Mechanisms Regulating Graft-versus-host Disease

Mechanisms Regulating Graft-versus-host Disease

One of the main topics of our laboratory is to investigate novel therapeutic strategies to mitigate Graft-versus-host Disease (GVHD) in transplanted recipients using murine HSCT models. Gastrointestinal GVHD is the dominant contributor to acute GVHD-related mortality and of primary importance is to underline pathways regulating gut epithelium homeostasis. In this scenario, we have identified a novel mechanism that can potentially be translated into novel clinical strategies to prevent or ameliorate GVHD.

The following are summaries of projects that address the mechanisms underlying the pathophysiology and amelioration of GVHD:

Role of Interleukin-22 in Regulation of Host Damage During Graft Versus Host Disease

In the paper recently published by Alan Hanash et al. we demonstrated that Interleukin-22 (IL-22) is a critical regulator of

tissue sensitivity to GVHD and a survival factor for the maintenance of intestinal stem cells (ISC) during intestinal inflammation. We found that IL-22 deficiency led to increased GVHD morbidity, mortality and pathology. IL-22 was produced post-transplant by IL-23-responsive radioresistant host-derived innate lymphoid cells (ILCs), and these cells as well as the ISCs were eliminated during GVHD. Our data also indicated that ISCs, necessary for normal epithelial maintenance, were targets of GVHD, and that IL-22 may be critical for the protection of these ISCs during GVHD. (1) Moreover, in order to better investigate the physiological importance of IL-22 in regulating intestinal homeostasis, we have recently employed a 3D intestinal crypt culture system described by Dr. Hans Clevers’s lab at the Hubrecht Instititute, The Netherlands.

Influence of the Microbiome on Outcomes Following Allogeneic Bone Marrow Transplantation

For decades, researchers have hypothesized that cross-talk between the intestinal flora and the immune system can either maintain healthy homeostasis or, if perturbed, can lead to excessive inflammation. In collaboration with Eric Pamer and colleagues, we are using 16s rRNA gene sequencing techniques to characterize how the microbiota can interact with GVHD.

In a recent paper by Robert Jenq et al. we have demonstrated that in murine and human recipients of HSCT, intestinal inflammation secondary to GVHD is associated with major shifts in the composition of the intestinal microbiota, and, in turn, gut flora can modulate the severity of intestinal inflammation. Mice that developed GVHD exhibited a reduction in flora diversity with an expansion in the order of Lactobacillales and decrease in the order of Clostridiales. This change in microbiota diversity was also observed in human settings in patients with GVHD. These results suggest that GVHD deeply impacts microbiota balance and that manipulation of the flora may be translated in clinical therapy to improve outcomes for transplant recipients.

Pathophysiology of Thymic GVHD

Along with conditioning related damage we, and others, have previously demonstrated that GVHD can cause further damage to the thymus in allo-HSCT. Thymic GVHD results in loss of double positive thymocytes, thymic epithelial cells, and architectural integrity. One of the interests of our lab is to explore the pathophysiology of thymic GVHD and to develop strategies that can ameliorate its effects, thereby enhancing T cell reconstitution in recipients of allo-HSCT.

Brain GVHD

Although skin, gut, liver, thymus and lung are all GVHD targets, neurological complications have also been reported following allo-HSCT. We have recently demonstrated that the central nervous system (CNS) can be a direct target of alloreactive T cells following allo-HSCT in mice. We found significant infiltration of the CNS with donor T lymphocytes and cell death of neurons and neuroglia in allo-HSCT recipients with GVHD. Importantly, we also found that allo-HSCT recipients with GVHD had deficits in spatial learning/memory and demonstrated increased anxious behavior. These findings highlight CNS sensitivity to damage caused by alloreactive donor T cells, and represent the first characterization of target cell subsets as well as neurological complications during GVHD. Therefore, these clinically relevant studies offer a novel and rational explanation for the well-described neurological symptoms observed after allo-HSCT.