WO1998047520A1 - Prevention et traitement de maladies allergiques, par l'augmentation ciblee de l'immunite assuree par les lymphocyte t de protection - Google Patents

Prevention et traitement de maladies allergiques, par l'augmentation ciblee de l'immunite assuree par les lymphocyte t de protection Download PDF

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Publication number
WO1998047520A1
WO1998047520A1 PCT/US1998/008248 US9808248W WO9847520A1 WO 1998047520 A1 WO1998047520 A1 WO 1998047520A1 US 9808248 W US9808248 W US 9808248W WO 9847520 A1 WO9847520 A1 WO 9847520A1
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antigen
immunity
allergic
immune response
target organ
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PCT/US1998/008248
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English (en)
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David E. Bice
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Lovelace Respiratory Research Institute
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Priority to AU71549/98A priority Critical patent/AU7154998A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/208—IL-12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/217—IFN-gamma
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Asthma and other allergic diseases of the respiratory system combined represent one of the largest costs to the health care delivery system of the developed world. It is estimated, for example, that over 6.5 billions of U.S. dollars ($6.5 billion) are expended each year in the treatment of asthma in the United States alone. If rhinitis and other related allergic conditions are included, the figure increases significantly. Moreover, asthma incidence is on the rise; the incidence of asthma increased approximately 50% in the United States in the period 1986-1996 with no generally accepted explanation.
  • Allergic diseases are caused by immune responses to allergens such as pollen, cat allergen, dust mites, mold spores, and the like. All current treatments for allergy-related maladies involve the application of medicinal products that interfere with the production or action of "mediator" substances from immune cells stimulated by allergens.
  • Three classes of drugs generally are used: (1 ) glucocorticoids which reduce inflammation when administered systemically or by inhalation; (2) beta blockers that reduce the smooth muscle responses in the patient's airways; and (3) mast cell function inhibitors that reduce histamine release.
  • These modes of treatment are all directed to easing the symptoms of the allergic condition. None is intended to cure allergic diseases or attack directly the underlying, immunological cause of allergies. The prevention or elimination of allergic immune responses would alleviate the need for the toxic drugs presently widely used to treat allergic diseases.
  • U.S. Patent No. 5,599,545 to Stanford states that it appears that killed cells of Mycobacterium vaccae promote the immune response characteristic of Th1 cells.
  • the '545 patent indicates the use of M. vaccae as an adjuvant for injected vaccines to prevent mycobacterial disease, particularly tuberculosis and leprosy. Prophylactic topical application of M. vaccae alone, as a means of preventing allergic disease in a specific organ caused by elevated Th2 responses is not taught.
  • U.S. Patent No. 5,116,144 to Rook et al. also discloses that antigenic material derived from M. vaccae may be injected as an adjunct to chemotherapy of leprosy and tuberculosis.
  • Th2 immune responses Most commonly encountered allergies, such as asthma and related maladies, are the result of abnormally elevated Th2 immune responses.
  • abnormally elevated Th1 immune responses can also lead to various types of disease, as discussed by Weigle, W.O., in "Advances in Basic Concepts of Autoimmune Disease,” Clinical Laboratory Medicine, September 1997; 17(3):329-340. If the onset of abnormally elevated Th1 immune response is prevented, or if abnormal levels can be reduced, the associated disease is prevented or treated.
  • the invention relates to prevention and treatment of disease by targeted development of protective T-helper lymphocytes.
  • Certain disease is manifest in "target organs" where the disease is symptomatic, for example, gastric disease is manifest in the "target organ” of the digestive system and membranes.
  • local application of selected type Th2 immune response-inducing immunostimulants to target organs inhibits or blocks the production of detrimental type Th1 immune response in the target organ.
  • Th1 immune response-inducing immunostimulants to target organs inhibits or blocks the production of otherwise detrimental type Th2 immune response in the target organ.
  • a primary object of the present invention is to provide a composition and method for preventing and treating certain immunologically related diseases on a broad basis.
  • a primary advantage of the present invention is the provision of a composition and method for inducing a protective type Th2 immune response in a target organ, thereby foreclosing or ameliorating a type Th1 immune response in the target organ to provide prophylaxis or treatment of disease.
  • compositions for the prevention of diseases manifested by immunological response in a target organ comprising an immunostimulant topically
  • the invention relates to the prevention and treatment of immunologic allergic diseases and diseases associated with immune disorders.
  • Allergic diseases are diseases caused by the action of antibodies, as in allergic hypersensitiveness to allergens. Manifestations of allergic disease most commonly involve the respiratory tract, and often are characterized by a reaction to the release of histamine or histamine-like substances from immune cells. Allergic conditions associated with allergic disease include, but are not limited to, allergic rhinitis, hay fever, and bronchial asthma.
  • Th1 immune response Most humans produce a Th1 immune response to allergens.
  • the Th1 immune response usually is protective, and individuals having a Th1 type of response do not exhibit symptoms of allergic disease, such as nasal congestion, tearing, sneezing, wheezing, coughing, and itching.
  • the Th1 immune response therefore, normally (but not universally) is beneficially free of undesirable symptoms.
  • Type Th2 immune responses involve the production of immunoglobulin gamma E (IgE) antibodies to allergens, particularly but not exclusively inhalant allergens such as dusts, pollens, fungi, animal dander, and the like.
  • IgE immunoglobulin gamma E
  • Th1 and Th2 lymphocyte responses can be differentiated by the production of cytokines by immune cells.
  • Immune cells from the lungs of non-asthmatics for example, produce IL-2, IL-12, and IFN ⁇ (type 1 immunity), while immune cells from the lungs of asthmatics produce IL-4, IL-5, and IL-10 (type 2 immunity).
  • the production of IL-2 and IFN ⁇ in type 1 immune responses results in cell-mediated immunity and the production of lgG 1 ⁇ 2 ⁇ 3 .
  • type 2 immune responses the release of IL-4, IL-5, and IL-10 supports the production of IgE and lgG 4 in the lungs of humans as well as the recruitment and activation of eosinophils into the lungs.
  • the present invention is a new approach to the treatment and prevention of asthma and other immune diseases as a result of the identification of how type 1 and type 2 immune responses are induced and regulated in the lungs of nonatopics and target organs in individuals genetically susceptible to or suffering from the development of allergic diseases and diseases associated with immune disorder.
  • the IgE antibody that causes allergic symptoms is distributed throughout the body of an individual suffering from an allergic disease. Presumably, therefore, all organs and tissues in the body should be equally sensitive to allergens. On the contrary, the symptoms of allergic diseases usually are manifested predominantly, or even exclusively, at certain "target organs.” For example, the bronchi and/or lung is the predominant target organ for allergic disease in individuals suffering from asthma.
  • a target organ is an organ, including without limitation the lungs, nasal mucosa, trachea, bronchi, and eyes, where the symptoms of the allergen-antibody reaction are acutely manifest to the discomfort of the sufferer.
  • Other possible target organs include the skin, small intestine, bladder, urethra, vagina, rectum, and gastric mucosa.
  • allergic individuals may suffer more than one type of allergic disease, and may have different predominant target organs which respond to different allergens, and may exhibit symptoms which vary in severity for different allergens. (It is possible, for example, to suffer from hay fever due to ragweed, and asthma due to fungus spores.)
  • An aspect of the present invention is the determination that lungs and other target organs are immune-competent organs that develop immune responses separate from the systemic immune system, and the lung or other affected organ reacts independently to allergen exposures. This independence is total.
  • One organ e.g., the lung or nasal airways
  • One organ e.g., the lung or nasal airways
  • Autonomous immunity in individual organs is the reason one allergic individual suffers predominantly from rhinitis (hay fever) while another allergic individual has predominantly asthma.
  • the lungs are more sensitive to allergen exposures in individuals with asthma, and the nasal airways are more sensitive in individuals with rhinitis.
  • the increased sensitivity of the lungs or nasal airways is due to the localization of allergic Th2 immune responses in the lungs or other organs.
  • the localized production of anti-allergen IgE in either the lungs or nose selectively increases the sensitivity of these organs to allergen exposures.
  • Whether an individual develops asthma but not hay fever depends not only on heredity but also on the individual's history of localized exposures of his lungs or nasal airways to allergens and/or infections early in life.
  • Certain environmental exposures induce immune responses in the lungs or nose toward allergic Th2 immunity. Examples include exposures to high concentrations of allergens, pulmonary infections with viruses, and passive inhalation of cigarette smoke.
  • bacterial infections appear to induce the development of protective Th1 immune responses.
  • Increased bacterial infections in individuals living in underdeveloped countries have been observed to correlate with an elevated level of protective Th1 immune responses in their lungs and nasal airways.
  • Th1 immunity in the lungs or nasal airways prevents the development of allergic Th2 immunity to inhaled allergens, with the result that fewer individuals living in these countries have allergic diseases. In comparison, individuals who do not have airway infections are more likely to develop allergic Th2 immunity to inhaled allergens.
  • the lungs become the only source of antibody production after exposures to antigens, and the level of antibody is higher in the lung than in blood or other tissues.
  • Antibody produced in the lung is distributed throughout the body.
  • the production of anti-allergen antibody in the lung results in higher concentrations of anti-allergen antibody in the lung than anywhere else in the body.
  • some individuals have predominantly asthma, but not hay fever, because anti-allergen antibody is produced in their lungs.
  • immune responses to allergens in nasal airways result in high levels of anti-allergen antibody in the nasal mucosa. The production of this allergic antibody in the nose is the cause of hay fever.
  • compositions may be prepared from bacterial, fungal, viral, parasite, or protein sources which, when inhaled, induce protective Th1 immunity in the lungs.
  • the development of protective Th1 immunity in human or animal lungs by such substances provides immune cells necessary in the lung to produce protective Th1 immunity to inhaled allergens.
  • the production of Th1 immunity to inhaled allergens in the lungs prevents the development of Th2 immunity to allergens and asthma.
  • the compositions which induce protective Th1 immunity are delivered to the lungs to protect the lungs from developing allergic Th2 immune responses which cause asthma. Immunizing systemically with Th1 antigens is ineffective or less effective in establishing Th1 immunity in the lungs.
  • the invention includes the topical application of specific purified, nontoxic immunostimulants to the lungs, and/or nasal/pharyngeal area, or other target organ(s) to induce a protective Th1 immune response. It is contemplated that preventative application be performed on young children at risk for developing disease, but any person may be benefitted by the invention.
  • the establishment of Th1 immunity in the lungs prevents the later development of Th2 immune responses to allergens, and thus prevents asthma.
  • the production of Th1 immunity in the nasal airways prevents the development of Th2 immunity and rhinitis.
  • This topical application may be done to separately and specifically immunize the nasal passages and the lungs to prevent asthma, rhinitis, allergic bronchitis, and related diseases.
  • Th1 immunity in target organs, especially those of children, prevents the development of allergic diseases in the treated target organ.
  • the nose is the target organ for rhinitis
  • hay fever is caused by Th2 immune responses in the nasal airways.
  • Treatment of the nasal passages of children with selected compositions establishes protective Th1 immunity in the nasal airways.
  • the establishment of Th1 immune cells in the nasal airways prevents the production of Th2 immunity to allergens deposited in the nose, thereby preventing the development of hay fever.
  • Similar approaches may be used to prevent the development of Th2 immunity in other target organs, including without limitation the eyes and digestive tract, particularly the mouth.
  • antigens may be used to develop compositions which stimulate Th1 immune responses in target organs. Published studies of bacteria indicate that intracellular bacteria and/or their products usually induce mostly Th1 immunity. Some bacterial antigens are known to induce Th1 immunity. These include antigens from bacteria genera Bordetella, Mycobacterium, Pseudomonas, Francisella, Brucella, Yersinia, Salmonella, Morganella, Klebsiella, Serratia, Escherichia ,Chlamydia, Listeria, Shigella, and Streptococcus. Antigens from other bacteria may also be important in the development of compositions that induce Th1 immunity. In addition to bacteria, antigens prepared from viruses, fungi, and parasites may also be used.
  • Th1 or Th2 immune responses potentially are stimulated by viruses, fungi, and parasites.
  • Intracellular viruses and parasites tend to induce Th1 immunity while extracellular viruses and parasites, including helminths, usually induce Th2 immunity.
  • antigens for compositions which induce Th1 immunity must be prepared from viruses, fungi, or parasites that induce primarily, or exclusively, Th1 immune responses, and not from those that induce Th2 immunity.
  • proteins may also be used.
  • keyhole limpet hemocyanin induces primarily Th1 immunity, and other proteins likely may be used as antigens to induce Th1 immunity.
  • the addition to the inventive composition of at least one cytokine which promotes, or is beneficial to, the development of Th1 immunity to antigens increases the induction of Th1 immunity. Examples of these cytokines include interleukin-2, interleukin-12, and interferon gamma. Four bacteria provide the preferred sources of antigens to induce Th1 immune responses in the lungs.
  • Mycobacterium vaccae Mycobacterium vaccae
  • Brucella abortus Brucella abortus
  • Streptococcus pneumoniae Streptococcus pneumoniae
  • Bordetella pertusius The most preferred bacterium for use in the invention is the bacteria M. vaccae.
  • Killed M. vaccae has been used to modify the immune responses in patients with tuberculosis or leprosy.
  • injections of killed M. vaccae suppress Th2 immunity and elevate Th1 immunity to mycobacterial antigens.
  • Th1 immunity immune protection
  • Th2 immunity tissue destruction
  • injections of killed M injections of killed M.
  • vaccae do not cause granulomas, and have not been shown to produce a measurable Th2 immune response. Injection of killed M. vaccae is safe to use in modulation of immune responses in humans. Because M. vaccae induces substantially exclusively a Th1 immune response, the preferred source of Th1 antigen for asthma prevention and treatment is killed M. vaccae. The capability of producing type 1 immunity without producing granulomas, the possible suppression of type 2 immune responses, and the lack of toxicity when injected into humans are reasons why M. vaccae is a preferred Th1 antigen for the present invention.
  • a source of M. vaccae used in human studies is Stanford Rook, Ltd., London, England.
  • the preferred specific preparation of killed M. vaccae is SRL 172.
  • SRL 172 available from Stanford Rook, Ltd, other strains of M. vaccae may be employed.
  • the "type strain” (ATCC 15483) and ATCC strain 29678 are available from the American Type Culture Collection Rockville, Maryland.
  • IL-12 to antigens increases the level of Th1 immunity produced. Therefore, the addition of IL-12 to the bacterial antigens described above optionally may be used to increase their effectiveness in the induction of Th1 immune responses in the lungs. Recombinant human IL-12 could be used to increase the level of Th1 immunity produced to Th1 antigens.
  • Antigens inducing Th1 immunity are delivered to the allergic target organs.
  • the preferred method for the induction of Th1 immunity in the lungs is by the delivery of Th1 antigens or cytokines to the lungs.
  • Th1 antigens are administered as an inhaled aerosol with a particle size that deposits in the small airways and/or alveoli of the lung.
  • the antigens need not be mixed with any other substances, but may be delivered in the form of fine powder.
  • aerosol inhalants may be a dry protein powder, soluble protein droplets, or protein aggregates.
  • the compositions are applied in a delivery medium, such wet or dry aerosols, nasal sprays, or nose drops, using known solutions to suspend and carry the antigen.
  • a delivery medium such wet or dry aerosols, nasal sprays, or nose drops
  • the compositions are delivered by eye drops.
  • Immunizing systemically with Th1 antigens is ineffective or less effective in establishing Th1 immunity in the lungs. It has been determined that primary immune responses are produced in the lung-associated lymph nodes after instillation of antigen into the lung, and that antigen-specific IgM, IgG, and IgA antibody-forming cells (AFC) produced in the lung-associated lymph nodes are released into the blood. Large numbers of AFCs are recruited from blood mainly into the lung exposed to antigen.
  • AFC antibody-forming cells
  • Th1 an antigen
  • Th2 an antigen
  • AFCs AFCs that are recruited from the corresponding lymph nodes, through the blood, into the target organ exposed to the antigen.
  • the induction of inflammation in the exposed target organ is responsible for the localized recruitment of AFCs.
  • the local production of antibody by these cells significantly increases the specific antibody in the lung or other target organ.
  • Immune memory lymphocytes for antibody-mediated immunity are recruited into lung or other target organ tissues exposed to antigen, and these memory cells respond in the lung to subsequent challenges with a localized production of high levels of antigen-specific antibody.
  • the induced immunity according to the invention is not wholly transient; the immunization and challenge of selected lung lobes, for example, induces long-term antibody production only in the exposed lung lobe. This localized antibody production continues for at least 5 years without the need for additional exposures to antigen.
  • the cells responsible for long-term antibody production are located predominantly in the interstitial tissues of the lung.
  • This invention also stems from a determination that cells in lung tissues produce significant amounts of antibody with little or no antibody production n lymphoid tissues that drain the lung or in distant lymphoid tissues. After comparing the level of antibody produced in control and immunized lung tissues as well as from lymphoid tissues at 2 years after the last exposure to antigen, it was determined that tissues from immunized lung lobes are the only site of significant antibody production. An evaluation of data concerning antibody production in immunized donor lungs transplanted into nonimmune recipients indicated that antibody continued to be produced in the immune donor lung for over 300 days.
  • the invention also is a recognition that a converse mode of prevention/therapy also applies, i.e., certain diseases associated with elevated levels of Th1 immune responses may be alleviated by inducing a targeted protective type Th2 response.
  • Th1 immune response is generally beneficial and protective against the adverse symptoms of the type Th2 response.
  • certain deleterious conditions are associated with elevated Th1 immune responses.
  • Disorders linked to elevated Th1 responses are, similarly to asthma for example, localized in specific organs. Stimulation of elevated Th1 lymphocyte responses in the digestive system causes periodontal disease, and has also been associated with ulcerative colitis and Crohn's disease.
  • Gastric disease may be induced by the stimulation of Th1 immune responses to Helobacteria.
  • Another aspect of the present invention therefore is the determination that certain organs are immune-competent organs that develop Th1 immune responses separate from the systemic immune system.
  • One organ or tissue e.g., the gastric mucosa
  • Th2 immunity localized in the gastrointestinal tract
  • systemic immunization with Th2 antigens is ineffective in producing targeted protective Th2 immunity in the gastric mucosa. Therefore, induced specific infection of the intestinal tract may establish protective immune responses localized to these tissues that prevent the development of diseases associated with Th1 response.
  • the immunological processes involved in developing this protective Th2 response are generally similar to those described above for the inducement of beneficial Th1 responses; the detrimental and beneficial roles of the respective T-helper immune responses are merely reversed. Accordingly, the stimulation of Th2 immunity by controlled administration of
  • Th2 antigens is prophylactic or therapeutic for diseases associated with abnormally elevated Th1 responses.
  • the stimulation of Th2 immunity in the digestive tract by topical application of Th2 antigens treats the aforementioned colitis and other gastric diseases.
  • Diseases of the genital or urinary tract may be treated by direct exposure to Th2 antigens; the balance of Th1 and Th2 immunity is important in the occurrence of vaginal infections, for example.
  • Th2 antigens are also associated with the stimulation of Th1 lymphocytes.
  • the administration of Th2 antigens thus also is a mode of treatment for these diseases. Stimulation of the production of cytokines by Th2 lymphocytes therefore is therapeutic for these varieties of autoimmune disorders.
  • Th1 immune responses are also important in graft rejection and graft-versus-host responses, exposures to Th2 antigens may be used to modulate the Th1 immune responses that cause the rejection of transplanted organs and in graft-versus-host disease.
  • Compositions may be prepared from, for example, parasite sources which when administered induce protective Th2 immunity.
  • Th2 immunity in human or animal lungs by such substances provides immune cells necessary in the target organ to produce protective Th2 immunity to exposure to Th1 response stimulators.
  • the production of Th2 immunity in the bladder or vagina for example prevents the development of Th1 immunity.
  • the compositions which induce protective Th2 immunity may be delivered topically by inhalation, ingestion, or vaginal or rectal suppository, or by transdermal or transcutaneous application, depending upon the target organ to be treated. Immunizing systemically with Th2 antigens is ineffective or less effective in establishing Th2 immunity in any particular organ or system.
  • Th2 immune responses There are a variety of antigens known to stimulate Th2 immune responses. Antigens isolated from helminth parasites (particularly ascarids) usually stimulate Th2 lymphocytes. Certain allergens also stimulate Th2 immune responses. Nevertheless, any antigen that stimulates Th2 immunity could be used to induce the protective/therapeutic response.
  • the antigens used in the invention to induce either type of protective immunity may be delivered in a variety of ways, depending upon the target organ to be treated. Topical application to the lungs is accomplished by direct inhalation of antigen powders; particles sizes may be, for example below 10 ⁇ m for inhalation into the alveoli. Dry antigen powder aerosols may be generated, for example, with the atomizer apparatus disclosed in United States Provisional Application No. 60/065,417, filed November 13, 1997, to Gerde, entitled "Dust Gun,” incorporated herein by reference. The production of aerosols of soluble materials is within the known art, and a variety of nebulizers may be used.
  • Topical application to the digestive tract may be by oral ingestion. Rectal and vaginal suppositories composed of antigen in known carrier materials are possible for use in topical application to corresponding associated target organs. Nose and eye drops of known composition may also be used to carry antigen to target organs.
  • known diluents typically composed of saline solutions (e.g. 0.9% saline from distilled water, optionally including human serum albumin) may be utilized.
  • the quantity of antigen employed in any given treatment or prevention plan depends somewhat upon the age and health of the patient. In all instances, it is preferred to apply the antigen in fractional doses over a period of time, rather than a single large dose application. Repeated fractional doses over a period of weeks or months is desirable in pediatric or geriatric patients.
  • a total cumulative dosage quantity of from about 400 ⁇ g to about 1 mg of antigen, per lung is indicated for the typical adult patient. The dosage for the typical child is about 100 ⁇ g antigen per lung cumulative quantity.
  • the invention can also be used to treat allergic diseases in target organs in children or adults who have already developed allergic diseases.
  • exposure of an allergic target organ with the composition increases the production of protective Th1 immunity to allergens and down-regulates allergic Th2 immunity.
  • Increasing Th1 immunity and decreasing Th2 immunity to allergens in target organs not only reduce allergic symptoms, but directly addresses the cause of the allergic disease.
  • Allergic immune responses in animals also cause serious clinical disease. Cats develop allergic immune responses to allergens which cause asthma. Dogs also develop allergic immune responses to many allergens they inhale. Because dogs have large airways relative to the size of their lung volume, they do not exhibit symptoms of asthma. However, dermal contact with allergens to which they are sensitized produces allergic dermatitis. Other animals, such as horses, cattle, and other livestock, also develop asthma-like allergic diseases to inhaled allergens. Allergic diseases can be prevented in animals by the inhalation of antigens that induce a primarily type Th1 immune response. To prevent allergic Th2 immune responses in animals, the lungs and nasal passages of newborn animals are exposed to Th1 antigens. Adult animals already allergic can be treated by inhalation of antigens which induce Th1 immunity in their lungs.
  • Example 1 Materials Industrial Applicability The invention is further illustrated by the following non-limiting examples. Example 1
  • a series of treatments are performed using killed M. vaccae SRL 172 to prevent asthma in beagle puppies.
  • Total IgE and the number of eosinophils in blood are determined to identify a puppy susceptible to the development of Th2 immunity.
  • the puppy is exposed by inhalation of an aerosol-borne killed M. vaccae
  • SRL 172 commencing at 3 weeks of age. After four weekly exposures to M. vaccae antigen, the puppy is exposed weekly by inhalation of ragweed extract. Serum samples are obtained every two weeks to evaluate blood eosinophilia and total IgE levels. When the puppy is 3 months of age, the levels of total IgE in blood and in lavage fluids from the lung are determined. Anti-ragweed and anti- vaccae IgE, IgA, IgM and the four subclasses of IgG are measured. Levels of cell-mediated immunity to M. vaccae and ragweed are evaluated by antigen-specific stimulation of lymphocytes from the blood and lung.
  • M. vaccae antigen prevents Th2 immunity to ragweed, the puppy is found not to produce IgE, eosinophilia, increased airway mucous, or to have increased airway reactivity to ragweed.
  • the topical application of M. vaccae serves to prevent the development of the asthma disease in the puppy.
  • Example 2 A series of treatments are performed using killed M. vaccae SRL 172 to treat existing asthma in beagle dogs.
  • An asthmatic dog having elevated IgE production in its lungs induced by inhaled ragweed is treated to reverse the effects of the type Th2 immunity.
  • the level of Th2 immunity to ragweed is evaluated in three selected lung lobes in the dog.
  • the three lung lobes are then instilled weekly with saline, ragweed, or M. vaccae SRL 172 respectively. More specifically, lunge lobe 1 (left cardiac) is instilled with ragweed, lung lobe 2 (right cardiac) is instilled with killed M. vaccae, and lung lobe 3 (right intermediate) is instilled with saline as a control.
  • Treatment of the animal on a "per lobe" basis presents the advantage of permitting direct comparisons of immune responses in exposed and control lung lobes.
  • the level of anti-ragweed Th2 immunity in the saline control lobe, the lobe challenged with ragweed, and the lobe instilled with M. vaccae By comparing the level of anti-ragweed Th2 immunity in the saline control lobe, the lobe challenged with ragweed, and the lobe instilled with M. vaccae, the ability of antigens from M. vaccae to change Th2 immunity in the lungs to a protective Th1 response can be observed.
  • Blood and lung lavage samples from the three lung lobes are obtained at 1 , 3, 5, 7, 10, 12, and 14 days after each exposure. The following is evaluated using serum, lavage fluids, and lavage cells from each of the lung lobes: levels of total IgE in blood and in lavage fluid from the lung, and anti-ragweed and anti- . vaccae IgE, IgA, IgM, and the four subclasses of IgG are measured; levels of cell-mediated immunity to ragweed and M.
  • vaccae are evaluated by antigen-specific stimulation of lymphocytes from the blood and lung; cells present in lung lavage samples are identified as neutrophils, eosinophils, lymphocytes, or alveolar macrophages and counted; levels of airway hyperactivity to methacholine is measured; production of mucus in the airways is evaluated; and lung pathology, e.g., airway inflamation with neutrophils, eosinophils, plasma cells, and lymphocytes is examined. Because exposure to M.
  • vaccae at least partially changes the Th2 immune response to Th1 immunity, the levels of anti-ragweed IgE, the production of mucus in the airways, the number of eosinophils in lavage fluid, and the level of airway reactivity is reduced in the lung lobe treated with killed m. vaccae. Responses are observed to be significantly higher in the lung lobes not exposed to M. vaccae but challenged with ragweed. Thus, M. vaccae antigen delivered to the lungs converts an established Th2 immune response (asthma) to a protective Th1 immune response, consequently effecting a direct treatment of the asthmatic disease.
  • Th2 immune response asthma

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Abstract

L'invention concerne une composition pour prévenir et traiter les maladies allergiques dans des organes particuliers. On applique à un ou plusieurs organes cibles des antigènes sélectionnés qui induisent principalement ou exclusivement une réponse immunitaire type des Th1 (lymphocytes T), pour induire une réponse immunitaire type des Th1 à l'intérieur desdits organes. La réponse immunitaires induite des Th1 se prolonge de sorte que soit supprimée l'apparition ultérieure de réponses immunitaires allergiques du type Th2 dans l'organe, en vue de la prévention de la maladie allergique ou de l'atténuation de la réponse immunitaire allergique du type Th2 en cours, dans des organes ayant déjà été atteints, pour le traitement de l'allergie. Les sources d'antigènes et les modes d'administration préférés sont décrits ainsi qu'une méthode et une composition pour prévenir et traiter les maladies associées à une réponse immunitaire de type Th1 anormalement élevée, par l'induction d'une réponse immunitaires des Th2 de type protectrice, thérapeutique et préventive.
PCT/US1998/008248 1997-04-24 1998-04-23 Prevention et traitement de maladies allergiques, par l'augmentation ciblee de l'immunite assuree par les lymphocyte t de protection WO1998047520A1 (fr)

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US4460497P 1997-04-24 1997-04-24
US60/044,604 1997-04-24
US93528297A 1997-09-22 1997-09-22
US08/935,282 1997-09-22
US6449498A 1998-04-22 1998-04-22
US09/064,494 1998-04-22

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WO2007072230A2 (fr) * 2005-12-21 2007-06-28 Institut Pasteur Controle de syndromes inflammatoires intestinaux avec une preparation de bacteries tuees ou non infectieuses

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002074334A1 (fr) * 2001-03-20 2002-09-26 Stanford Rook Limited Extraits de microbacteries et leur utilisation dans le traitement de la maladie intestinale inflammatoire
WO2007072230A2 (fr) * 2005-12-21 2007-06-28 Institut Pasteur Controle de syndromes inflammatoires intestinaux avec une preparation de bacteries tuees ou non infectieuses
WO2007072230A3 (fr) * 2005-12-21 2007-11-22 Pasteur Institut Controle de syndromes inflammatoires intestinaux avec une preparation de bacteries tuees ou non infectieuses

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