Partial Monocyte Transplant Improves Survival in Mouse Study

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by Steve Bryson, PhD |

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Monocyte immune cells from bone marrow partially transplanted into a mouse model of cystic fibrosis (CF) improved survival and reduced inflammation, a study found.

Meanwhile, transplanting monocytes from CF mice into healthy mice triggered CF-like symptoms and limited survival, suggesting that these defective immune cells may cause symptoms, the scientists noted.

“This research suggests a new strategy to improve the symptoms of cystic fibrosis, especially the body’s ability to fight infections,” first author Zhichao Fan, PhD, at the La Jolla Institute for Immunology (LJI) in California, said in an LJI press release.

Added Klaus Ley, MD, the study senior author and member of the LJI Center for Autoimmunity and Inflammation: “The transplant is enough for a better life — at least in mice.”

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The study, “Bone Marrow Transplantation Rescues Monocyte Recruitment Defect and Improves Cystic Fibrosis in Mice,” was published in the Journal of Immunology.

In CF, genetic mutations lead to a faulty or missing CFTR protein, resulting in the buildup of sticky mucus in the lungs and digestive tract, accompanied by recurring infections and inflammation. People with CF must take multiple medications and undergo chest physiotherapy to loosen mucus in their lungs.

“These are young people, but they’re taking 10 to 30 medications a day. There’s a huge treatment burden,” said Douglas Conrad, MD, a study co-author and pulmonologist with University California San Diego Health and director of the Adult Cystic Fibrosis Clinic.

Advances in CFTR modulators, such as the combination therapy Trikafta, have significantly improved CF outcomes.

“This has been a transformational event over the last two years,” Conrad said. “It has turned a very severe disease into a kind of a mild disease.” Yet not all patients are eligible for treatment with Trikafta.

“We don’t have a cure yet,” Conrad added. “And about 10 percent of patients are not eligible for this kind of CFTR modulator therapy. Living with cystic fibrosis, especially if you can’t use CFTR modulators, is a very scary thing to go through.”

Emerging evidence suggests that a defective CFTR also affects monocytes — an immune cell that develops in the bone marrow and transforms in tissues into microbe-engulfing macrophages and dendritic cells, which alert other immune cells to potential invaders.

Monocytes from CF patients have a deficiency in the activation of integrins, which are protein receptors on the cell surface that facilitate cell-to-cell interactions. As a result, CF monocytes cannot adhere to other cells and tissues, lessening their ability to fight infections.

“These monocytes can’t get to where they need to go in the gut or the lung,” Ley said.

Ley then wondered whether replacing faulty monocytes by transplant might overcome what he referred to as “the monocyte problem.”

Ley and colleagues tested this idea in a CF mouse model that carried the most common CF-causing mutation, F508del. The team focused on a partial transplant because a full transplant would suppress patients’ immune response, leaving them vulnerable to infection.

“A lot of cystic fibrosis patients are dealing with chronic infections, so they are not suitable candidates for a full bone marrow transplantation,” Fan said.

In a preliminary experiment, cell-to-cell adhesion defects were confirmed in CF monocytes.

Before transplant, the mice underwent radiation treatment to eliminate a portion of CF monocytes. After transplant, between 60% and 80% of CF monocytes were replaced with healthy monocytes (WT).

Compared with control mice, transplant with healthy monocytes extended survival and lowered inflammation.

“We showed that around a 60 to 70 percent replacement of bone marrow in mice can improve the symptoms of inflammation in cystic fibrosis,” Fan said. “This was really good.”

Because monocytes affected by CF were still present, monocyte recruitment to the lungs and intestines was impaired. Further, monocytes from transplanted mice were more effective against bacterial infection than CF monocytes. Fan noted the next step is to challenge treated mice with an infection.

In a reverse experiment, bone marrow from CF mice was transplanted into healthy mice, which induced CF-like symptoms and limited their survival, “suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease,” the researchers wrote.

Finally, selectively deleting CFTR production from monocytes prevented weight gain and exacerbated induced colitis — inflammation of the colon’s inner lining.

“Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients,” the scientists wrote.

The researchers also plan to investigate the molecular defect that impairs monocytes in CF.

“What is the molecular mechanism behind this defect?” Fan asked. “If we can study this, we might be able to design a drug that can target it.”