Abstract
The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.
Highlights
We recently found that bone marrow (BM) infiltrating allogeneic donor T lymphocytes are associated with loss of osteoblasts in allo-hematopoietic stem cell transplantations (HSCT) patients and hampered B cell regeneration in GVHD
Bone Marrow Infiltration of Donor T Lymphocytes after Allo-HSCT
The donor Lineage− Sca-1+ c-Kit+ (LSK) cells are essential for immune reconstitution of the host after lethal irradiation as conditioning therapy, since the hematopoietic cells of the host are fully depleted by the lethal irradiation
Summary
In the setting of allogeneic HSCT (allo-HSCT) acute graft-versushost disease (aGVHD) is an additional major, survival-limiting complication, mediated by donor T lymphocytes attacking the recipient’s tissue. HLA typing serves to determine the histocompatibility of donor cells, which is critical for the success of allo-HSCT. HLA molecules of the donor and recipient are matched as closely as possible to reduce the risk of a rejection reaction (host-versus-graft) and graftversus-host. HLA typing may reduce the risk but since only 25–30% of patients can find an HLA matched familial donor (HLA identical siblings), most allogeneic transplants are performed using grafts from unrelated donors [4]. Acute GVHD is an inflammatory disease that is unique to allo-HSCT due to the recognition of the recipient’s tissues by transplanted donor immune cells. Previous studies showed a higher risk of fractures after HSCT compared to healthy untreated individuals, whereby the causes are probably multifactorial [8,9,10]
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