The successful activation of T cells is critical to the immune system's ability to clear infections. A new retrospective study from China found that COVID-19 patients had remarkably low T-cell counts in their blood. And they had sky-high levels of some pro-inflammatory cytokines such as IL-6—which Roche’s Actemra targets.
Actemra has previously shown promise at controlling potentially life-threatening cytokine storm in COVID-19 patients in China and France, and Roche is running a large phase 3 to confirm its effectiveness in treating patients with COVID-19.
In the study from China, published in Frontiers in Immunology, a group of scientists analyzed T-cell counts in 499 COVID-19 patients being treated for the disease in the city of Wuhan. They found a negative correlation between T-cell numbers and cytokines. The team suggested that the novel coronavirus doesn’t attack T cells directly, but rather triggers an overproduction of cytokines, which in turn contributes to the depletion and exhaustion of T cells.
The Chinese researchers noticed that about 76% of patients had insufficient T cells, and the level was much lower in those in intensive care. They then examined the concentrations of cytokines from the blood of these patients and found that the levels of TNF-alpha, IL-6 and IL-10 were significantly increased in infected patients. The elevation was even more pronounced in ICU patients. TNF-alpha is known to promote T-cell death, and dysregulated IL-6 has been shown to induce chronic inflammation.
As the patients gradually recovered, their T cell counts improved, while levels of those cytokines dramatically declined. So the researchers hypothesize that the depletion of T cells in COVID-19 patients may be the result of cytokines impeding T-cell survival or proliferation.
What’s more, the T cells that did survive showed signs of exhaustion, with markedly higher expression of immune-inhibitory factors such as PD-1 and Tim-3 on their surface. That was a sign that their functioning was impaired, the researchers reported.
Based on these findings, the team argued the secretion of pro-inflammatory cytokines likely does not come from T cells, but that the cytokine storm may promote the death of the critical immune cells.
Finding new ways to restore the vigor of immune cells has been of interest in the biomedical research community, notably in oncology. A team at the University of Pennsylvania, for example, found that a protein called TOX in T cells controls the balance of effector T cells and exhausted T cells, suggesting it could be targeted to improve immuno-oncology treatments. And scientists at the La Jolla institute for Immunology recently showed that crippling all three proteins of Nr4a transcription factors could rejuvenate exhausted CAR-T cells to fight solid tumors in mice.
Based on their findings, the Chinese team suggested that future COVID-19 research should focus on identifying more drugs that provide much-needed support to T cells.
“We should pay more attention to T cell counts and their function, rather than respiratory function of patients,” the study’s corresponding author, Yongwen Chen of the Third Military Medical University in China, said in a statement, adding that “more urgent, early intervention may be required in patients with low T lymphocyte counts.”