Title:  Prophylaxis of allergic disease

United States Patent:  6,333,038

Assignee:  TVW Telethon Institute for Child Health Research Princess Margaret Hospital (Subiaco, AU)

Filed:  August 26, 1996

PCT NO:  PCT/AU94/00780

102(e) Date:  August 26, 1996

PCT PUB. Date:  June 29, 1995

Foreign Application Priority Data:  Dec 22, 1993[AU] (PM 3077)

The invention provides a method for preventing allergic disease in an individual susceptible to such disease, comprising administering an allergen to which the individual has not been sensitized previously. The allergen is administered in a dose and form effective to establish a stable population of allergen-specific T-helper-1-like memory lymphocytes capable of inhibiting activity or amplification of allergen-specific T-helper-2-like lymphocytes responsible for stimulating production of IgE antibodies specific for the allergen. Compositions for use in the method of the invention are also disclosed.

SUMMARY OF THE INVENTION

The present inventor now proposes that the T-lymphoid system in humans engages in active surveillance for environmental "allergens" throughout life, and that it is the nature of (as opposed to the mere presence of) allergen-specific T-cell responses in individuals that determines whether they express the allergic (atopic) or immunologically normal (non-responder) phenotype. The inventor has recognised that selection of the appropriate T-cell population is an antigen-driven process which occurs during the early stages of immune responses in the naive (unsensitised) host. If selection favours the growth of allergen-specific T-cells of the T-helper-1-like (TH-1)-like phenotype low-grade non-pathogenic IgG and IgA responses ensue, whereas the emergence of TH-2-like cells can lead to IgE production and eosinophilia and ultimately atopic disease. Additionally, TH-1-like cytokines actively suppress the expansion of TH-2-like clones, and hence a dominant, stable TH-1-like response to an allergen is proposed to be actively protective against the development of TH-2-like dependent allergic disease. With respect to T-cell responses to ubiquitous environmental allergens, the inventor's review of the recent paediatric literature has identified early childhood as the life period during which this selection normally occurs, and shows that the process can take several years to complete. Once the significance of the selection is appreciated, sufficient information is already known of how this natural selection process operates to contemplate controlling.it in vivo, via deliberate administration of allergen(s) in a form adapted to preferentially stimulate the development of host-protective TH-1-like immunity.

Our data suggest that "bystander" cell populations, in particular CD8⁺ and/or T_{.gamma./.delta.} cells, can actively assist the overall TH-1-like selection process, and the term "TH-1-like immunity" in this specification is to be understood to include the contribution of these cells.

According to a first aspect, the invention provides a method of prevention of allergic disease in an individual susceptible to such disease, comprising the step of administering to a previously unsensitised individual a dose and form of allergen effective to induce establishment of a stable population of allergen-specific T-helper-1-like memory lymphocytes, said lymphocytes being capable of inhibiting activity or amplification of allergen-specific T-helper-2-like lymphocytes responsible for stimulating production of IgE antibodies specific for said allergen.

Preferably the allergen is an environmental antigen, and may be administered either singly or as a combination of two or more such allergens. The allergen may be in its naturally-occurring form. Alternatively the allergen may be a protein prepared using recombinant DNA technology, or may be a synthetic peptide. The allergen may be in purified form or may be impure or partially purified. The allergen may represent either the whole allergen molecule, or may be a part thereof, for example including one or more epitopes. Allergens contemplated to be suitable for use in the invention include those from house dust mite, animal danders such as cat, dog or bird dander, cockroach, grass pollens such as those from ryegrass or alternaria, tree pollens such as those from birch or cedar, feathers and moulds. The most suitable allergens will depend on the geographical location. For example, birch and cedar pollens are a major cause of allergies in northern Europe and Japan, but are of minor importance in Australia.

For both aspects of the invention, the allergen may be administered by the oral, intranasal, oronasal, rectal, intradermal, intramuscular or subcutaneous route. The adjuvant is preferably a liposome or a microbial cell wall product.

The allergen may optionally be administered together with an adjuvant. Suitable adjuvants will be known to the person skilled in the art. An adjuvant which selectively stimulates T-helper-1-like lymphocytes is preferred.

The dose of allergen will generally be in the nanogram to milligram range, depending on the allergen, the route of administration, and whether or not an adjuvant is used. The person skilled in the art will readily be able to determine the number and frequency of doses, using well-established principles. It is expected that for parenteral administration the dose range will be of the order of micrograms, that for intranasal administration the dose range will be in the microgram to milligram region, and that for oral or rectal administration the dose will be in the milligram to gram range. It will be appreciated that the dose could vary depending on whether an adjuvant is used, and depending on the nature of the adjuvant.

The method of the invention is suitable only for treatment of individuals who are not already allergic, i.e. hypersensitive, to the allergen being administered.

In general, the method is most suitable for treatment of children between 3 months and 7 years old, but is also applicable to individuals older than 7 years. Preferably the immunization is administered to children not less than 6 months old, more preferably not less than 9 months old.

Because in early childhood most individuals will not yet have been exposed to sensitisation by environmental allergens, it is considered that this period provides the optimum opportunity to select for allergen-specific host-protective TH-1-like mediated immunity. It is especially preferred that immunisation against airborne allergens, ie. allergens to which the individual is exposed by inhalation, be effected during early childhood.

According to one preferred embodiment of the invention, allergen is administered orally or intranasally during early childhood.

According to a particularly preferred embodiment, which is considered to provide selective induction of TH-1-like response to allergens with minimal stimulation of TH-2-like response, a mixture of two or more allergens of the airborne type is administered parenterally together with a TH-1-like selective adjuvant during early childhood.

According to a second aspect, the invention provides a sterile composition comprising an environmental allergen, together with an adjuvant capable of selectively stimulating T-helper-1-like lymphocytes, and optionally a pharmaceutically-acceptable carrier.

The allergen may be impure or purified, and may be of natural origin, produced by recombinant DNA technology, or synthetic.

Preferably the allergen is selected from the group which consists of house dust mite, animal danders such as cat, dog or bird dander, cockroach, grass pollens such as those from ryegrass or alternaria, tree pollens such as those from birch or cedar, feathers and moulds.

Preferably the composition is adapted for oral, intranasal, oronasal or rectal administration, but intradermal, subcutaneous or intramuscular administration may also be used.

Claim 1 of 12 Claims

What is claimed is:

1. A method for the prophylactic treatment of allergic disease triggered by an environmental allergen in a human individual susceptible to such disease, comprising the step of administering to an individual who has not been sensitized by said environmental allergen a dose and form of said environmental allergen effective to induce establishment of a stable population of allergen-specific T-helper-1-like memory lymphocytes, said lymphocytes being capable of inhibiting activity or amplification of allergen-specific T-helper-2-like lymphocytes responsible for stimulating production of IgE antibodies specific for said environmental allergen.

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