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Protein’s shocking role gives clues to minimize graft-vs.-host illness

Proteins that defend people with inflammatory bowel illness have a very different outcome in graft-vs.-host illness, a challenging adverse effect of bone marrow transplants.

Researchers from the University of Michigan’s Rogel Cancer Center displayed how the protein NLRP6 heightened the problematic indications of gastrointestinal graft-vs.-host ailment. Removing this protein in mice resulted in considerably improved survival chances and GVHD that was less severe.

The graft-vs.-host illness is a reaction to the donor bone marrow. Normally, the mechanisms that result in colitis, are the same as the ones causing GVHD, hence most treatments are alike.

Researchers figured as NLRP6 decreases colitis symptoms it would influence the graft-vs.-host illness as well.

“There are a lot of reasons NLRP6 seemed to work well in those other diseases, but in the case of GVHD, it seemed to do the opposite. In mice where we knocked out NLRP6, instead of doing worse, they did better. That was a big surprise,” stated senior study author, Pavan Reddy, M.D.

The research team related mouse models expressing NLRP6 with those with the protein removed. Mice in both models had had a bone marrow transplant.

Mice were developed in a sterile setting and then subjected to a microbiome with/without the NLRP6. Every time, the ones in the absence of the NLRP6 had better results.

Researchers also discovered a metabolite ‘taurine’, thought to partially be responsible for turning on the NLRP6 and eventually worsening the GVHD. Alterations in the microbiome can result in excess taurine, which ultimately triggers GVHD.

“Just measuring changes in the microbiome is not always sufficient. We have to look at what specifically changes and the consequences of those changes. A change that leads to the generation of metabolites like taurine or other proteins or enzymes will need to be understood to comprehend the effects of the microbiome on GVHD,” author Grace Chen, Ph.D., says. She is the associate professor of hematology/oncology at Michigan Medicine.

“Conceptually, if we can target this protein and block NLRP6, we can mitigate intestinal GVHD. Or, if you look at it the other way, changing the diet or microbiome to avoid an excessive amount of taurine could be another way to reduce GVHD,” states Reddy.

Blocking NLRP6 could restrict GVHD and not limit the anti-tumor effects of the transplant.

Reddy says no blocker presently exists for NLRP6 and the possible clinical benefits still need exploring.