Immunomodulators: Two for the price of one?

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The novel immunosuppressant drug FTY720 (fingolimod) is a sphingosine-1-phosphate analog that can clear chronic viral infections in mice.

A novel immunosuppressant drug — FTY720 (fingolimod) — has counter-intuitively now also shown promise as an agent that can clear chronic viral infections in mice.


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Writing in Nature, Premenko-Lanier and colleagues examined why some microbial infections are cleared by some individuals, yet persist in others. Two strains of lymphocytic choriomeningitis virus that have different outcomes in mice were used as a model. The Armstrong strain induces transient profound lymphopaenia, but mice are able to clear the infection. By contrast, the clone 13 strain does not induce the same degree of lymphopaenia, and chronic infection of the virus occurs.

Lymphocytes were demonstrated to be sequestered in the lymphoid tissue in higher numbers in the Armstrong-infected mice than the clone-13-infected mice. In light of this, the authors proposed that forced lymphopaenia in the clone-13-infected mice might aid in the clearance of the virus, and chose short-term treatment with FTY720 to induce this effect.

Exit of immune cells from the lymph nodes is regulated by the S₁P₁ receptor, one of five receptors for sphingosine-1-phosphate (S1P). Phosphorylated FTY720 is a S1P analogue that binds to S₁P₁ (and three other S₁P receptors) and blocks the egress of lymphocytes from lymph nodes and Peyer's patches.

Intravenous administration of low doses of FTY720 soon after time of infection to clone-13-infected mice resulted in viral titres that were significantly lower in the serum, brain and kidney in comparison with control mice. Moreover, short-term administration of FTY720 in an established infection of clone 13 also cleared infection, even in organs that harbour the virus for the lifetime of untreated mice.

Although the exact mechanism of action of FTY720 is unclear, it was demonstrated that CD4 T cells are necessary for the immune-enhancing effects of FTY720, and that clearance of the virus is mediated by the immune system and not due to direct antiviral effects of the drug. FTY720 has already been tested in clinical trials for treating multiple sclerosis and preventing kidney transplant rejection, and so the strategy identified by the authors might be readily translatable to novel potential immunotherapies for chronic microbial infections in humans.

Man Tsuey Tse

References

Premenko-Lanier, M. et al. Transient FTY720 treatment promotes immune-mediated clearance of chronic viral infection. Nature 454, 894–898 (2008) | Article | PubMed |