Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease

Abstract

Despite advances in immunosuppressive prophylaxis and overall supportive care, gastrointestinal (GI) graft-versus-host disease (GVHD) remains a major, lethal side effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has become increasingly clear that the intestinal epithelium, in addition to being a target of transplant-related toxicity and GVHD, plays an important role in the onset of GVHD. Over the last two decades, increased understanding of the epithelial constituents and their microenvironment has led to the development of novel prophylactic and therapeutic interventions, with the potential to protect the intestinal epithelium from GVHD-associated damage and promote its recovery following insult. In this review, we will discuss intestinal epithelial injury and the role of the intestinal epithelium in GVHD pathogenesis. In addition, we will highlight possible approaches to protect the GI tract from damage posttransplant and to stimulate epithelial regeneration, in order to promote intestinal recovery. Combined treatment modalities integrating immunomodulation, epithelial protection, and induction of regeneration may hold the key to unlocking mucosal recovery and optimizing therapy for acute intestinal GVHD.

Fig. 1. The pivotal role of the intestinal epithelium and epithelial damage in GVHD onset.

Irradiation, chemotherapy, and/or immunotherapy used in the conditioning regimen before HSCT damages the intestinal epithelial cells and disrupts barrier protecting the recipient from luminal pathogens. Translocating pathogen-associated molecular patterns (PAMPs) and released damage-associated molecular patterns (DAMPs) bind to their corresponding pattern recognition receptors (PRRs) and activate the innate immune system, including professional antigen presenting cells (APCs). Antigen presentation by APCs, including the intestinal epithelium, lead to the propagation and activation of alloreactive T cells, which cause further damage through cytokine- and cell–cell-mediated toxicity in the then developed GVHD. Created with BioRender.com.

Fig. 2. Opportunities for intestinal protection and repair over the course of HSCT.

Damage to the intestinal epithelium over the course of HSCT occurs in different phases. As such, opportunities for protection against the insult and repair of the injury occur in parallel, rather than after the fact. The timing of these different approaches will be crucial, since certain treatment opportunities may have pleiotropic effects on other cell types at different time points during the posttransplant period. Created with BioRender.com.

Fig. 3. The intestinal crypt as a GVHD target, and mechanisms of protection.

The intestinal epithelium is maintained by intestinal stem cells (ISCs) which reside at the base of intestinal crypts, interspersed between their supportive Paneth cells (PCs) in the small intestine. Along the crypt-villus axis the ISCs differentiate into transit amplifying (TA) cells and their destined lineage, including absorptive (e.g., enterocyte), secretory (e.g., PC, Goblet cell, Tuft cells) and enteroendocrine cells. In the vasculature near the intestinal crypt the addressin MAdCAM-1 is expressed, which binds α4β7-integrin expressed on gut-directed immune cells. Several approaches of protection at the level of the intestinal epithelial cell in general, or in addition at the ISC and PC level specifically, are indicated in red. A4β7 blockade inhibits the influx of T cells into the lower crypt regions of the small intestine; the serine protease inhibitor Spi6 present in the epithelium protects against GVHD-induced damage, possibly through inhibition of caspase 3/7; intestinal epithelial Inhibitor of Apoptosis Proteins (IAPS) inhibits the function of pro-apoptotic caspases; the SDHA enzyme is reduced in IECs after allo-T cell insult, increasing reactive oxygen species (ROS) levels; Ruxolitinib (Rux) inhibits JAK1/2-STAT1 signaling, relieving interferon (IFN)-y induced epithelial apoptosis; and 17AAG was reported to suppress ER stress and thereby cell death in a.o. Paneth cells. Created with BioRender.com.

Fig. 4. Regenerative treatment options in GI-GVHD.

Restoration of the epithelial barrier during the course of GVHD may occur at several levels. The epithelium reconstitutes from within, deriving from progenitors under the influence of supportive niche factors. It can also be supported in its regeneration from its immediate surroundings, for instance through the action of immune cells or particular excreted cytokines, growth factors and hormones. Finally microbial components can contribute to intestinal epithelial healing. Created with BioRender.com.