JP2003513933A - Interferon gamma for asthma treatment - Google Patents

Abstract

  (57) [Summary] The present invention discloses the clinical application of interferon gamma (IFN-γ), which was the first successful treatment of bronchial asthma in humans. Clinical data clearly demonstrate that continuous administration of IFN-γ at relatively low doses can be used effectively for long-term treatment of severe bronchial asthma, especially for glucocorticoid-resistant asthma. The present invention also relates to a combination therapy for administering IFN-γ and glucocorticoid, each of which alone is ineffective or insufficient in treating asthma.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention is the first successful example of clinical application of interferon gamma (IFN-γ) for the treatment of bronchial asthma in humans. Clinical data clearly show that continuous administration of relatively low doses of IFN-γ is effective in the long-term treatment of severe bronchial asthma, especially asthma resistant to glucocorticoids. The present invention also relates to combination therapies in which IFN-γ and glucocorticoids are administered, which alone are ineffective or ineffective in treating asthma.

BACKGROUND OF THE INVENTION Bronchial asthma is defined by WHO as a "chronic inflammatory disease of the trachea" and is a helper type 2 phenotype due to the profile of several types of inflammatory cells in the bronchial mucosa, especially cytokines. It is due to chronic infiltration and activation of CD4 ⁺ T lymphocytes, which are defined as (phenotype) (Th2) (Bousquet
et al., 1990, N. Engl. J. Med. 323: 1033-1039; Broide et al., 1991, J. A.
llergy Clin. Immunol. 88: 637-648; Robinson et al., 1992, N. Engl. J. Med
326: 298-304; Woodley et al., 1994, Eur. Resp. J. 7: 1576-1584). Chronic inflammation of the respiratory mucosa plays a fundamental role in the pathogenesis of asthma, with 10 in industrialized countries.
As many as one person is affected (Roche et al., 1989, Lancet. 1: 520-523). The inflammatory response in asthma is closely associated with airway hyperreactivity, a hallmark of asthma, and is isolated from eosinophils, basophils, mast cells, and, most importantly, asthmatic lungs. Many types of cells are involved, including Th2 lymphocytes, which are able to. Upon activation, these cells show interleukin (IL) -4, IL-5, IL
It may induce inflammatory mediators and cytokines such as -10 and GM-CSF, amplify the inflammatory response and remodel lung structures. In addition, IL-13, a pleotropic cytokine produced in large quantities by activated Th2 lymphocytes, is associated with chronic tracheal inflammation, hypermucus secretion, subepithelial fibrosis, and eotaxin that are characteristic of bronchial asthma. ) Production (Zhou et al., Z.
, 1999, J. Clin. Invest. 103: 779-788). More importantly,
Inhibition of IL-13-dependent immune response in an IL-13-deficient mouse model completely abolishes bronchial hyperresponsiveness (Wills-Karp et al., 1998, S
cience 282: 2258-61; Grunig et al., 1998, Science 282: 2261-63).

Th2 cells secrete IFN-γ while Th2 cells promote tracheal inflammation in asthma
One cell is said to protect against allergic disease by reducing the activity of Th2-effecting cells. Th1 cells suppress the proliferation and thus development of Th2 cells (Drazen et al., 1996, J. Exp. Med. 183: 1-5), and IFN-γ suppresses IgE synthesis in some cases. (Derdak et al., 1992, Am. J. Physiol. 263: L
283-L290). For example, traditional allergen immunotherapy that improves symptoms in patients with allergies and asthma reduces IL-4 production (markhluf et al., 1996, J. Investi.
g. Dermatol. 107: 856-859) and increase IFN-γ production in an antigen-specific manner (Schmitt-Graff et al., 1994, Virchows Arch. 425: 3-24; Phipps et a.
L., 1989, Am. J. Respir. Cell Mol. Biol. 1: 65-74). Heat-sterilized Listeria monocytogenes (Siro) as an adjuvant with an IL-12 modified allergen (Schleimer et al., 1992, J. Immunol. 148: 1086-1092).
ni et al., 1994, Blood. 84: 1913-1921), a naked DNA plasmid containing cDNA for IL-12 in the trachea or for an allergen (Bochner et al.
, 1995, J. Immunol. 154: 799-803; Wegner et al., 1990, Science. 247: 456-4.
59) immunization resulted in a shift in cytokine production in antigen-specific CD4 ⁺ T cells and caused a decrease in allergen-induced tracheal hyperreactivity (Paolieri et al., 1997, Allergy. 52: 521-531).

Furthermore, these observations suggest that the antigen-specific Th1 response suppresses the cellular inflammation characteristic of bronchial asthma. Together with the inventor's initial clinical results, these data provide a sufficient basis for conducting a Phase II clinical trial for the use of IFN-γ in the treatment of bronchial asthma.

Interferon-γ is a natural glycoprotein with a molecular weight of about 17 kD, which is nowadays commercially produced by recombinant technology. As already mentioned above, along with (other) cytokines, interferon-γ plays an important role in the human immune system and usually exerts an immunomodulatory effect (cell activation and location-dependent immune stimulation or immunity). Means a suppressive effect). However, interferon-γ
There are still unsolved mysteries about the full and true role of. What is certain is that at least three types of immune system cells (CD4T helper 1, natural killer (na
tural killer, CD8 cytotoxic suppressor
)) Produced in an organism by at least four different cell types (C
D4T helper 2, macrophages, natural killer, B cells).

Interferon-γ as a pharmaceutical compound has been successfully used today against several viral infections and especially against tumours. On the other hand, IFN-γ
Is effective, for example, alone or in combination with other anti-inflammatory agents, in the treatment of rheumatoid arthritis and the production of additional surfactant in the lungs of patients suffering from respiratory distress syndrome (RDS). It is known that there is. Despite these findings, with the exception of tumors, most of the findings obtained with IFN-γ are based on data in-vitro or in animal models, with no or poor clinical support. It must be pointed out that

DISCLOSURE OF THE INVENTION According to the present invention, interferon-gamma is combined with prednisolone to interstitial lung, each idiopathic pulmonary fibros.
has been successfully applied to disease: the mechanisms that regulate certain types of immunobiology in bronchial asthma are unknown. From a comparative study of chronic inflammatory reactions,
In idiopathic pulmonary fibrosis characterized by an immune response by Th2, IFN-g
It has been shown that the clinical application of is improved lung function and alters the immune response by reversing the Th2 response (Ziesche et al., 1996, Chest 110: 25S, EP-A1).
-0795 332). Furthermore, in vivo data on the regulation of cell function obtained by administration of IFN-γ to human lung fibrosis indicate that the administration not only reverses the response of the immune part, but also induces epithelial growth and growth factors ( growth factor) beta 1 and connective tissue growth factor have also been shown to reduce transcription of growth factors that are closely related to extracellular matrix regulation (Ziesche et al., 1999, N.). Engl. J
Med. 341: 1264-1269; EP-A1-0795332). Interferon-γ can usually be administered parenterally, preferably by subcutaneous injection. The highest serum concentration is seen after 7 hours and the plasma half-life is 6 hours.

The main side effects are fever, chills, sweating, headaches, muscle aches and drowsiness. These effects are seen within the first few hours after injection. Rare side effects are local pain and erythema, liver enzyme elevations, reversible granulocyte and platelet loss and cardiotoxicity. No specific antibody to any recombinant interferon-γ has been found to date.

The present invention provides improved therapies for the treatment of chronic asthma and, preferably, glucocorticoid-resistant asthma. "Glucocorticoid-resistant asthma", as used herein, refers to asthma-type and asthma-like disorders that are wholly or substantially resistant to treatment with glucocorticoids as monotherapy.

Although it is known that it does not affect Th2-like responses in animal models, there is no hint in the prior art that interferon-γ has once been attempted for application in the treatment of bronchial asthma. The present invention provides the first clinical evidence of interferon-γ in the treatment of asthma and glucocorticoid resistant asthma. Although some unproven prophetic hints that IFN-γ may be useful in the treatment of asthma (eg WO87 / 07842, WO91 / 07984), asthma, especially glucocorticoid resistance There is no real clinical proof or exact teaching for clinical medication of asthma. The treatment method according to the present invention has significant advantages over traditional treatment methods with high doses of glucocorticoids and / or immunosuppressants alone or in combination. The present invention shows that using the agents described above and below, the symptoms of the disease are clearly reduced or alleviated and the quality of life is improved.
Furious and severe asthma attacks are reduced and can finally be stopped. This is accomplished by administering interferon-γ at low doses and over extended periods of time. Surprisingly, the simultaneous administration of glucocorticoids produces a definite effect, even though monotherapy of glucocorticoid-resistant asthma is ineffective. This effect allows not only glucocorticoids, but also IFN-γ to be administered to patients with clearly lower single and overall doses. In addition, the amount of glucocorticoid depends on the first initial stage of administration.
It can be reduced within the range of (phase).

Known amounts of IFN-γ usually used for the treatment of viral infections and tumors (about 100 μg-5 mg per unit body surface area M ² per dose and per day, up to 7 times per week, eg WO 87 / It is shown in the present invention that the dose can be reduced in principle than that of 07842), and it can be proved to be effective in treating bronchial asthma. Furthermore, it can be shown that the use of the following agents enables a long-term treatment method that significantly improves the health and condition of patients.

Thus, a new use of low dose interferon gamma (IFN-γ) or a combination of low dose IFN-γ and glucocorticoids for drug manufacture,
Or it is an object of the present invention to provide a pharmaceutical combination for the long-term treatment of bronchial asthma.

It is a particular object of the present invention to provide the use of interferon gamma when glucocorticoid therapy is ineffective or substantially ineffective against bronchial asthma when administered alone. According to the present invention, IFN-γ can be successfully used not only for long-term treatment of bronchial asthma but also for acute treatment.

A further object of the invention is a long-term method of treating bronchial asthma, which comprises administering to a patient a low dose of interferon gamma (IFN-γ) or a low dose of a combination of IFN-γ and a glucocorticoid. The administration period of IFN-γ is 4-24 months, preferably 4-15 months.

Interferon-γ was found to be effective at a dose of 5-100 μg, administered 1-5 times a week, preferably 2-3 times a week for 4-24 months, preferably 10-15 months. . The above single dose of interferon-γ is administered to the patient parenterally, preferably subcutaneously, three times a week. Thus, the weekly dosage for a patient is about 1
Between 5 and 300 μg interferon. However, this weekly dosage can be administered in three or more divided doses.

Therefore, low doses of interferon gamma (IFN-γ) or low doses of I
It is an object of the present invention to provide a use for a long-term treatment of bronchial asthma, characterized in that a combination of FN-γ and glucocorticoid is administered to a patient, wherein a single dose of 5-100 μg of IFN is provided. -γ is administered 1-5 times a week.

It is a preferred use of the present invention that the total weekly dose of IFN-γ administered to a patient does not exceed 300 μg.

A further preferred object of the invention is the low dose of interferon gamma (IFN-
γ) is administered to a patient for use in a long-term treatment of bronchial asthma, wherein a single dose of 5-100 μg of IFN-γ is given weekly.
-5 doses for 4-24 months.

As mentioned above, the combination of IFN-γ and glucocorticoids shows advantageous results, and even in the case of asthma to which glucocorticoids do not respond, IFN-γ does not affect the efficacy and treatment period. And the dose of glucocorticoid can be reduced. Suitable glucocorticoids are, for example, cortisol, prednisone, cortisone, prednisolone and 6-α-methylprednisolone. A preferred compound according to the invention is prednisolone.

The dose of glucocorticoid administered to a patient is between 10-100 according to the invention.
It can vary between mg / single dose, more preferably between 15-80 mg. The initial dose is preferably 75 mg.

The glucocorticoid is administered in the first stage for 1-4 weeks, preferably 2-3 weeks. The dose for this first step is 20 and 100 mg, preferably 50-75
between mg. After this initial stage, the dose can be reduced to 10-5 mg. During the next few months of treatment, the dose is continuously reduced and finally discontinued.

Thus, it is another object of the present invention to provide a method of use and treatment wherein a single dose of glucocorticoid administered in the initial stage of 1-4 weeks is 20-100 mg, and then 10-0 mg. Is the purpose.

In general, the optimal therapeutically acceptable dosage and dose ratio for interferon-γ and glucocorticoids administered to a patient within the ranges above will depend on a variety of factors, namely the activity of the particular active agent used, age and , Weight, general health, sex, diet, time and route of administration, clearance rate or therapeutic purpose.

The term “parenteral” as described above and below includes subcutaneous, intravenous, intraarticular and intratracheal injection and infusion techniques. Oral administration can only be used with glucocorticoids. This method of administration is not suitable for polypeptides such as interferon, since the organism becomes unavailable after it has passed through the digestive tract.

Interferon is preferably another suitable carrier for interferon-γ,
It is administered in the form of pharmaceutical compositions and formulations containing excipients, diluents and the like. The term "pharmaceutically acceptable carrier or excipient" as used herein refers to an inert, non-toxic liquid excipient, diluent, solvent or solution which contains the active substance or the patient. Refers to those that do not cause harmful reactions. Suitable liquid carriers include sterile water, saline, dextrose water, sugar water, ethanol, glycols and oils such as petroleum, animals,
It is well known in the art including those of plant or synthetic origin. The formulation also
It may contain adjuvants or solvents typical of parenteral administration. With regard to so-called suitable formulations, it must be pointed out that interferon-γ and glucocorticoids eventually change their solubility by forming pharmaceutically acceptable salts with non-toxic organic or inorganic acids. As the inorganic acid, for example,
Acid metal salts such as hydrochloric acid, sulfuric acid or phosphoric acid and sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids include acetic acid, glycolic acid, lactic acid,
Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid,
Mention may be made of mono-, di- and tricarboxylic and sulphonic acids such as salicylic acid. Salts of amino acid components with a carboxy terminus include non-toxic carboxylic acid salts formed with suitable inorganic or organic bases. These salts include, for example, alkali metals such as sodium and potassium, alkaline rare earth metals such as calcium and magnesium, and organic primary, secondary and tertiary amines such as trialkylamines.

According to the invention, IFN-γ in combination with other therapeutically active agents such as antiallergic agents such as phenylbutazone, acetylsalicylic acid, ibuprofen or lipocortin, non-steroidal anti-inflammatory agents or antipyretics. Can also be used. These agents can be administered in dosages and formulations well known in the art per se.

Surprisingly, it can be seen that the treatment of asthma patients as indicated above and in the claims has other distinct effects. In many cases of chronic asthma, patients develop extensive nasal polyps that classical standard treatments such as glucocorticoid monotherapy cannot prevent. Therefore, the only possibility to help the patient is to surgically remove the polyp. However, in all cases, nasal polyps recurred,
This is only a temporary relief as it continues to grow again. With the treatment method according to the invention, after surgical removal, nasal polyps can be treated, in principle, if after 12-24 months all severe asthma symptoms have diminished or become negligible. Recurrence has the effect that it can be prevented even after the administration has ended.

Therefore, relapse after surgical removal of nasal polyps associated with asthma and asthma-like diseases, characterized by administering IFN-γ or IFN-γ in combination with a glucocorticoid to a patient as described above. It is another object of the invention to provide a method of preventing continuous growth.

Although not yet proven, nasal polyposis caused by diseases other than chronic asthma through similar biological and / or immunological processes or based on similar inflammatory responses may also be treated with IFN-γ alone or It is also realistic to consider that it can be successfully used in combination with steroids and non-steroidal anti-inflammatory agents.

By examining the transcription of genes associated with the inflammatory mediators TGF-β1 and IL-13, the levels of these mediators are increased and the levels of IFN-γ are decreased and deficient in bronchial mucosal tissues of asthmatic patients. It became clear that even one could be seen. Since these factors are known to be involved in epithelial growth and its regulation, it can be inferred that treatment with IFN-γ is effective in diseases showing overexpression of these factors.

Therefore, an increased expression of inflammatory mediators in bronchial mucosal tissues of asthmatic patients, characterized in that a low dose of IFN-γ or a low dose of IFN-γ is administered in combination with a glucocorticoid. It is another object of the invention to provide a method of reducing IL-13 and TGF-β1.

In such a situation, inflammatory mediator I in bronchial mucosal tissue characterized by administering IFN-γ or a combination of IFN-γ and glucocorticoid
It is also an object of the present invention to provide a method of treating people with elevated levels of L-13 and TGF-β1.

Example 1 The following patient had severe, glucocorticoid-resistant exogenous bronchial asthma and excessive nasal polyposis, had multiple nasal surgery for severe asthma recurrence with polyposis, When first admitted to our outpatient clinic, the development of bacterial bronchopulmonary disease complicated the situation. At this time, the patient had been receiving oral glucocorticoid (50 mg / day) for 8 months or longer with complete antiallergic treatment. The history of the disease was characterized by frequent asthma attacks at night, even when there was no exacerbation due to bacteria.

Analysis of gene transcription of the relevant inflammatory mediators in the bronchial mucosa of this and two other patients according to the method described by Ziesche et al., 1999, Ic, showed that IL-13 and TGF-β1. A marked deficiency of IFN-γ was revealed, along with high transcription of γ.

Due to the severe illness of this patient and the imminent risk of a fatal asthma attack, 1 in combination with an oral prednisolone dose initially (20 mg daily)
IFN-γ (IFN-γ-1b, Boehringer Ingelheim at a dose of 00 μg three times a week)
, Germany) was prescribed. One glucocorticoid prescription was 7 days a day after 3 weeks.
． Reduced to 5 mg. Figure 2 shows IFN-γ (300 μg / week) and 7.5 m / day
It shows the history of disease for 12 months in patients under continuous administration of g-prednisolone. On the other hand, the patient has been on IFN-γ for 25 months. Oral glucocorticoid administration was discontinued 14 months after treatment with IFN-γ and replaced with a single inhalation of fluticasone dry power (standard formulation). Fourteen months after initiation of IFN-γ treatment, the patient underwent nasal surgery again.
Multiple nasal polyps were removed. To date, no recurrence has been observed. Side effects of IFN-γ treatment were fever and chills for the first 2 weeks, and two episodes of headache. All side effects disappeared completely after 3 weeks of treatment.

Patient lung volume (total lung volume (TLC), functional exhalation (
functional expiratory) vital capacity (FVC) and functional expiratory volume (FEV))
Tables 1 and 2 show the changes in the partial pressure of blood gas (pO ₂ , pCO ₂ ). FEV1
Values from 3.1 liters to about 4.5 liters (+ 48.4%), FVC values from about 4.4 liters to 6.5 liters (+ 47.7%) and TLC values from 7.1 in the first 12 months. 7.
It has increased to 6 (+ 7%).

[0037]

[Table 1]

[0038]

[Table 2]

Example 2: The second case was followed for 5 months. Once again, the patient had extrinsic bronchial asthma without severe nasal polyposis. The initial daily dose of prednisolone was 75 mg. This medication did not prevent severe asthma attacks from occurring at night or at night. IFN-γ (300 μg per week) administered with the first 15 mg of prednisolone resulted in a FEV ₁ of 2.4 l to 3.1.
increased to 1. About two weeks after the start of treatment, the patient reported a marked improvement in activity capacity.

Industrial Applicability From these individual observations, treatment with IFN-γ can be used effectively in patients with bronchial asthma resistant to glucocorticoids with only minor side effects. You can conclude that you can.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE, TR), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ , UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, C H, CN, CR, CU, CZ, DE, DK, DM, EE , ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, K P, KR, KZ, LC, LK, LR, LS, LT, LU , LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, S G, SI, SK, SL, TJ, TM, TR, TT, TZ , UA, UG, US, UZ, VN, YU, ZA, ZW F-term (reference) 4C084 AA02 BA03 BA44 CA62 DA24                       MA01 NA14 ZA591 ZA592                       ZB112                 4C086 AA01 AA02 DA10 MA02 MA04                       MA07 NA14 ZA59 ZB11

Claims (26)

[Claims] 1. A low dose of interferon gamma (IFN-γ) or a low dose of IF for producing a drug or a combination of drugs for the long-term treatment of bronchial asthma.
Use of a combination of N-γ and glucocorticoid. 2. The use of interferon gamma (IFN-γ) according to claim 1, wherein bronchial asthma is resistant or substantially resistant to glucocorticoid treatment when the glucocorticoid is administered alone. 3. Use of interferon-γ according to claim 1 or 2, wherein bronchial asthma is associated with nasal polyposis. 4. The use according to any of claims 1-3, wherein the single dose of IFN-γ is 5-100 μg for administration 1-5 times per week. 5. The use according to claim 4, wherein the total weekly dose of IFN-γ does not exceed 300 μg. 6. A single dose of glucocorticoid in an initial stage of 1 to 4 weeks is 20 to 100 mg, and thereafter is 10 to 0 mg.
Use as described. 7. The use according to claim 6, wherein the dose of glucocorticoid is continuously reduced after the initial stage. 8. The use according to claim 7, wherein the glucocorticoid is prednisolone. 9. The use according to any one of claims 1-8, wherein the drug or combination of drugs is provided for administration for a period of 4-24 months. 10. Use according to claim 9, wherein said period is 4-15 months. 11. Interferon gamma (IFN-γ) or IFN for the manufacture of a drug for the prophylactic prevention of recurrence and continuous growth of nasal polyps after surgical removal associated with asthma or similar inflammatory process-based diseases. -Use of a combination of γ and glucocorticoids. 12. A low dose of interferon gamma (IFN-γ) or a low dose for producing a drug for reducing the inflammatory mediators IL-13 and TGF-β1 which are increased in bronchial mucosal tissues of asthmatic patients. Use of a combination of IFN-γ and glucocorticoid. 13. IL-13 and TGF-β1 increased in bronchial mucosal tissue
Interferon gamma (I) for the manufacture of a drug for the treatment of persons with levels
FN-γ) or the combination of IFN-γ with a glucocorticoid. 14. A low dose of interferon gamma (IFN-γ) or a low dose of IFN-γ in combination with a glucocorticoid is administered, and the administration period is 4-2.
Long-term treatment of bronchial asthma patients characterized by being for 4 months. 15. The long-term treatment method according to claim 13, wherein the administration period is 4 to 15 months. 16. A low dose of interferon gamma (IFN-γ) or a low dose of IFN-γ in combination with a glucocorticoid is administered and a single dose of 5
A long-term treatment method for bronchial asthma patients, characterized in that -100 μg of IFN-γ is administered 1-5 times a week. 17. The total weekly dose of IFN-γ administered to a patient is 300.
The long-term treatment method according to claim 15, which does not exceed μg. 18. A low dose of interferon gamma (IFN-γ) is administered, and a single dose of 5-100 μg of IFN-γ is administered 1-5 times a week for 4-24 months. -Term treatment for patients with bronchial asthma. 19. A low dose of interferon gamma (IFN-γ) is administered, and the total weekly IFN-γ dose administered to a patient does not exceed 300 μg, and the administration period is 4 to 24 months. A long-term treatment method for a patient with bronchial asthma, characterized in that 20. The long-term treatment method of any one of claims 13-18, wherein asthma is resistant or substantially resistant to glucocorticoids when administered alone. 21. A single dose of glucocorticoid administered during the first 1-4 weeks of the initial stage is 20-100 mg, and then 10-0 mg.
9. The long-term treatment method according to any one of 9 above. 22. The long-term treatment method according to claim 20, wherein the dose of glucocorticoid is continuously reduced after the initial stage. 23. The glucocorticoid is prednisolone, 13-
21. The long-term treatment method according to any one of 21. 24. Recurrence after surgical removal of nasal polyps associated with asthma and similar inflammatory process-based diseases, characterized in that the patient is administered IFN-γ or a combination of IFN-γ and glucocorticoids. How to prevent continuous growth. 25. IL-13, an increased expression of inflammatory mediator in bronchial mucosal tissue of asthmatic patients, characterized by administering low dose IFN-γ or a combination of low dose IFN-γ and glucocorticoid. And methods for reducing TGF-β1. 26. Increased inflammatory mediator I in bronchial mucosal tissue characterized by administering IFN-γ or a combination of IFN-γ and glucocorticoids.
A method for treating a person having L-13 and TGF-β1 levels.