Pathophysiology of GvHD and Other HSCT-Related Major Complications

Abstract

For over 60 years, hematopoietic stem cell transplantation has been the major curative therapy for several hematological and genetic disorders, but its efficacy is limited by the secondary disease called graft versus host disease (GvHD). Huge advances have been made in successful transplantation in order to improve patient quality of life, and yet, complete success is hard to achieve. This review assimilates recent updates on pathophysiology of GvHD, prophylaxis and treatment of GvHD-related complications, and advances in the potential treatment of GvHD.

Keywords: T cells; graft versus host disease; haematopoietic stem cell transplantation; pathophysiology; prophylaxis.

Figure 1

Initiation of graft versus host disease. Conditioning regimen leads to destruction of epithelial cells and their integrity. Damaged epithelia secrete uric acid and adenosine triphosphate (ATP) that result in production of pro-inflammatory cytokines. Pathogen recognition receptors, such as toll-like receptors (TLRs), NOD-like receptors (NLRs), and P2XRs, are activated by pathogen associated molecular patterns (PAMPs) and danger associated molecular patterns (DAMPs). These signals ultimately activate antigen-presenting cells (APCs) that lead to donor T-cell activation. Adopted and modified from Ref. (37).

Figure 2

Pathophysiology of acute graft versus host disease. Conditioning regimen cause profound damage to the host tissues leading to release of inflammatory cytokines like tumor necrosis factor and interleukin-1. These cytokines activate host antigen-presenting cells (APCs) in phase I. In addition, loss of microbial diversity and metabolites thereof leads to loss of epithelial and immune homeostasis. Host APCs activate mature donor T cells present in stem cell inoculum in phase II. T cells subsequently proliferate and differentiate into Th1 and Th17 type, which are involved in activation of CD4 cytotoxic T lymphocyte (CTL), CD8 CTL, and natural killer cells that mediate tissue damage. In phase III, effector T cells together with pro-inflammatory cytokines attack the epithelial cells of skin, liver, lung, and gastrointestinal tract. This damage is further supported by the lipopolysaccharide (LPS) that has leaked through damaged intestinal mucosa, which then recruits myeloid cells to further produce pro-inflammatory cytokines and thus enhance the cytokine storm. Adopted and modified from Ref. (13).

Figure 3

Skin explant grades I–IV. The outcome of the skin explant assay is histopathological damage ranging from grade I GvHR (with minimal vacuolization in the epidermis) to grade II GvHR (with vacuolization and dyskeratotic bodies) to grade III GvHR (with sub epidermal cleft formation) and finally to grade IV GvHR (with separation of the dermis from the epidermis).