Pathophysiology of acute graft‐versus‐host disease

Abstract

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. In step 1, the conditioning regimen leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines. As a consequence, the expression of MHC antigens and adhesion molecules is increased enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T cell interaction with host APCs and subsequent proliferation, differentiation and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host. The following review discusses the three-step process of the pathophysiology of experimental acute GVHD.

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

“…Human acute GVHD is believed to occur in 3 phases: (phase 1) recipient conditioning, (phase 2) donor T cell activation, and (phase 3) effector cells mediating GVHD [49]. In this study, we found evidence that all three of these phases were replicated in the development of lethal X-GVHD in NOD/SCID-β2m null mice injected with huT cells.…”

“…Studies in both humans and animals have demonstrated that acute GVHD is closely associated with the intensity and toxicity of the recipient conditioning regimen [49]. In this study, we found that TBI (phase 1) was essential to consistently induce lethal acute X-GVHD in NOD/ SCID-β2m null recipients injected with huT cells.…”

“…One possibility is that TBI provides additional immunosuppression, thereby permitting increased huT cell engraftment and subsequent development of lethal X-GVHD [23]. Consistent with this hypothesis, we found significantly increased huT cell engraftment in the peripheral blood of NOD/SCID-β2m null mice after increasing the TBI dose from 250 cGy to 300 cGy and decreasing the time between irradiation and huT cell injection from 24 h to <6 h. A second possibility is that the pre-transplant irradiation prompts massive cytokine induction, also known as the "cytokine storm", which promotes huT cell engraftment, activation and development of lethal X-GVHD [49]. In allogeneic transplantation, the TBI-induced release of TNF-α, IL-1, IL-6, and lipopolysaccharide (LPS) promotes the development of acute GVHD through the activation of host antigen presenting cells (APC) and up-regulation of MHC antigens [55][56][57].…”

“…This late huT cell expansion without the development of lethal X-GVHD may be attributed to the absence of irradiationinduced inflammatory changes that contribute to GVHD pathophysiology. [49] In murine allogeneic transplant models, others and we have shown that the severity of GVHD is reduced or abolished following delayed infusion of alloreactive donor T cells. [45,[51][52][53][54] The mechanism/s by which pre-transplant irradiation of NOD/SCID-β2m null recipients increases the incidence of lethal X-GVHD induced by huT cells remains unknown.…”

“…During the second phase of human acute GVHD, allogeneic donor T cells become activated by encountering residual host APCs or donor-derived APCs, which cross present host alloantigens [49]. Although this allo-response is believed to be mediated primarily by dendritic cells (DCs), other nonprofessional APCs, including B cells, macrophages and nonhematopoietic cells, may play a role.…”