Genetic Variants Associated with Inflammatory Bowel Disease and Gut Graft-versus-host Disease

Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single nucleotide polymorphisms SNPs and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2-4 gut GVHD. No other candidate variants were associated with stage 2-4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.

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Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease

Frontiers in Immunology ◽

10.3389/fimmu.2021.705342 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eileen Haring ◽

Robert Zeiser ◽

Petya Apostolova

Keyword(s):

Inflammatory Bowel Disease ◽

Gastrointestinal Tract ◽

Graft Versus Host Disease ◽

Bowel Disease ◽

Intestinal Barrier Function ◽

Type I ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Inflammatory Bowel

The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn’s disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.

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