22 January 2003 9:00 GMT

by Sabine Louët

Dust mite, CDC

A British biotech company claims to have proved the in vivo validity of a novel therapeutic approach to suppress the allergic response to house dust mites. But, warn critics, such an approach might not succeed in countering the many ways that the immune system has developed to cause allergic reactions.

The company in question, Lorantis, found that Notch signaling controls the balance between suppression and activation of the immune response. By targeting the Notch receptor, which is present on the surface of T-cells, Lorantis researchers were able to focus on the antigen-specific responses of the immune system. The researchers found that over-expression of Notch signaling leads to an increase in the regulatory T-cell response and a decrease in the immune response, which could represent a useful way to treat allergies.

"Our latest preclinical results suggest that the original proof-of-concept carried out ex vivo can be reproduced in vivo," said Mark Bodmer, Lorantis CEO. "If you deliver the [house dust mite] antigen together with the Notch response, you can educate the immune system not to respond to the antigen," he added. Lorantis' researchers showed that mice treated with a combination of antigen-presenting cells that over-express Notch binding protein (ligand), together with a common house dust mite allergen, were rendered tolerant to the dust mite.

The idea of reversing vaccinating against allergens, driving suppression rather than activation of the immune response, is "pretty novel" but could present technical difficulties, says Kingston Mills, professor of biochemistry at Trinity College Dublin.

To solve the technical difficulties of delivering both the genes encoding Notch binding protein and a dust mite allergen (known as Der p1) in vivo, Lorantis recently made a deal with British drug delivery company Powderject. The latter provide the system to administer both genes in a DNA plasmid through a high velocity needle-less injector. A proportion of the DNA coated gold particles is delivered directly into the nuclei of a patient's antigen presenting cells, where the genes can be expressed. This avoids many safety issues associated with viral vector delivery.

"The trouble is that there is no system to actually target the relevant cells," said Salah Mecheri, head of the immuno-allergy unit at the Pasteur Institute in Paris. It is difficult to know which proportion of DNA injected through the skin actually makes it to the antigen presenting cells.

Back at Lorantis, Bodmer says that the key advantage of this strategy, thanks to its antigen-specificity, is that it targets the immune system more selectively than existing immune therapies. Existing therapies may be effective, but they compromise the normal function of the immune system, he says.

But, says Mills in Dublin, "The big weakness is that you are making an assumption that you know what the antigen target is." The house dust mite allergen target identified by Lorantis may be one among many others. "It is an awful lot more difficult than when you have a DNA vaccine which has a single target," he said.

Targeting just one antigen is not enough, says the Pasteur Institute's Mecheri. "There are dozens of antigens related to house dust mite," he said. What is more, when the immune response against a major antigen is suppressed, the immune system compensates, and minor antigens take over and become major antigens. The solution would be to inject a cocktail of genes that represent all the antigens relating to the house dust mite, he says.

And although this approach is specific to a given antigen related to house dust mite, Mecheri is concerned that it is does not discriminate vis-à-vis the body's own antibody response. When the body is attacked, it systematically produces antibodies that can either be protective (IgG antibodies) or trigger an allergic response (IgE antibodies). The Lorantis approach disables the body's ability to produces its natural IgG protective mechanism (primarily geared against infectious diseases), while removing the IgE allergic response altogether.

In the long run, Lorantis aims to develop selective antigen-specific upregulation or downregulation of immune responses for other applications. Besides allergies, many diseases result from an excessive immune response to antigens. For instance, autoimmune diseases such as rheumatoid arthritis and multiple sclerosis respond to self antigens, while transplant rejection results from differences between donor and recipient antigens.

Conversely, suggests Lorantis, it might be possible to increase the immune response by decreasing Notch signaling, and apply this technique when vaccination does not work as well - as in the case of cancer, where the immune system fails to see the tumor as foreign.

Send us your comments for publication. See also: Lorantis: creating new medicines for selective treatment of immunological diseases [Feature] Mark Bodmer Drug Discovery Today, 2002, 7:5:S19-S21 Molecular aspects of allergy Sylvia M. Miescher and Monique Vogel Also corresponding author. Molecular Aspects of Medicine, 2002, 23:6:413-462 Novel vaccines protecting against the development of allergic disorders: a double-edged sword? [Revi Klaus J. Erb and Gisela Wohlleben Current Opinion in Immunology, 2002, 14:5:633-643

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