Bone Marrow GvHD after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

The bone marrow is the origin of all hematopoietic lineages and an important homing site for memory cells of the adaptive immune system. It has recently emerged as a graft-versus-host disease (GvHD) target organ after allogeneic stem cell transplantation (alloHSCT), marked by depletion of both hematopoietic progenitors and niche-forming cells. Serious effects on the restoration of hematopoietic function and immunological memory are common, especially in patients after myeloablative conditioning therapy. Cytopenia and durable immunodeficiency caused by the depletion of hematopoietic progenitors and destruction of bone marrow niches negatively influence the outcome of alloHSCT. The complex balance between immunosuppressive and cell-depleting treatments, GvHD and immune reconstitution, as well as the desirable graft-versus-tumor (GvT) effect remains a great challenge for clinicians.

Keywords: GvHD; GvL; GvT; alloHSCT; bone marrow; bone marrow stroma; memory niche; minor antigen.

Figure 1

Bone marrow niches and their response to preconditioning and alloHSCT. Left: niches for hematopoietic stem cells (HSCs) are located at the endosteal border and comprise osteoblasts and specialized mesenchymal cells partly immunoprotected by adjacent regulatory T cells (Treg). Alternatively, HSCs can seed into perivascular niches (not shown). B cell progenitors and recirculating memory T, B (memCD4, memCD8, and memBC), and plasma cells occupy additional specialized perivascular niches. Upon preconditioning, bone marrow cells are differently affected by the treatment as indicated by the flash size. Right: after alloHSCT, alloreactive T cells are massively activated (not shown) leads to systemic influx of soluble inflammatory factors into the bone marrow where they cause upregulation of Fas on various cell types and harm donor and recipient HSCs alike. Infiltrating alloreactive donor T cells deplete residual host hematopoietic cells and support disintegration of endostial and perivascular niches by means of cytolytic and soluble factors. Consequently, efflux of hematopoietic lineages and seeding capacity for donor-derived hematopoietic stem and memory cells is diminished.