Lung surfactant proteins SP-A and SP-D, analysis of roles in innate immunity and assessment of use as therapeutics

Lead Research Organisation: MRC Immunochemistry Unit

Abstract

Surfactant proteins A and D (SP-A and SP-D) are components of the fluid layer lining in the lungs and are important in controlling lung inflammation and providing defence against infection. Certain patients with lung problems, such as premature babies, patients with cystic fibrosis and smokers with emphysema are all know to be deficient in surfactant proteins A and D - and it is possible that they could benefit from the administration of recombinant forms of these human proteins (made in large amounts in bacteria) and not suffer undesirable side-effects sometimes seen with other lung therapeutics. A fragment of SP-D, which can be produced in large amounts in bacteria, has been found to be as effective as the intact protein in its anti-inflammatory properties, and thus is a prime candidate as a new therapeutic for treatment of lung inflammation. However, it is important to fully study the properties and understand the mechanism of action, at the cellular level, of any such recombinant forms/fragments of SP-A, or SP-D, before entering into human trials with new therapeutics of this type - and thus much of the Units research is concerned with elucidating the manner by which these proteins modulate the immune system and reduce inflammation.

Technical Summary

The major objective, over the next five years, is to assess the potential of the use of recombinant fragments of the human lung surfactant proteins, SP-A and SP-D, as therapeutic agents in a wide range of allergies and infections of the lung. A mouse model of lung allergy, against the fungal allergens derived from Aspergillus fumigatus has been established in the Unit and mouse models of lung allergy have also been developed against house dust mite allergens (derived from Dermatophagoides pteronyssinus), against allergens derived from various grass pollens and against ovalbumin (as an example of a non-glycosylated allergen). Investigation of the mechanisms (at the cellular and molecular levels) by which SP-A and SP-D modulate lung allergy and inflammation is a major objective and this section of the research makes use of knock-out mice deficient in SP-A or SP-D. The SP-D knock-out mice have been shown to develop a chronic low-grade form of emphysema and we have shown that this condition can be reversed by treatment with a, relatively small, recombinant fragment of human SP-D - which is therefore a prime candidate as a therapeutic agent for lung inflammation induced by allergy or infection. Mouse models of lung infection by H.influenzae and A.fumigatus have also been set up to test the therapeutic effectiveness of the SP-A and SP-D preparations. Synthetic, and animal-derived surfactant preparations, lacking the SP-A and SP-D proteins, are presently successfully used to treat a range of patients with respiratory distress problems, but often these patients succumb to infections after the treatment. The testing of administration of recombinant forms of SP-A, or SP-D, as therapeutics on their own, or along with such therapeutic surfactant preparations is a major overall, long term, clinical aim. The direct interaction of purified SP-A and SP-D with a variety of material which may predispose to inflammation, such as apoptotic debris, DNA fragments etc is also being examined, especially with respect to clearance of these targets and the presentation of them, in a complex with SP-A or SP-D, to cells, such as denditic cells. Structural studies (solution NMR and X-ray crystallography) are also in progress, with the aid of collaborators on: recombinant fragments of SP-A, SP-D (in complexes with carbohydrate ligands); the globular heads of the serum complement protein C1q (as individual modules and as complexes with C-reactive protein); recombinant forms of TSR modules of the complement control protein properdin.

Publications

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