Complex interactions of cellular players in chronic Graft-versus-Host Disease

Abstract

Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.

Keywords: GvHD pathogenesis; cell-cell communication; chronic graft-versus-host disease; hematopoietic stem cell transplantation; immune cell networks.

Figure 1

Mechanisms and targeting of T cell pathogenicity in cGVHD. Pathogenic mechanisms in cGVHD include thymic injury and subsequent dysregulation of Treg responses and Th1/Th17 skewing. Pro-inflammatory signaling from other cell types promotes inflammation in target tissues. Increased numbers and signaling of Tfh additionally stimulate pathogenic B cell responses. The pathogenic role of mixed chimerism within TRM compartment and potential antigens for a specific allo-reaction remain topics of open investigation. Therapeutic agents in clinical use (green) or agents to reduce cGVHD in pre-clinical models (blue) targeting the different disease mechanisms are highlighted. Grey arrows indicate potential involvement of EV in pathological processes.

Figure 2

B cell compartment aberrations in cGVHD. B cell compartment aberrations include increases in memory B cells with exhausted phenotype, and in germinal center GC B cells promoted by increased Tfh signaling, where therapeutic benefit could be seen by monoclonal antibody blockade in mouse models. Hyperresponsive BCR signaling and autoantibody production, as well as production of pro-inflammatory cytokines further promotes disease pathogenesis, partly mediated by loss of Treg-controlled B cell help. Regulatory B cell functions are diminished, as well as certain memory subsets controlling infections. Ibrutinib inhibits the B cell survival regulating kinase BTK and additionally suppresses Th2 responses via blocking ITK. B cell derived EV signals regulating T cell and B cell activation could influence proinflammatory immune responses.

Figure 3

Dual role of NK cells in cGVHD pathogenesis. NK cells that reconstitute early after transplantation can acquire several properties that render them GVHD promoting or GVHD protective. Through lysis or suppression of T cells or APC in the circulation and in target tissues they can reduce inflammation. On the other hand, proinflammatory cytokine production and increased alloreactivity through a donor NK cell receptor (including KIR) repertoire can support disease pathology. Their interaction with mesenchymal stem cells (MSC) could modulate effects of MSC-based therapies. EV released from NK cells can induce Th1 polarization, thereby potentially contributing to cGVHD pathology. .

Figure 4

APCs as cGVHD disease drivers. APC are instrumental in cGVHD development through presentation of allo-antigens to T cells and production of pro-inflammatory cytokines. Antibodies targeting these mechanisms are in clinical use (in green). Structural cells, such as epithelial cells can obtain MHC class II antigen-presenting properties presenting allo-antigen in the gut of mice. In cGVHD macrophages with M2 polarization are expanded and contribute to tissue fibrosis, which in mouse models could be ameliorated by pirfenidone. There are several lines of evidence that EV release by APC mediate processes implicated in cGVHD pathology.

Figure 5

Microbiome-mediated effects in cGVHD. GVHD development in the gut is associated with a disturbed microbiome. In cGVHD decreased microbial diversity with reduced Faecalibacterium and increased Akkermansia and Streptococcus species are reported, whereas high abundance of Lachnoclostridium is protective. Microbial metabolites are critical mediators of gut immune responses. Butyrate promotes Treg and regeneration of epithelial cells. Trp metabolites derived from microbes can protect the epithelium via IL-22 induction and microbial or tissue cell derived Trp metabolites promote Treg differentiation. Paneth cells in the gut produce antimicrobial peptides, and are targets of destruction by alloreactive T cells, leading to impaired host defense. Damaged epithelial cells have defective oxygen utilization, leading to loss of physiologic hypoxia in GVHD which drives microbial dysbiosis. Microbiota can release EV that modulate host immune responses.