When mice infected with influenza A are treated with a protein that targets OX40, a costimulatory molecule expressed on recently activated T cells, the animals' flu symptoms disappear.
"In the lung you tend to see an immune response that far exceeds what is needed to clear the pathogen," said team leader Tracy Hussell at Imperial College London, UK, whose latest data are published in the Journal of Experimental Medicine. It is this excessive immune response that causes symptoms such as coughing and wheezing.
Unlike other anti-inflammatory treatments, including corticosteroids that affect all T cells, the OX40 treatment only inhibits cells recently activated with antigen. "It specifically dampens down those cells that are responding at that time," she said. If treatment is stopped while some cells remain in the lung, sufficient numbers enter the T cell memory pool to allow cellular immunity to develop.
Another advantage of the treatment is that it is not specific for a particular pathogen and so can be used to treat a range of inflammatory disorders.
Andrew Weinberg, a researcher at the Providence Portland Medical Center in Oregon, USA has shown that in animal models of autoimmunity, such as the mouse model of multiple sclerosis, so-called experimental autoimmune encephalomyelitis (EAE), downregulation of OX40 signaling blocks the initial waves of inflammation.
"We have shown that OX40 positive T cells are the autoantibody-specific T cells within the inflammatory lesions of EAE," he said. Blocking OX40 signalling, or deleting OX40 positive cells, reduces the symptoms without affecting the rest of the T cell repertoire, he says.
And the versatility of this molecule as a target for immunotherapy does not stop with downregulation. Upregulating OX40 signalling can enhance desirable immune responses. Indeed, Weinberg thinks the greatest therapeutic potential for OX40 regulation may lie in cancer therapies.
"Our group and others have now shown that giving an agonist OX40 antibody to mice with tumours has profound proinflammatory effects leading to the eradication of tumours in several models," he said. The treatment also increases the number of memory T cells, thereby enhancing antigen specific cellular immunity.
Fortunately, the OX40 molecule is highly conserved between mice and humans and both Hussell and Weinberg hope that OX40 technologies will reach the clinic soon. Plans are afoot to test it on healthy individuals and asthmatics - a group who could benefit greatly as viral infections exacerbate asthma.
However, Weinberg sounds a note of caution. "Unfortunately, these recombinant fusion proteins are expensive to produce and therefore expensive for treatment," he said. But, he added, "If small molecules could be found to inhibit OX40-specifically then you could possibly treat flu symptoms with a nasal spray and everyone could take advantage of this technology at a reasonable price."
BioMedNet
13 November 2003
Original web page at BioMedNet
