair mechanisms within the skin that might occur through resident skin stem and progenitor cell proliferation, substantial evidence now exists that the bone marrow (BM) contains cells that can persist in mucocutaneous epithelia [5][6][7][8][9][10].…”

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

“…19 23,24 and that after hematopoietic cell transplantation these cells are able to engraft in the skin of the recipient, especially in sites affected by graft-versus-host disease. 25 Finally, directly or systemically administered BM cells have been shown to promote healing of skin wounds, 26,27 which are the hallmark of RDEB.Therefore, we hypothesized that stem cell populations from adult marrow may be capable of migrating to the integument and the internal mucosal sites, where they can modulate pathology through col7 protein production. If biochemical and phenotypic correction could be demonstrated in a relevant animal model, this would support the development of a novel therapeutic approach for children and adults with RDEB.…”