The immune system overreaction to COVID-19 has become a key target for therapeutic research, including a new trial at the University of Minnesota using stem cells to try to suppress the body's response to infection and repair the damage it causes.

While COVID-19 patients can die from heart disease, stroke or blood clots, many die from respiratory failure caused by a "cytokine storm," the release of immune-signaling proteins that can ultimately clog the lungs and cut off the oxygen supply to blood.

"Sometimes it's the lungs themselves and the cytokine storms," said Dr. David Ingbar, a critical care and pulmonary specialist leading the U trial. "Sometimes it's making people so weak and ill that they are set up for other complications."

Minnesota has totaled 1,685 COVID-19 deaths along with 62,993 infections with the coronavirus that causes the infectious disease.

The Minnesota Department of Health also reported that 308 people were hospitalized for COVID-19 on Thursday — including 154 who needed intensive care due to breathing problems and other complications — and that 5,742 people have been hospitalized since the pandemic arrived in the state six months ago.

U researchers have been planning from the start to study the potential therapeutic benefits of mesenchymal stem cells (MSCs) against severe COVID-19. The U pioneered the use of these cells — which are produced in bone marrow to repair cartilage and bone in the body — in the treatment of other severe immune-related diseases.

The U announced the trial Thursday following approval by the U.S. Food and Drug Administration to test the stem cell therapy in patients who have already been hospitalized for COVID-19 and placed on ventilators due to respiratory distress.

The first enrollee received an infusion Wednesday, though it's unclear in the comparative blind trial whether that person received the stem cells or a non-medicating placebo.

The study is the second this month announced by the U to target the cytokine storm reaction. The other seeks to use a therapy derived from "natural killer" cells, the sentry dogs of the immune system that attack viruses while tailored antibody responses are developed.

The NK study is more preventive, enrolling patients who have not yet suffered respiratory distress during their COVID-19 hospitalizations but appear at risk.

While there are many types of cytokines, the commonality is that they are released as signals to the immune system of what to target and how forcefully to respond. The release of excessive cytokines can be toxic to the lungs on its own, but it also dilates the blood vessels, which leak fluid that can build up in the lungs and inhibit oxygen flow.

Many patients are "full of" virus but don't show severe symptoms until after the immune system response, said Dr. Frank Rhame, a virologist for Allina Health in Minneapolis. "That really sharply illustrates that it's the reaction, not the illness, that does this."

A COVID-19 Treatment Guidelines team formed by the National Institutes of Health has reviewed evidence for using mesenchymal stem cells to treat this hyperimmune response but does not recommend them outside of clinical trials.

"It's very much not ready for clinical implementation and clinical use," said Dr. Jason Baker, a Hennepin Health doctor who is part of the NIH review team. "There is potential, but it very much needs to be proven."

COVID-19 research so far has shown that the drug remdesivir has antiviral properties that can prevent severe respiratory symptoms if given early in hospitalizations, and that the steroid dexamethasone may fight inflammation in severe cases and reduce the risk of death.

The U was involved in the national remdesivir trial and also conducted trials that found that hydroxychloroquine did not prevent the onset of symptoms in people exposed to the coronavirus. The U also is continuing a COVID-19 trial of losartan, a drug usually administered to treat high blood pressure.

One of the U's first successes with mesenchymal stem cells was in the treatment of graft-versus-host disease, a condition in which the body's immune system rejects transplanted organs.

Mesenchymal stem cells are promising for COVID-19 because they gravitate toward the lung tissue that is inflamed by the immune response to the virus and because they target all types of cytokines, said Dr. John Wagner, director of the U's Institute for Cell, Gene and Immunotherapy.

"The reason we believe this might be a better approach to inhibiting the cytokine storm is because it tackles all of them simultaneously," he said.

The U had been an early user of a cancer drug, tocilizumab, as an immune-fighting therapy — including in the treatment of a young Ironman athlete in March who was Minnesota's first COVID-19 case to be placed on a ventilator and into a medically induced coma. That drug targets a single cytokine, IL-6, that appears to play a key role in the immune response to COVID-19.

Small studies out of China and Italy raised the prospect of some benefit in the use of MSCs against COVID-19, but they enrolled few patients and had no placebo comparison.

The stem cells seem to have a suppressive effect for only 48 hours, so the U trial will provide patients with three infusions during the critical week in which they first suffer respiratory distress.

Timing will be crucial, because the deterioration can be rapid, Ingbar said. Consent will often have to come via video from the patients' designated medical decisionmakers, because patients will be on ventilators and unable to give the OK on their own.

The end-value of this stem cell therapy could depend on the development of other preventive therapies for COVID-19 or a vaccine, but Wagner said it could end up as a vital treatment option in this pandemic and for other causes of severe respiratory distress.