Innate Lymphoid Cells and Crohn’s Disease

What role do innate lymphoid cells play in conditions like Crohn's disease, and could bone marrow transplant help?

A built-in component of the innate immune system, natural killer cells are aptly named: They kill cancer. As a young pediatric hematology-oncology fellow, Michael Verneris, MD, was intrigued enough by that property to spend a significant chunk of his career studying them, and they’ve led him in some unexpected directions — most recently to the investigation of the role of innate lymphoid cells in an astonishing array of diseases.

Down the NK cell rabbit hole

By now most medical professionals are familiar with the immune theory of cancer: that mutant cells emerge in the body all the time, the wayward result of glitches in the genetic code, and the immune system naturally recognizes and kills them.

The real mystery is not that the glitch occurred, but why the immune cells tasked with killing the defective cells — natural killers, or NK cells — failed to do their job. And, importantly, whether they could be made to treat established cancers.

“When a cell becomes cancer, it displays proteins on its surface that signal it’s abnormal or distressed. NK cells see those signals and target those cells. Our lab participates in the international effort to characterize that process and use it as therapy,” says Dr. Verneris. “Part of the problem is that there’s no good way to grow NK cells in the lab.

“So we started down the rabbit hole,” he says.

That was 20 years ago, when cancer immunology was less an accepted medical reality than a pipe dream. In some ways, the work has come full circle. Dr. Verneris’ team has described the entire process of culturing NK cells using stem cells extracted from umbilical blood.

But in some ways, the more intriguing aspect of that work was another cell type whose differentiation the team’s landmark 2020 study describes — a cell type that, ten years ago, no one knew existed.

Natural killers and natural healers

In 2009, a couple of studies came out describing a mysterious subset of NK cells with the capability to produce IL-22, a growth factor that helps repair the intestine, among other things. Dr. Verneris read them with interest.

“NK cells usually circulate in the blood. These cells were found in tissue,” he recalls. “It was like, ‘That’s weird. What are those cells doing there?’”

Then he went directly to the lab to run a quick assay to see if any of his stem cell-derived NK cells were producing IL-22, and indeed: Some of them were.

It soon became clear they weren’t NK cells at all. These cells produced similar surface proteins and expressed similar genes. They had clearly differentiated from the same bone marrow stem cells. But their function was radically different.

NK cells produce cytokines to destroy malignancies. The new cells, eventually named innate lymphoid cells, or ILCs, produced factors that signaled and contributed to tissue repair.

And the more Dr. Verneris’ lab has looked, the more they’ve found ILCs implicated in an astonishing array of disease processes: cancer, allergy, multiple sclerosis, neurodegeneration, diabetes, psoriasis, eczema, nasal polyps.

“The skin, the intestine, the liver, the lungs, they’re in all the sites where we meet the world and bad things can happen,” says Dr. Verneris. “They’re a sort of a first line of defense.”

Dr. Verneris’ clinical specialty, and another area of research interest, is bone marrow transplant, and he’d often thought about how bone marrow transplant might be used to treat autoimmune conditions like inflammatory bowel disease. A couple of intriguing published case studies had described Crohn’s disease patients who developed cancer and got bone marrow transplants to treat it, and their Crohn’s improved.

His findings on ILCs and their role in repairing tissue — and how bone marrow transplant could potentially reset how they work in the intestine — got him thinking about that again.

How bone marrow transplant affects solid tissue

Laura Cobb, MD, has a lot experience with Crohn’s disease. Her disease course — diagnosed at 13, didn’t respond to therapy — is not unusual for kids. Many don’t. Another 50% lose response over time. Close to 80% need surgery. Forty percent, like Dr. Cobb, need multiple operations.

But she had no intention of studying it. Instead she went into hematology-oncology with an interest in bone marrow transplant, which is how she found herself in the lab of Dr. Verneris.

“I actually didn’t even know she had Crohn’s.” He chuckles. “I was pitching the idea to fellows every year, hey, want to do this Crohn’s project? And everyone was like, ‘nah, nah.” Until Laura.”

Dr. Cobb was interested.

The idea wasn’t entirely new. A couple of groups had investigated with small animal models, but they’d induced Crohn’s using various chemical combinations intended to irritate the gut. Drs. Verneris and Cobb wanted a model that was truer to the disease process.

Working with pediatric gastroenterologist Edwin deZoeten, MD, PhD (“His office is literally five doors down from mine,” says Dr. Verneris), they secured two models: one genetically engineered to overproduce the cytokine TNF alpha — also overproduced in Crohn’s — which induces inflammation in the small bowel, and another engineered to lack an immune system, which, somewhat mysteriously, given T cells from a healthy animal model, develop Crohn’s-like inflammation in the large bowel. The work won a pilot grant from the University of Colorado’s GI and Liver Innate Immune Program.

For Dr. Cobb, the exciting thing is not only the potential of allogenic transplant to potentially cure or durably improve the disease, but the prospect of what stands to be learned even if the experiment fails.

“Most studies involving bone marrow transplant are focused on blood cells,” she says. “So much of what happens in our tissues after transplant is unknown. We like to think that this project will help us understand those processes better, and maybe why patients that get bone marrow transplant for other reasons might have success.”

“There are more lymphocytes in skin and intestine than in the blood and bone marrow,” Dr. Verneris adds. “They’re hard to study. It’s hard to figure out, does a cell plonk in the intestine and stay there its whole life, or does it break off and circulate in the blood, and if it does, does it come back to the same spot or a different spot? If you get a bone marrow transplant, which cells in a given spot are from the donor and which are from the patient, and how does that change over time? We’re going to learn all that.”

The things that strike you

Natural killers are among the first cells to bounce back after bone marrow transplant, and research has shown the more robustly they do, the better the outcome. This year, Dr. Verneris’ lab will begin a clinical trial giving leukemia patients NK cells cultured from their donors after transplant.

The lab also found that both ILCs and NK cells develop in secondary lymphoid tissues like tonsils, which led them to study tonsils removed from kids with Down syndrome, who tend to be prone to upper respiratory infection and pneumonia. They found significant differences in cell type and activation status compared to their disomic counterparts. They secured $3 million in funding from the NIH to continue that investigation.

And then there’s the small animal model genetically engineered to lack lymph nodes that, under certain conditions, Dr. Verneris discovered, will spontaneously grow them. “I don’t even want to talk about that yet,” he says.

That’s all just this year.

They’re all exciting projects, but what most excites Dr. Verneris is projects like Dr. Cobb’s. Projects he can hand off to a promising young researcher and, in so doing, help launch a promising career.

“A long time ago, I went to a talk with a famous immunologist, and he said, ‘If you’re in the crowd, you’re probably in the wrong spot,’” Dr. Verneris recalls. “It’s so funny the things that strike you. But he was so right.

“When I was starting out,” he continues, “this cancer immunology stuff was way out on the fringe. Now we’re looking at these lymphoid tissues, what kind of role they could play in disease recovery and how we could manipulate that, and we don’t think anyone else is really thinking about that right now. It’s beyond the fringe.”