Targeting Intestinal Epithelial Ceacam1 Expands Peripheral Tregs and Prevents Steroid-Refractory Acute Gut Graft-Versus-Host Disease

Steroid refractory gut graft-versus-host disease (SR-Gut-aGVHD) is the major cause of non-relapse death after allogeneic hematopoietic cell transplantation (Allo-HCT). Understanding SR-Gut-aGVHD pathogenesis and developing methods for prevention and treatment remains an urgent need. We recently reported that increase of IL-22⁺ donor T cells, IL-22-dependent dysbiosis, and loss of anti-inflammatory CX3CR1^hi mononuclear phagocytes (MNP) play critical roles in SR-Gut-GVHD pathogenesis, but the mechanisms remain largely unclear. Ceacam1 on Intestinal epithelial cells are proposed to regulate bacterial translocation and subsequent immune response in the gut tissues. We found that Ceacam1 expression is enhanced on intestinal epithelial cells in murine and human SR-Gut-aGVHD, and Ceacam1 deficiency on host intestinal epithelial cells effectively ameliorate murine SR-Gut-aGVHD. Mechanistically, Ceacam1 deficiency on intestinal epithelial cells has multiple effects, including 1) augmenting pathogenic donor IL-22⁺CD4⁺ T cell conversion into FoxP3⁺IL-10⁺ pTregs and inhibiting Th/Tc1 cell expansion and cytokine production; 2) increasing of beneficial bacteria that augment colonic pTregs expansion; 3) reducing pathogenic bacteria and blocking E. Coli's interaction with Ceacam1⁺ intestinal epithelial cells; and 4) expanding anti-inflammatory CD103^-CX3CR1^hi MNP that produced IL-10 and IDO while reducing pro-inflammatory CD103⁺CX3CR1^lo DCs that produced TNF-α. Thus, targeting Ceacam1 on intestinal epithelial cells represents a novel approach for prevention of SR-Gut-aGVHD.

Figure legends: (A) Using image mass cytometry (IMC), Ceacam1 expression on epithelial cells were evaluated on colon biopsies from SR-Gut-GVHD (n=3) and Non-SR-GVHD patients (n=4). (B) Lethally irradiated WT or Ceacam1-/- BALB/c recipients were engrafted with cells from WT C57BL/6 donors, recipients were given total four injections of DEX on days 3, 10, 15 and 20 (4-DEX) after HCT, plots of %Original bodyweight, %mice without diarrhea, and %Survival are shown. n=10 from two replicate experiments.

Nakamura:BluebirdBio: Consultancy; Helocyte Inc: Research Funding; Kadmon: Consultancy; Omeros: Consultancy; Sanofi: Consultancy; Magenta Therapeutics: Consultancy. Martin:AltruBio (formerly AbGenomics): Research Funding; Enlivex Pharmaceuticals: Consultancy; Mesoblast: Consultancy; Pfizer: Other: Data and Safety Monitoring Board; Procter and Gamble: Current equity holder in publicly-traded company; Rigel: Consultancy; Talaris: Consultancy; Xenikos: Research Funding; Janssen Pharmaceuticals: Honoraria; Mallinckrodt: Honoraria.