A protein can provide clues for the treatment of graft versus host disease


When an immunodeficient person receives an implant containing immunocompetent cells (bone marrow, thymus, etc.), it usually causes immunological damage to the cells in this person but not the graft. This phenomenon is called Graft-versus-host disease (GVHD). 

The host tissue antigen is also a foreign substance to the donor immune cells, so the donor immune cells attack the recipient. As the immune reaction enhance, it can produce graft versus host response. The organs most commonly implicated are the skin, liver and gastrointestinal tract. Symptoms of GVHD include fever, skin flushing, rash, hepatosplenomegaly, abnormal liver function, complete cytopenia, hepatitis, severe diarrhea, hard bone marrow infection, and infection. And several severe cases could be fatal.

A recent study published in Nature Microbiology has revealed that protective proteins in patients with inflammatory bowel disease exacerbate the symptoms of gastrointestinal graft-versus-host disease -- one of the common and challenging side effects of bone marrow transplantation. Knocking out this protein in mice can significantly improve survival and reduce the severity of GVHD.

The protein NLRP6 has previously been shown to alleviate the symptoms of colitis. Therefore,  researchers at the University of Michigan Roger Cancer Center set out to study the effects of NLRP6 on GVHD.

The team gave two groups of mice a bone marrow transplant respectively. The two groups of mice include a mouse model expressing NLRP6 and another mouse model lacking the protein. And they then found that mice that knocked out NLRP6 performed better in the case of GVHD, as opposed to NLRP6, which worked well in other diseases. 

In this study, the researchers also measured the levels of various microbes and then worked to alter the microbiome, destroy certain microbes or breed them together to share their microbiome. They put the mice in a sterile environment and then exposed them to a group of microorganisms with or without NLRP6. Each time, mice lacking NLRP6 performed better.

Previous studies have demonstrated that the protective effect of NLRP6 is directly related to microbes in the gut: the more microbes, the stronger the protective effect. However, the researchers performed all of these operations and the protection of NLRP6 knockout mice still exists. The composition of the microbiome does not seem to matter. They then concluded that NLRP6 played a role independent of the microbiome in the case of GVHD.

After intensive research, the researchers discovered a metabolite called taurine that activated NLRP6 to some extent, eventually leading to a worsening of GVHD. Changes in the microbiome can result in excess taurine, which emits an NLRP6 signal, triggering GVHD in turn.

So they thought that it is not enough to measure changes in the microbiome. It is also necessary to look at the specific changes and the consequences of these changes. And the reasons for the changes in the production of metabolites such as taurine or other proteins or enzymes need to be understood deeply.

In theory, if we can target NLRP6 with this protein, we can reduce intestinal GVHD. Or, changing the diet or microbiome to avoid excessive taurine may be another way to reduce GVHD.

The co-senior author Reddy pointed out that there are currently no blocking agents for NLRP6 and any potential clinical benefits remain to be discovered. They plan to do more research on taurine and other metabolites, as well as how changing them affects NLRP6 and GVHD.

Cite this article

CUSABIO team. A protein can provide clues for the treatment of graft versus host disease. https://www.cusabio.com/c-20892.html
 

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