New Cell Type Ruled Out in Asthma

SOUTHAMPTON, England, April 4 -- The research focus in asthma should shift back to conventional T-cells and away from the newly discovered invariant natural killer cells, according to investigators here.

A series of experiments in volunteers with asthma and chronic obstructive pulmonary disease showed they had the same levels of the new cells in their airways as did healthy controls, said Pandurangan Vijayanand, M.D., of the University of Southampton.

The finding, reported in the April 5 issue of the New England Journal of Medicine, is in sharp contrast to one last year that said 60% of the CD4-positive T-cells found in the airways of people with asthma were invariant natural killer cells. (Newly Recognized Immune Cell Unveiled in Asthma)

It is known, the researchers said, that patients with asthma have an increased number of type 2 helper CD4-positive T-cells in their airways. Also, there is evidence from animal models - as well as last year's report in humans - that many are invariant natural killer T-cells, rather than conventional class II major-histocompatibilitycomplex-restricted cells.

But in experiments looking at bronchoalveolar-lavage fluid, induced sputum, and lung tissue, Dr. Vijayanand and colleagues said, the proportion of invariant natural killer T-cells was less than 2% in all volunteers.

The new study "strongly questions the significance of invariant natural killer T-cells in the pathogenesis of asthma," Dr. Vijayanand and colleagues said. "Therapeutic strategies in asthma should therefore continue to be focused on class II MHC-restricted T-cells rather than on invariant natural killer T-cells."

The difference between the two studies was that Dr. Vijayanand and colleagues were "stringent" in eliminating false positives from such sources as macrophages and monocytes, commented Ling-Pei Ho, M.D., Ph.D., of the Oxford Centre for Respiratory Medicine in Oxford, England, in an accompanying editorial.

But, Dr. Ho noted, the "balance of evidence" in animal models suggests that the killer cells play some role in the pathogenesis of asthma.

Exactly what that role is remains to be cleared up, Dr. Ho said, adding "we still have some way to go to fully understand how immune cells are regulated in the lungs."

Invariant natural killer T-cells, a subset of CD4-positive T-cells, express a receptor that responds to glycolipids, rather than peptides. They usually make up less than 1% of peripheral-blood mononuclear cells, and activated natural killer cells spark chemokine and cytokine release, as well as promoting the maturation of dendritic cells and the production of antibodies.

The researchers used a variety of techniques, including flow cytometry and real-time polymerase chain reaction analysis, to come to their estimates. They targeted two receptors characteristic of invariant natural killer cells, V?24 and V?11.

They recruited 24 volunteers with mild or moderate asthma, 10 with Stage 0 to Stage 3 COPD, and 12 healthy controls.

In initial flow-cytometric analysis, 11 of the asthma group underwent bronchoalveolar lavage and analysis with monoclonal antibodies to the V?24 and V?11 receptors showed that killer T-cells made up less than 2% of the cells expressing CD3 (all T-cells) and less than 1.5% of the cells expressing both CD3 and CD4.

Induced sputum analysis allowed the researchers to test a larger number of volunteers, including the controls, and volunteers with both stable COPD and COPD during an infectious exacerbation.

Again, the proportion of invariant natural killer T-cells was low, Dr. Vijayanand and colleagues said - less than 1.3% in all cases. There were no significant differences between the groups and the controls.

Because cells in mucosa could differ from luminal cells, the researchers also took bronchial biopsies in 11 asthma patients. Again, the proportion of invariant natural killer T-cells ranged from 0 to 1.7% of CD3-positive T-cells.

The researchers also examined bronchoalveolar-lavage fluid and induced sputum samples from several volunteers, using PCR to look for the RNA associated with the genes for the two killer cell receptors. While T-cells were readily detected, there was no sign of the two receptors, Dr. Vijayanand and colleagues said.

Dr. Ho reported he had no conflicts.