What is already known
Graft-versus-host disease (GVHD) is a condition associated with bone marrow and stem cell transplants, and it occurs when the donor’s stem cells attack and damage the recipient’s healthy cells. In GVHD, immune cells respond to antigens presented by protein complexes, called MHC-I and MHC-II, found on the surfaces of specific cells that help the immune system recognize foreign substances.
What this research adds
Researchers have found that genetically identical mice acquired from distinct vendors have a different intestinal microbiota and expression of MHC-II in the small intestine. This results in discordant GVHD severity. Gut bacteria that induced the expression of MHC-II were sensitive to the antibiotic vancomycin, and vancomycin treatment dampened GVHD severity. The gut microbiota from patients undergoing blood stem cell transplant was associated with acute GVHD and transplant-related mortality.
Conclusions
The findings uncover how gut microbes may contribute to trigger GVHD, suggesting potential targets for therapies.
A major cause of death after bone marrow and stem cell transplants is graft-versus-host disease (GVHD), a condition that occurs when the donor’s stem cells attack and damage the recipient’s healthy cells. A new study done in mice reveals that the gut microbiota is a key factor in determining the severity of this condition.
The findings, published in Immunity, uncover how gut microbes may contribute to trigger GVHD, suggesting potential targets for therapies.
In GVHD, immune cells respond to antigens presented by protein complexes, called MHC-I and MHC-II, found on the surfaces of specific cells that help the immune system recognize foreign substances.
Recent research has shown that MHC-II is expressed by cells that make up the lining of the ileum — the last section of the small intestine — under the influence of the gut microbiota and specific immune molecules. Mice whose intestinal epithelial cells do not express MHC-II are protected from some of the detrimental effects of GVHD, including damage to the gut, researchers have previously found.
Now the same team, led by Motoko Koyama at the Fred Hutchinson Cancer Center in Seattle, Washington, set out to examine the influence of gut microbes on MHC-II expression by ileal intestinal epithelial cells. To do so, the researchers obtained genetically identical mice from different vendors.
Microbiota differences
The researchers compared MHC-II expression by ileal intestinal epithelial cells between mice derived from The Jackson Laboratory and mice from Taconic Biosciences, Charles River Laboratories or an Australian-derived colony maintained at the Fred Hutchinson Cancer Center. MHC-II expression was absent in mice from The Jackson Laboratory, but it was present and expressed at similar levels in mice from other vendors.
The intestinal bacterial composition of mice from The Jackson Laboratory also differed from that of mice from other vendors, the researchers found. Mice from The Jackson Laboratory had high levels of Bacteroidales, whereas the other mice had increased abundances of Lactobacillus animalis/apodemi and Clostridium.
“The bacterial landscape was largely determined by the host origin […] rather than minor genetic variation,” the authors say.
The gut microbiota from patients undergoing blood stem cell transplant was associated with acute GVHD and transplant-related mortality, the researchers also found.
Transplant outcomes
The team identified different bacteria that either induce or suppress the expression of MHC-II in fecal and ileal samples from the mice analyzed. MHC-II inducers were more abundant in mice from other vendors than in those from The Jackson Laboratory, the researchers found.
Unlike mice from other vendors, those from The Jackson Laboratory did not develop a lethal form of GVHD after transplant. “These data indicate that despite being genetically identical, recipients harboring MHC-II inducers display more severe gut GVHD,” the researchers say.
Further experiments showed that inducers of MHC-II expression were sensitive to the antibiotic vancomycin. Treating mice with vancomycin from 14 days before to 7 days after transplantation reduced GVHD severity, the researchers found.
The findings, they say, “provide a broad framework that defines potential microbiota-focused strategies to prevent the initiation of severe acute GVHD and demonstrate the significant impact of non-genetic, environmental determinants to transplant outcome.”
