WO2011040052A1

WO2011040052A1 - Therapeutic agent for atopic dermatitis

Info

Publication number: WO2011040052A1
Application number: PCT/JP2010/052394
Authority: WO
Inventors: 桑原正人; 本庄三知夫; 川鍋美紀子
Original assignee: 学校法人日本大学
Priority date: 2009-10-01
Filing date: 2010-02-10
Publication date: 2011-04-07
Also published as: JP5818685B2; JPWO2011040651A1; WO2011040651A1

Abstract

Disclosed are: a kit for treating atopic dermatitis in human and an animal; a method for treating atopic dermatitis; and others. Specifically disclosed are: an administration method; and a drug kit in which the monitoring, measurement and evaluation of a TGF-β1-Th3 biological reaction (a Th3 cell), a Th2 biological reaction (both a Th2 cell and a Th9 cell, or any one of the Th cells), a Th1 biological reaction (a Th1 cell and a Tfh cell or a Th1 cytokine) and a cytokine are carried out sequentially to select the quantity of each of the Th agents and the period of administration of each of the Th agents, thereby formulating a therapeutic agent.

Description

Atopic dermatitis treatment

The present invention relates to a therapeutic agent (treatment kit) for atopic dermatitis (AD) which is a kind of allergic disease. Specifically, the present invention relates to a therapeutic drug for atopic dermatitis in mammals. The present invention also relates to a method for treating atopic dermatitis, a kit for detecting atopic dermatitis (simple diagnostic kit), a method for evaluating a pathological condition of atopic dermatitis, and the like.

Atopic dermatitis (AD) is a skin disease whose main symptom is itchy eczema that repeats hatred and remission, and is an immediate type I allergy involving IgE and a type IV allergic delayed type It develops due to the combined involvement of allergies, and the subject is thought to be predominantly Th2. Further, the inventor has estimated Th9 cells Tfh cells (vesicular Th cells / Th2 biological reaction) at the time of onset.
In the treatment of atopic dermatitis, steroids mainly composed of corticosteroids are widely used for the purpose of suppressing itching and preventing inflammation. In addition to steroids, drugs such as antiallergic agents and antihistamines have been used to suppress histamine release or to inhibit antagonists of the H1 receptor (“Rullan P et al.,“ Two cases of chronic dermatitis ”. treated with soluble tumornecrosis factor receptor therapy. ", J. Drugs Dermatol., 2009, Sep; 8 (9): 873-876.").
On the other hand, atopic dermatitis is also said to be related to diet. Therefore, attempts have been made to relieve atopic dermatitis by diet therapy. For example, as a method for reducing plant allergens from meals, a method of removing foodstuffs containing allergens from foods or a method of rotating meals of other varieties regularly and sequentially has been proposed. In addition, there are Th cytokines such as interferon (IFN) and therapies using hygiene hypotheses (“Hanzlikova J et al.,“ TH1-TH2 responses and the patients with inpatients with reproduction ”,“ Failure ”). J. Reprod.Immunol., 2009, Mar; 61 (3): 213-220. "And" Brand U et al., "Allergen-specific immunity production and TH1 response induced by cit. I. ", J. Allergy Clin. Immunol., 1999, Nov; 104 (5): 1052-1059 "etc.).

However, the use of steroids has the disadvantage that it involves side effects such as edema, hypertension, and skin cracks. As a result, it induces oxidative cholesterol dermatitis, resulting in incurable skin. Even if the symptoms could be temporarily alleviated, recurrence and worsening of the symptoms occurred when the administration was stopped, and it was difficult to cure the disease fundamentally. In addition, it is an immune-mediated skin disease that recurs clinically and recurs clinically by stimulation such as scratching.
Under such circumstances, development of a completely different therapeutic agent (treatment kit) for atopic dermatitis has been desired instead of conventional therapy.
The present invention has been made in view of the above situation, and the following atopic dermatitis treatment kit, atopic dermatitis treatment method, atopic dermatitis detection kit, atopic dermatitis pathology A method for evaluating the above is provided.
(1) A kit for treating atopic dermatitis (including anti-Th3 drug and anti-Th2 drug), wherein an anti-Th3 drug is administered to a mammal, and then an anti-Th3 drug is administered instead of the anti-Th3 drug The kit, wherein the kit is used as described above.
The AD treatment kit of the present invention includes, for example, a kit further containing a Th1 drug, and is used so that a Th1 drug is administered in place of the anti-Th2 drug after administration of the anti-Th2 drug. It is done.
The AD treatment kit of the present invention is, for example, one that is used so that an anti-Th2 drug is administered after the start of administration of the anti-Th3 drug and a decrease in the Th3 biological response is observed. Examples include those that are used so that an anti-Th2 drug is administered after the start of administration, after a decrease in Th3 biological response and an increase in Th2 biological response are observed.
As the AD therapeutic kit of the present invention, for example, after the start of the administration of the anti-Th3 drug, the anti-Th2 drug is administered after normalization of the Th3 biological reaction is observed, and after the start of the administration of the anti-Th2 drug, the Th2 biological reaction What is used so that a Th1 modulator is administered after a decrease is observed, specifically, after the start of administration of an anti-Th3 drug, a decrease in Th3 biological response and an increase in Th2 biological response are observed, It is administered, and after the start of administration of the anti-Th2 drug, a Th1 regulator is administered after a decrease in Th2 biological reaction and a decrease in Th1 biological reaction are observed.
(2) A treatment kit for atopic dermatitis including an anti-Th3 drug and a Th1 regulator, wherein the anti-Th3 drug is administered to a mammal, and then a Th1 regulator is administered instead of the anti-Th3 drug. The kit, which is used as described above.
The AD treatment kit of the present invention includes, for example, a kit further containing an anti-Th2 drug, and is used so that an anti-Th2 drug is administered in place of the Th1 drug after administration of the Th1 drug. Can be mentioned.
The AD treatment kit of the present invention can be used, for example, in such a way that a Th1 regulator is administered after the start of administration of an anti-Th3 drug and a decrease in Th3 biological response is observed. Examples thereof include those used to administer a Th1 regulator after the start of administration and after a decrease in Th3 biological response and a decrease or enhancement in Th1 biological response are observed.
As the AD treatment kit of the present invention, for example, after the start of administration of an anti-Th3 drug, a decrease in Th3 biological response is observed, and then a Th1 adjustment drug is administered. After the start of administration of a Th1 adjustment drug, the Th1 biological reaction is enhanced. Alternatively, the anti-Th2 drug is administered after the decrease is observed, and more specifically, after the start of the administration of the anti-Th3 drug, the Th3 biological reaction is decreased and the Th1 biological reaction is decreased or enhanced. Examples include those used to administer an anti-Th2 drug after the regulator is administered, and after the start of administration of the Th1 regulator, an increase or decrease in the Th1 biological response and an increase in the Th2 biological response are observed.
In the AD therapeutic kits of (1) and (2) above, examples of the anti-Th3 drug include a drug (including a single drug) containing Lingzhi or an extract thereof as an active ingredient, a Lindsay, and an anticancer drug. The dosage of the anti-Th3 drug is, for example, 1 to 120 mg / kg body weight per day.
In the kit for treating AD of (1) and (2) above, examples of the anti-Th2 drug include a drug (including a single agent) containing IPD, ganoderma or an extract thereof as an active ingredient. The dose and administration period of the anti-Th2 drug are, for example, 0.1 to 10 mg / kg body weight per day and used within 150 days.
In the AD therapeutic kits of (1) and (2) above, examples of the Th1 regulator include interferon-γ (IFN-γ), interferon-α (IFN-α), nanban seeds or an extract thereof, nanbanata Or the extract and the chemical | medical agent (a single agent is also included) which contains at least 1 sort (s) chosen from the group which consists of cinnamon or its extract as an active ingredient. The dosage of the Th1 regulator is, for example, 1% to 30 MU (unit / body) per day or one-hundred percent other than subcutaneous administration (injection).
In the AD therapeutic kits of (1) and (2) above, the dosage forms of the anti-Th3 drug, anti-Th2 drug and Th1 regulator are, for example, oral administration, subcutaneous administration, intravenous administration, buccal administration, buccal administration, Examples include sublingual administration, gingival application, mucosal administration, and spray administration.
In the kit for treating AD according to (1) and (2) above, mammals include, for example, humans and non-human mammals. Examples of non-human mammals include dogs, cats, cows, horses, pigs, Guinea pigs or hamsters can be mentioned.
(3) An atopic dermatitis characterized by administering an anti-Th3 drug to a non-human mammal developing atopic dermatitis and then administering an anti-Th2 drug instead of the anti-Th3 drug Treatment methods.
Examples of the therapeutic method of the present invention further include a method of administering a Th1 modulator instead of the anti-Th2 drug after the anti-Th2 drug.
The therapeutic method of the present invention is, for example, a method of administering an anti-Th2 drug after the start of administration of an anti-Th3 drug and a decrease in the Th3 biological response is observed, and more specifically, after starting administration of an anti-Th3 drug, And a method of administering an anti-Th2 drug after an increase in Th2 biological response is observed.
As a treatment method of the present invention, for example, after the start of administration of an anti-Th3 drug, a decrease in Th3 biological reaction is observed, and then an anti-Th2 drug is administered. After administration of the anti-Th3 drug, more specifically, after the decrease in the Th3 biological reaction and the increase in the Th2 biological reaction are observed, the anti-Th2 drug is administered, and the anti-Th2 drug is administered. Examples include a method of administering a Th1 regulator after initiation of the decrease of the Th2 biological reaction and the decrease of the Th1 biological reaction.
Examples of the therapeutic method of the present invention include a method in which the administration of an anti-Th3 drug is performed while monitoring a Th3 biological reaction, and a method in which a Th2 biological reaction is further monitored. Moreover, the method of performing anti-Th2 drug administration while monitoring a Th2 biological reaction, and the method of performing Th1 biological reaction monitoring further are mentioned. Moreover, the method of performing administration of an anti- Th1 regulator while monitoring Th1 biological reaction is mentioned.
(4) An atopic dermatitis characterized by administering an anti-Th3 drug to a non-human mammal developing atopic dermatitis, and then administering a Th1 regulator instead of the anti-Th3 drug Treatment methods.
Examples of the treatment method of the present invention further include a method of administering an anti-Th2 drug instead of the Th1 modulator after the Th1 modulator.
The therapeutic method of the present invention includes, for example, a method of administering a Th1 regulator after the start of administration of an anti-Th3 drug and a decrease in the Th3 biological response is observed, and more specifically, after starting administration of an anti-Th3 drug, And a method of administering a Th1 modulator after a decrease or enhancement of the Th1 biological response is observed.
As the therapeutic method of the present invention, for example, after the start of administration of an anti-Th3 drug, a decrease in Th3 biological response is observed, and then a Th1 modulator is administered. After the start of administration of a Th1 modulator, Th1 biological reaction is enhanced or decreased. In particular, after the start of administration of the anti-Th3 drug, a decrease in Th3 biological reaction and a decrease or enhancement of the Th1 biological reaction are observed, and then a Th1 modulator is administered. Examples include a method of administering an anti-Th2 drug after the start of administration of a regulator and after an increase or decrease in Th1 biological response and an increase in Th2 biological response are observed.
Examples of the treatment method of the present invention include a method in which the administration of an anti-Th3 drug is performed while monitoring a Th3 biological reaction, and a method in which a Th1 biological reaction is further monitored. In addition, a method in which the anti-Th1 modulator is administered while monitoring the Th1 biological reaction, and a method in which the Th2 biological reaction is monitored are further included. Moreover, the method of performing administration of an anti- Th2 drug while monitoring a Th2 biological reaction is mentioned.
In the AD treatment methods (3) and (4) above, examples of the anti-Th3 drug include a drug (including a single agent) containing Lingzhi or an extract thereof as an active ingredient, a Lindsay, and an anticancer drug. The dosage of the anti-Th3 drug is, for example, 1 to 120 mg / kg body weight per day.
In the AD treatment methods of (3) and (4) above, examples of the anti-Th2 drug include a drug (including a single drug) containing IPD, ganoderma or an extract thereof as an active ingredient. The dose of the anti-Th2 drug is, for example, 0.1 to 10 mg / kg body weight per day.
In the AD treatment methods of (3) and (4) above, examples of the Th1 modulator include interferon-γ, interferon-α, nanban seeds or extracts thereof, nanbani or extracts thereof, and cinnamon or extracts thereof. A drug (including a single agent) containing at least one selected from the group consisting of as active ingredients. The dosage of the Th1 regulator (Th1 cytokine / interferon) is, for example, 1 to 30 MU (M unit / body) per day. Used to be one-hundredth.
In the above (3) and (4) AD treatment methods, the dosage forms of the anti-Th3 drug, anti-Th2 drug and Th1 regulator are, for example, oral administration, subcutaneous administration, intravenous administration, buccal administration, buccal administration, sublingual Administration, gingival application, mucosal administration, spray administration. For example, 1 to 30 MU (M unit / body) is used per day.
In the AD treatment methods of (3) and (4) above, examples of the non-human mammal include dogs, cats, cows, horses, rabbits, guinea pigs, and hamsters.
(5) A kit for detection of atopic dermatitis characterized by containing an anti-TGF-β antibody (simple diagnostic kit, kit for making a decision to use a drug (TGF-β inhibitor, anti-Th3 drug, etc.)).
(6) A method for detecting TGF-β in the plasma of a test mammal and evaluating the pathology of atopic dermatitis (AD) using the detection result as an index (drug (TGF-β inhibitor, anti-Th3 drug, etc.) How to decide the intention to use).
In the AD disease state evaluation method of the present invention, the test mammals include, for example, humans and non-human mammals. Examples of the test non-human mammals include dogs, cats, cows, horses, guinea pigs, and hamsters. Can be mentioned.
In the present invention, TGF-β1 is preferred as TGF-β.

FIG. 1 is a diagram showing the dosage and the course of the medication treatment effect during that period in the treatment (step method) of atopic dermatitis according to the administration sequence of Example 1. Th1% (= Th1 biological reaction), Th2% (= Th2 biological reaction) and Th3% (= Th3 biological reaction) indicate the superficial (phenotypic) biological reactions of Th1, Th2 and Th3, respectively. Th1 cytokine, Th2 cytokine and Th3 cytokine are respectively IFN-γ ⁺ , IL-4 ⁺ and TGF-β1 ^+, and each cell number (ie, “Th cytokine (+) CD4 (+) cell” and “Th cytokine (−)”) The number of cells of “CD4 (+) cell”) is calculated according to the following formula.

Here, Th% is a measured value of only Th cells, and the amount of change in each Th% that was improved or worsened while having a medicinal effect or having a disease state was measured as a Th biological reaction (definition).
FIG. 2 is a diagram showing the course of medication treatment effect in the treatment of atopic dermatitis of Example 1. In addition to the changes in Th1%, Th2% and Th3% shown in FIG. 1, the order of administration of Th1 regulator (Th1 agent), anti-Th2 agent (anti-Th2 agent) and anti-Th3 agent (anti-Th3 agent) (Anti-Th3) , Anti-Th2, adjustmentTh1 (IFN) -Therapy However, in human and animal atopy exhibiting the most severe atopy and immunodeficiency, a Th3 enhancer is administered, and this judgment is judged from the TGF simple measurement kit and Th3 biological reaction. (Refer to the results of the most severe atopy in humans) The timing and duration of administration are also shown.
FIG. 3 is a diagram showing temporal changes (before treatment and after treatment) of the skin appearance of the upper arm portion of the patient in the treatment of severe atopic dermatitis of Example 1. Dark red atopy infiltration characteristic peculiar to atopy and normalization (white skin color) upper arm during healing.
FIG. 4 is a graph showing changes over time in the patient's symptom score (SCORAD) in the treatment of severe atopic dermatitis in Example 1.
FIG. 5A is a diagram showing the course of medication effect in the treatment of atopic dermatitis of Example 2 (step method based on the administration sequence of Anti-Th3, anti-Th2, adjustmentTh1 (IFN) -Therapy). . sTh1 (that is, sTh1% (hereinafter the same)), sTh2 (sTh2%), and sTh3 (sTh3%) indicate the superficial (phenotypic) biological reactions of Th1, Th2, and Th3, respectively, and Th1 cytokine, Th2 The cytokine and Th3 cytokine are IFN-γ ⁺ , IL-4 ⁺ and TGF-β1 ⁺ , respectively, and the number of cells (ie, “Th cytokine (+) CD4 (+) cell” and “Th cytokine (−) CD4 (+)”) Based on the result of measuring the number of cells of “cell”, it is calculated by the equation shown in the description of FIG. Note that iTh1 (iTh1%), iTh2 (iTh2%), and iTh3 (iTh3%) indicate intrinsic biological reactions of Th1, Th2, and Th3, respectively.
FIG. 5B is a diagram showing temporal changes (before treatment and after treatment) of the appearance of the skin of the patient's arm in the treatment of atopic dermatitis of Example 2.
FIG. 6 is a diagram showing temporal changes (before treatment and after treatment) of the appearance of the skin of the patient's back in the treatment of atopic dermatitis of Example 3.
FIG. 7 is a diagram showing details of a dosing method (Anti-Th3, anti-Th2, adjustmentTh1 (IFN) -Therapy step method) used in the treatment of canine atopic dermatitis in Example 4. The Th vital reaction deviated from normal, and the situation was predominant with Th2 or Th9.
FIG. 8 is a view showing temporal changes (before treatment and after treatment) of the appearance of the affected area of the dog in the treatment of canine atopic dermatitis of Example 4.
FIG. 9 is a diagram showing temporal changes (before treatment and after treatment) of the appearance of the affected area of the dog in the treatment of canine atopic dermatitis of Example 4. The score for skin improvement (the higher the score, the more severe) is also shown.
FIG. 10 is a diagram showing an outline of the detection kit for the most severe atopic dermatitis shown in Example 5.
FIG. 11 shows the measurement of the concentration (ng / ml) of TGF-β1 in the plasma of patients with atopic dermatitis and healthy subjects (Control) using a kit for detection of adult-type most severe atopic dermatitis. It is a figure which shows a result. The TGF-β1 concentration was statistically significant (risk rate 5% level) between patients with atopic dermatitis and healthy subjects, and it was clarified that the TGF-β1 concentration is effective in identifying atopic pathologies.
FIG. 12: is a figure which shows one Example of the detection kit of atopic dermatitis of this invention of (A) and (B).
(A) represents an example showing positive and negative detection results (upper figure is negative (one line), lower figure is positive (two lines)). For example, if you are positive, you can make a decision such as “Please administer the drug”, “Increase the drug”, or “Turn the drug back”. There is no reason to do this "or" Drug withdrawal is possible. " The test sample is placed in a round hole on the right side.
(B) is a detection kit having a different form from (A), and beads and a color former carrying an anti-TGF-β1 antibody are contained in a container on the tube. Place the sample in the tube and color will be positive.
FIG. 13 is a diagram showing data showing clinical effects on adult-type most severe atopic dermatitis.
FIG. 14 is a diagram showing the results of preliminary evaluation of plasma collected from an adult-type most severe atopic patient in Example 6 using the detection kit of the present invention. The result is positive and serves as the basis for decision making to start subsequent treatment.
FIG. 15 is a diagram showing the effect on each Th biological response to adult-type most severe atopic dermatitis. However, since it is the most severe atopic dermatitis, it is recognized that the Th3 vital reaction at the first visit is low.
Fig. 16 shows skin abnormalities (atopy infiltration) in adult-type most severe atopic patients before treatment (left figure; at the first visit) and after the final examination (right figure; appearance findings on the 74th day after the first visit). FIG.

Hereinafter, the present invention will be described in detail. The scope of the present invention is not limited to these explanations, and other than the following examples, the scope of the present invention can be appropriately changed and implemented without departing from the spirit of the present invention.
In addition, this specification includes the whole of Japanese Patent Application No. 2009-230019 specification (filed on October 1, 2009), which is the basis for claiming priority of the present application. In addition, all publications cited in the present specification, for example, prior art documents, and publications, patent publications and other patent documents are incorporated herein by reference.
1. Summary of the present invention
The present invention provides a therapeutic agent (treatment kit) for atopic dermatitis and a treatment method thereof, a kit for detection of atopic dermatitis (simple diagnostic kit), etc., which are completely different from any conventional treatments. It is.
Conventionally, it is known that helper T (Th) lymphocytes involved in acquired immunity are classified into several subsets including Th1 and Th2, depending on the difference in cytokines produced. Those that produce interferon (IFN) -γ, interleukin (IL) -2 and the like are referred to as Th1 cells (also simply referred to as Th1), and are mainly IL-4, IL-5, IL-6, IL-10 and IL-. Those producing 13 are referred to as Th2 cells (also simply referred to as Th2). A substance that produces latent transforming growth factor (TGF) -β at a high concentration is said to be a Th3 cell (cancer researchers call it a Tr cell) (also simply referred to as Th3). And in various diseases such as infectious diseases, cancer, autoimmune diseases and allergic diseases, the relationship between the intensity of multiple Th responses including Th9 or Th17 cells and the breakdown of balance and the disease has been clarified. .
The present inventor analyzed many atopic dermatitis patients and healthy subjects and their plasma specimens, so that atopic dermatitis is a biological reaction of specific helper T (Th) lymphocytes such as Th1, Th2 and Th3. Is found to be manifested when it is not normal, and the biological reactions of these Th1, Th2 and Th3 (superficial (phenotypic) Th biological reactions and intrinsic Th biological reactions) are set to normal values. From the above, the administration sequence, the dose and the period of treatment and cure for atopic dermatitis were found. Specifically, the present inventor showed that in patients with atopic dermatitis, TGF-β1 and Th3 or one of its Th2 biological responses (including Th9 cells) superiority and Th2 cells are enhanced. In addition, the present inventors have found that a characteristic that the Th1 biological reaction is out of the normal range (often below the normal range) is recognized. In addition, the present inventor has found that the Th3 biological reaction is suppressed by the most severe atopic dermatitis or significant immunosuppression (anergy). As a treatment method for atopic dermatitis (AD), for example, an anti-TGF-β1 drug is first administered, and an anti-Th3 drug is administered to a patient with the most severe and immunodeficiency to bring the Th3 vital reaction within the normal range. Then, an anti-Th2 drug is administered instead of the anti-Th3 drug, and the Th2 biological reaction is returned to the normal range, and then a Th1 adjustment drug is administered instead of the anti-Th2 drug, and the Th1 biological reaction is changed to the normal range. It has been found that if a method having a specific administration procedure (usage) is used, the atopic dermatitis can be effectively treated and cured, and recurrence can be almost completely prevented. The treatment of atopic dermatitis by such a specific administration procedure (usage) has a remarkably high therapeutic effect that is not comparable to conventional treatment, and patients with long-term or severe atopic dermatitis and nursing It is an extremely innovative treatment method that can achieve complete cure for some animals (some patients are 3 years after drug withdrawal).
Thus, the present invention relates to the treatment of atopic dermatitis, and provides an effective and epoch-making treatment method and therapeutic agent (treatment kit) based on a completely different idea from the conventional one.
2. Atopic dermatitis treatment kit
As described above, the treatment kit for atopic dermatitis of the present invention is other than the most severe atopic dermatitis or atopic dermatitis (AD) in which the Th3 biological reaction is suppressed by significant immunosuppression (anergy). A kit for treating atopic dermatitis comprising administering an anti-TGF-β1 drug, comprising an anti-Th3 drug and an anti-Th2 drug, and optionally further comprising a Th1 modulator, wherein the anti-TGF-β1 A drug or an anti-Th3 drug is administered, and then an anti-Th2 drug is administered instead of the anti-Th3 drug, and optionally, a Th1 regulator is administered instead of the anti-Th2 drug, Said therapeutic kit.
Moreover, as another aspect of the treatment kit for atopic dermatitis of the present invention, as described above, the treatment for atopic dermatitis includes an anti-Th3 drug and a Th1 regulator, and optionally further includes an anti-Th2 drug. An anti-Th3 drug is administered to a mammal, and then a Th1 regulator is administered in place of the anti-Th3 drug. In some cases, an anti-Th2 drug is administered in place of the Th1 regulator. The therapeutic kit is characterized by being used as described above.
The anti-Th3 drug contained in the therapeutic kit of the present invention means a drug having an inhibitory activity on Th3 reaction (Th3 biological reaction). Here, the Th3 biological reaction is a concept including the clinical significance of the test value by data profiling when an anti-Th3 drug is administered to an individual who develops atopic dermatitis or a normal individual. That is, the anti-Th3 drug is administered until the phenotype (clinical symptoms) disappears (until the superficial type (phenotype) Th3% reaches the normal range (normal value)). The administration period in this case is defined by the superficial (phenotypic) Th 3%, and the dosage is defined by the endogenous Th 3%. Anti-Th3 drug can also be defined as a drug that suppresses Th3 biological reaction, which is a treatment inhibitory factor, and allergic reaction caused by Th9 cells.
As described above, in the therapeutic kit of the present invention, an anti-Th3 drug is used to bring Th3% within the normal range, but in some cases, a Th3 biological reaction enhancer (Th3 enhancer) is used instead of the anti-Th3 drug. ) Can also be used. For example, in the case of severe human atopy (especially human severe atopy) and immunodeficiency (immune tolerance), or in the case of vulnerable dermatitis with immunosuppression in non-human animals, the Th3 biological reaction is low. Therefore, in such a case, it is preferable to use a Th3 biological reaction enhancer in order to bring Th3% within the normal range. Here, human most severe atopy can be defined as, for example, a state of having skin erythema in 36% or more of the body surface area in the severity classification of atopy. Most patients with lichenification are considered to fall into this severity category. In addition, the above-mentioned fragile dermatitis is defined as a skin abnormality accompanied by apoptosis in which TGF-β1 in plasma is low and there is no production of keratinoid growth factor (KGF) and there is a tendency to decrease the staining property pathologically. Is done.
Examples of the anti-Th3 drug that can be used in the present invention include a drug (including a single drug) containing ganoderma or an extract thereof (including a single drug) (Chinese medicine ganoderma (Nissan Chemical), etc.), Lindsay, IFN-α, IL- 4, Cyclosporin A (CsA), FK506, anticancer agents and the like are preferable, and among them, Kampo medicine Reishi (Nissan Chemical) is preferable. Moreover, as said Th3 biological reaction enhancer (Th3 enhancer), a zinc containing thing is preferable, for example, Specifically, the powder of the oyster shell etc. are mentioned preferably.
The anti-Th2 drug contained in the therapeutic kit of the present invention means a drug having an inhibitory activity on Th2 reaction (Th2 biological reaction). Here, the Th2 biological reaction means a difference in the degree of the root cause beyond the idea of atopic dermatitis, and the decision to use the drug is administered according to the same method of use as the anti-Th3 drug described above. Anti-Th2 drug can also be defined as a drug that suppresses Th2 cells and Th9 cells, which are the main forms of atopy.
As described above, in the treatment kit of the present invention, an anti-Th2 drug is used to bring Th2% within the normal range, but in some cases, a Th2 biological reaction enhancer (Th2 enhancer) is used instead of the anti-Th2 drug. ) Can also be used. When a significant decrease in Th2% is observed when trying to administer an anti-Th2 drug, as described above, it is preferable to use a Th2 enhancer instead of the anti-Th2 drug.
As an anti-Th2 drug that can be used in the present invention, for example, IPD (Daegu Pharmaceutical Industry; IPD C50, IPD-1151T), Onon, IFN-γ, Cyclosporin A (CsA), FK506, Ganoderma or an extract thereof is effective. Preferred examples include a drug (including a single drug) contained as a component (Chinese herbal medicine Reishi (Nissan Chemical), etc.), and IPD is more preferred. In addition, preferable examples of the Th2 biological reaction enhancer (Th2 enhancer) include various nucleic acids (from Fugu no Shiroko, etc.), various hormone agents (female hormones, male hormones, environmental hormones) and the like.
The Th1 modulator included in the therapeutic kit of the present invention is not limited, but, for example, enhances endogenous Th1 and suppresses superficial Th1 (that is, regulates endogenous Th1 and superficial Th1 simultaneously). ) Drugs and the like are preferred. Here, endogenous Th1 represents the strength of so-called anti-pathological condition, and means a biological reaction involved in the disappearance and maintenance of atopic allergy after improvement of skin symptoms of atopic dermatitis. In addition, the phenotype Th1 vital reaction (measured on the cell surface of Th1 lymphocytes) means the degree of skin barrier injury (higher than the measured normal value) (drug use decision based on data accumulated as profiling) I do).
Examples of the Th1 regulator that can be used in the present invention include INF-γ, INF-α, Nanban seeds or an extract thereof, Nanan eyelashes or an extract thereof, and cinnamon or an extract thereof as an active ingredient (single agent) Oral and oral IFN-α, oral intestinal solvent canine IFN-γ (can also be administered subcutaneously), and the like. Among them, IFN-α, IFN-γ, BRM agent (from Nihon University) Venture Snow Dream) and Ge132 are more preferred.
In addition, in the above-mentioned therapeutic kit of the present invention, those containing a TGF-β1 inhibitor (anti-TGF-β1 agent (anti-TGF-β1 drug)) are preferably mentioned. The anti-TGF-β1 agent is preferably administered to the mammal before the anti-Th3 drug is administered. Examples of the anti-TGF-β1 agent include drugs (including single agents) containing ganoderma or an extract thereof as an active ingredient (Chinese medicine ganoderma (Nissan Chemical), etc.), various anticancer agents, Lindsay, IFN-α, IL- 4, cyclosporin A (CsA), FK506 and the like are preferable. The evaluation of TGF-β1 level in plasma and confirmation of its suppression are not limited, but can be performed using, for example, the atopic dermatitis detection kit of the present invention described later. The detection kit contains an anti-TGF-β1 antibody, and can determine whether the TGF-β1 in the plasma is below a certain level or above that level. For example, in the case of human beings, if the concentration of TGF-β1 in plasma is 1.5 ng / ml or more, preferably 2.0 ng / ml or more, it can be evaluated that atopic dermatitis has developed significantly. Similarly, it is evaluated that atopic dermatitis is significantly developed when the TGF-β1 plasma concentration is 1.7 ng / ml or more in the case of cats and 2.0 ng / ml or more in the case of dogs. However, it is preferable that the plasma TGF-β1 concentration be lower than the above range prior to the administration of the anti-Th3 drug by administration of the anti-TGF-β1 agent.
Preferred examples of mammals to be used for the therapeutic kit of the present invention include both human and non-human mammals. Here, examples of the non-human mammal include dogs, cats, cows, horses, pigs, rabbits, guinea pigs, and hamsters, among which dogs and cats are preferable, and dogs are more preferable.
When the therapeutic kit of the present invention contains an anti-Th3 drug (agent), an anti-Th2 drug (agent), and optionally a Th1 regulator (agent), the anti-Th3 drug (agent) ), Anti-Th2 drug (agent) and Th1 regulator (agent) are each administered in this order. On the other hand, when the therapeutic kit of the present invention contains an anti-Th3 drug (agent), a Th1 regulator (agent), and optionally an anti-Th2 drug (agent), the anti-Th3 drug is used for the target mammal. It is important to administer (agent), Th1 regulator (agent), and anti-Th2 agent (agent) in this order. Therefore, using at least two of anti-Th3 drugs, anti-Th2 drugs, and Th1 regulators for atopy (that is, administering each Th drug at the same time) is a usage mode of the therapeutic kit of the present invention. Is not included. An antagonist that suppresses symptoms can be used separately from each Th agent.
In the present invention, each phenotypic Th biological reaction (measured on the cell surface of Th lymphocytes) serves as an index of the administration period of the drug (anti-Th3 drug, anti-Th2 drug and Th1 modulator), and each endogenous Th biological reaction ( (Measured in the cytoplasm of Th lymphocytes) is a judgment value for drug dosage and drug use decision making. When it is higher than the normal value, each anti-Th drug (antagonist) can be administered, and when it is lower than the normal value, each Th enhancer can be administered. In an individual who develops atopic dermatitis, for example, the Th3 biological reaction and the Th2 biological reaction may be high. In this case, the anti-Th3 drug and the anti-Th2 drug are sequentially administered. In addition to such a biological response modifier, an antagonist (chemical mediator antagonist) such as histamine that forms clinical symptoms may be administered in order to lower the value of each phenotype Th.
When the therapeutic kit of the present invention contains an anti-Th3 drug (agent), an anti-Th2 drug (agent) and optionally a Th1 regulator (agent), specifically, for example, after the start of administration of the anti-Th3 drug It is preferable that the anti-Th2 drug is administered after a decrease in the Th3 biological reaction is observed. In some cases, after the start of the administration of the anti-Th2 drug, a decrease in the Th2 biological reaction is observed, and further Th1 adjustment is performed. It is preferably used such that the drug is administered. Specifically, when the administration of an anti-Th3 drug to a mammal developing atopic dermatitis is started, the Th3 biological reaction is reduced, and thereby the Th3 (%) value (for example, superficial Th3 (%)) ) Is within the normal range, and at that stage, the administration is switched from the administration of the anti-Th3 drug to the administration of the anti-Th2 drug. Subsequently, when the administration of the anti-Th2 drug is started, the Th2 vital reaction decreases, and thereby the value of Th2 (%) (for example, superficial Th2 (%)) falls within the normal range. The administration of is terminated. Thereafter, in some cases, it can be switched to the administration of a Th1 regulator, but at the end of the administration of the anti-Th2 drug, whether the Th1 biological response is reduced or increased may vary depending on individual circumstances, As a Th1 regulator, it is possible to appropriately determine whether to use a drug that enhances the Th1 biological reaction or a drug that suppresses the Th1 biological reaction in consideration of the situation. In general, at the end of the administration of an anti-Th2 drug, the Th1 biological reaction often decreases, and therefore it is preferable to administer a drug that enhances the reaction. In the present invention, the Th3 biological reaction once adjusted within the normal range is not greatly influenced by the subsequent administration of the anti-Th2 drug or Th1 modulator, and continues within the normal range (or in the vicinity thereof). Retained. Similarly, the Th2 biological reaction once adjusted within the normal range is not greatly affected by subsequent administration of the Th1 regulator, and is continuously maintained within the normal range (or in the vicinity thereof).
On the other hand, when the therapeutic kit of the present invention contains an anti-Th3 drug (agent), a Th1 regulator (agent) and optionally an anti-Th2 drug (agent), specifically, for example, administration of an anti-Th3 drug It is preferable that the Th1 modulator is administered after a decrease in the Th3 biological response is observed after the start. In some cases, a decrease or enhancement of the Th1 biological response is observed after the start of the administration of the Th1 modulator. It is preferably used such that an anti-Th2 drug is administered later. Specifically, when the administration of an anti-Th3 drug to a mammal developing atopic dermatitis is started, the Th3 biological reaction is reduced, and thereby the Th3 (%) value (for example, superficial Th3 (%)) ) Is within the normal range, so switching from administration of anti-Th3 drugs to administration of Th1 regulators at that stage. Here, at the end of the administration of the anti-Th3 drug, whether the Th1 biological response is reduced or increased may vary depending on the individual situation. It is possible to appropriately determine whether to use a drug that enhances a biological reaction or a drug that suppresses a Th1 biological reaction. Generally, at the end of the administration of an anti-Th3 drug, the Th1 biological reaction often decreases, and therefore, it is preferable to administer a drug that enhances the reaction. Thus, when the administration of the Th1 modulator is started, the Th1 vital reaction is reduced or enhanced, and thereby the Th1 (%) values (for example, the endogenous Th1 (%) and the superficial Th1 (%)) are in the normal range. Therefore, the administration of the anti-Th1 drug is terminated at that stage. Thereafter, in some cases, the administration can be switched to administration of an anti-Th2 drug. When the administration of the anti-Th2 drug is started, the Th2 vital reaction decreases, and the value of Th2 (%) (for example, superficial Th2 (%)) falls within the normal range. Exit. In the present invention, the Th3 biological reaction once adjusted within the normal range is not greatly affected by subsequent administration of the Th1 regulator or anti-Th2 drug, and continues within the normal range (or in the vicinity thereof). Retained. Similarly, the Th1 vital reaction once adjusted within the normal range is not greatly affected by the subsequent administration of the anti-Th2 drug, and is continuously maintained within the normal range (or in the vicinity thereof).
Here, the normal range (normal value) of each Th (%) is not limited, and a known range known for each type of mammal to be treated may be adopted. In the case of surface type Th (%), Th3 (%) is preferably 2.0 to 10.0%, Th2 (%) is preferably 0.20 to 1.2%, and Th1 (%) Is preferably 20 to 60%.
Similarly, as an example when the mammal to be treated is a non-human animal, the normal range (normal value) of each Th (%) in a dog is, for example, Th3 ( %) Is preferably from 0.1 to 3.0%, more preferably from 0.2 to 3.0%, still more preferably from 0.5 to 2.5%, and Th2 (%) is 0. It is preferably 1 to 2.5%, more preferably 0.2 to 2.0%, still more preferably 0.4 to 1.5%, and Th1 (%) is 0.3 to 3.0%. %, More preferably 0.5 to 2.5%, still more preferably 0.5 to 2.0%. In the case of intrinsic type Th (%), Th3 (%) is preferably 0.5 to 4.0%, more preferably 0.6 to 3.5%, and still more preferably 0.8 to 2. 0.5% and Th2 (%) is preferably 0.1 to 2.0%, more preferably 0.2 to 1.5%, and still more preferably 0.3 to 1.3%. , Th1 (%) is preferably 0.5 to 4.0%, more preferably 0.5 to 3.5%, and still more preferably 0.6 to 2.5%.
The value of each Th (%) (for example, each superficial Th (%)) is determined by determining the helper T cell (Th: CD4SP) and each Th cytokine, Th1 (IFN-γ ⁺ ), Th2 (IL-4 ⁺ ), Th3 (TGF-β1) ⁺ ) And the number of cells (that is, the number of cells of “Th cytokine (+) CD4 (+) cell” and “Th cytokine (−) CD4 (+) cell))” is calculated according to the following formula: Can do.

Note that Th% is a measured value of only Th cells, and the amount of change in each Th% that is improved or worsened while having a medicinal effect or a disease state is measured as a Th biological reaction. The number of cells can be measured, for example, by using flow cytometry, FACS (fluorescence-activated cell sorter), a simple kit, etc., and measuring by counting desired cells or calculating the abundance ratio. Can do.
In addition, when the therapeutic kit of the present invention is used for mammals developing atopic dermatitis excluding the most severe and immunodeficiency, the following administration modes are particularly preferred. That is, after the start of the administration of the anti-Th3 drug, it is preferably used so that the anti-Th2 drug is administered after the decrease in the Th3 biological reaction and the enhancement of the Th2 biological reaction are observed. After the start of the administration, a Th1 regulator may be administered after a decrease in the Th1 biological response as well as a decrease in the Th2 biological response (Anti-Th3, anti-Th2, adjustmentTh1 (IFN)- (Therapy: step method).
In the use of the therapeutic kit of the present invention, for example, the anti-Th3 drug, the anti-Th2 drug, and the Th1 modulator are preferably used to be administered for at least 2 hours, and more preferably for at least 5 days. Preferably it is 5 to 60 days, and even more preferably 5 to 35 days. The total of the administration periods of the anti-Th3 drug, anti-Th2 drug, and Th1 regulator is preferably 180 days or less, more preferably 150 days or less, still more preferably 108 days or less, More preferably, it is 100 days or less.
Each of the anti-Th3 drug, anti-Th2 drug and Th1 regulator used in the therapeutic kit of the present invention is a pharmaceutical composition comprising the above-mentioned specific compounds as active ingredients, and further comprising a pharmaceutically acceptable carrier. It is preferably administered in the form. As used herein, “pharmaceutically acceptable carrier” refers to excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, viscous Agents, flavoring agents, solubilizing agents or other additives. By using one or more of such carriers, it can be prepared as a pharmaceutical composition in the form of injection, solution, capsule, suspension, emulsion or syrup. Such an anti-Th3 drug, anti-Th2 drug and Th1 regulator in the form of a pharmaceutical composition can be administered orally or parenterally, respectively. Examples of oral administration include oral administration, oral administration, sublingual administration, gingival application, mucosal administration, and spray administration. Examples of administration forms for parenteral administration include injections formulated by conventional methods (injections for subcutaneous administration and intravenous administration), mucosal administration by spray and the like, and spray administration. In the case of an injection, it can be produced by dissolving or suspending it in a pharmaceutically acceptable carrier such as physiological saline or commercially available distilled water for injection. In addition, in the administration of Th1 regulators, in particular, low-volume INF-γ (interferon-γ) (ordinary 1/100 dose) and (very) low-volume INF-α (interferon-α) (including canine genetic recombinants) ), Oral administration, specifically oral administration, oral administration, sublingual administration, gingival application, mucosal administration, and spray administration are preferable.
In addition, the dose of each of the anti-Th3 drug, anti-Th2 drug, and Th1 regulator is not limited, and can be appropriately set. For example, the type of the target mammal, for example, the target mammal (patient) May differ depending on age, sex, weight and symptoms, therapeutic effect, administration method, treatment time, and the like.
The dose of the anti-Th3 drug is not limited, but is preferably, for example, 1 to 120 mg / kg body weight per day, and more preferably 5 to 110 mg / kg body weight per day. In particular, when the target mammal is a human, the dosage of the anti-Th3 drug is preferably 1 to 120 mg / kg body weight per day, more preferably 5 to 30 mg / kg body weight per day. is there. In addition, when the target mammal is a dog, cat or the like, the dose of the anti-Th3 drug is preferably 1 to 120 mg / kg body weight per day, more preferably 5 to 30 mg / kg per day. kg body weight. Actually, the decision to use the drug is made by changing the biological response of the active TGF-β1 or Th3.
The dose of the anti-Th2 drug is not limited, but is preferably 0.1 to 10 mg / kg body weight per day, and more preferably 1 to 5 mg / kg body weight per day. In particular, when the target mammal is a human, the dosage of the anti-Th3 drug is preferably 1 to 10 mg / kg body weight per day, more preferably 2 to 8 mg / kg body weight per day. is there. In addition, when the target mammal is a dog, cat or the like, the dose of the anti-Th3 drug is preferably 3 to 5 mg / kg body weight per day, more preferably 5 to 30 mg / kg per day. kg body weight.
The dosage of the Th1 regulator is not limited, but is preferably 1 MU to 30 MU per day, and more preferably 4 MU to 10 MU per day. In particular, when the target mammal is a human, the dosage of the anti-Th3 drug is preferably 1 to 120 mg / kg body weight per day, more preferably 5 to 60 mg / kg body weight per day. is there. In addition, when the target mammal is a dog, a cat, or the like, the dose of the anti-Th3 drug is preferably 1 to 120 mg / kg body weight per day, more preferably 10 to 30 mg / kg per day. kg body weight.
The therapeutic kit of the present invention basically comprises Anti-Th3, anti-Th2, adjustment-Th1 / P. A kit that can be used for Therapy (step method) is mentioned as a preferred embodiment, but may contain other components in addition to the anti-Th3 drug, anti-Th2 drug, and Th1 modulator. Other constituent elements are not limited, and examples thereof include various buffers for lysis and dilution, instructions for use (use manual), and the like. In addition, the therapeutic kit of the present invention may include all components such as an anti-Th3 drug, an anti-Th2 drug, and a Th1 regulator, or may include at least a part of each component independently. It may be a thing and is not limited.
3. How to treat atopic dermatitis
As described above, the method for treating atopic dermatitis of the present invention comprises administering an anti-Th3 drug to a non-human mammal that has developed atopic dermatitis, and then replacing the anti-Th3 drug with an anti-Th2 drug. A method of treatment characterized in that a drug is administered and optionally a Th1 modulator is administered instead of an anti-Th2 drug.
In addition, as another aspect of the method for treating atopic dermatitis of the present invention, as described above, an anti-Th3 drug is administered to a non-human mammal that develops atopic dermatitis, and then anti-thinitis is administered. A therapeutic method characterized in that a Th1 modulator is administered instead of a Th3 drug, and optionally an anti-Th2 drug is administered instead of a Th1 modulator.
For the definition explanation and preferred specific examples of the anti-Th3 drug, anti-Th2 drug and Th1 modulator used in the treatment method of the present invention, see 2. above. The explanations in the sections are equally applicable.
As described above, in the therapeutic method of the present invention, an anti-Th3 drug is administered in order to bring the Th3% within the normal range. However, in some cases, a Th3 biological response enhancer (Th3 potentiator) is used instead of the anti-Th3 drug. Agent) can also be administered. For example, in the case of severe human atopy (especially human severe atopy) and immunodeficiency (immune tolerance), or in the case of vulnerable dermatitis with immunosuppression in non-human animals, the Th3 biological reaction is low. Therefore, in such a case, it is preferable to use a Th3 biological reaction enhancer in order to bring Th3% within the normal range. For the explanation and preferred specific examples of the Th3 biological reaction enhancer, see 2. above. The explanations in the sections are equally applicable. For the definition of human severe atopy (especially human severe atopy) and fragile dermatitis, see 2. The explanations in the sections are equally applicable.
In the above-described treatment method of the present invention, a TGF-β1 (TGF-β) inhibitor (anti-TGF-β1 agent (anti-TGF) is further added to non-human mammals developing atopic dermatitis. Administration of -β1 drug)) is also mentioned as a preferred embodiment. The administration of the anti-TGF-β1 agent is performed before the administration of the anti-Th3 agent. Specifically, after the inhibition of TGF-β1 is confirmed by the administration of the anti-TGF-β1 agent, the anti-Th3 agent is administered. It is preferable to do. The evaluation of TGF-β1 level in plasma and confirmation of its suppression are not limited, but can be performed using, for example, the atopic dermatitis detection kit of the present invention described later. The detection kit contains an anti-TGF-β1 antibody, and can determine whether the TGF-β1 in the plasma is below a certain level or above that level. For example, in the case of human beings, if the concentration of TGF-β1 in plasma is 1.5 ng / ml or more, preferably 2.0 ng / ml or more, it can be evaluated that atopic dermatitis has developed significantly. Similarly, it is evaluated that atopic dermatitis is significantly developed when the TGF-β1 plasma concentration is 1.7 ng / ml or more in the case of cats and 2.0 ng / ml or more in the case of dogs. Therefore, it is preferable that the plasma TGF-β1 concentration be less than the above range prior to the administration of the anti-Th3 drug by administering the anti-TGF-β1 agent. For the definition of the anti-TGF-β1 agent and preferred specific examples, see 2. above. The explanations in the sections are equally applicable.
The non-human mammal that is the target of the treatment method of the present invention is not limited as long as it is a non-human mammal that develops atopic dermatitis. For example, dogs, cats, cows, horses, pigs , Sheep, goats, mice, rats, rabbits, guinea pigs and hamsters, among which dogs and horses are preferred. The treatment method of the present invention can also be applied to humans.
In the treatment method of the present invention, an anti-Th3 drug, an anti-Th2 drug and optionally a Th1 modulator are administered in this order to a mammal developing atopic dermatitis, respectively, or an anti-Th3 drug, It is important to administer the Th1 modulator and possibly the anti-Th2 drug in this order. Therefore, it is not included in the embodiment of the treatment method of the present invention that at least two kinds of anti-Th3 drug, anti-Th2 drug and Th1 modulator are used in combination (that is, administered at the same time).
When the treatment method of the present invention is to administer an anti-Th3 drug, an anti-Th2 drug and optionally a Th1 regulator in this order, specifically, for example, after the start of the administration of the anti-Th3 drug, a decrease in the Th3 biological response It is preferable to administer an anti-Th2 drug after having been observed. In some cases, it is preferable to administer a Th1 regulator after the start of the administration of the anti-Th2 drug and after a decrease in the Th2 biological response is observed. Specifically, when administration of an anti-Th3 drug is started to a mammal developing atopic dermatitis, the Th3 biological reaction is reduced, and thereby the value of Th3 (%) (for example, superficial Th3 (%)) Is within the normal range, so switching from administration of anti-Th3 drugs to administration of anti-Th2 drugs at that stage. Subsequently, when the administration of the anti-Th2 drug is started, the Th2 vital reaction decreases, and thereby the value of Th2 (%) (for example, superficial Th2 (%)) falls within the normal range. The administration of is terminated. Thereafter, in some cases, the administration is switched to the administration of a Th1 modulator. At the end of the administration of the anti-Th2 drug, whether the Th1 biological response is reduced or increased may vary depending on individual circumstances. As such, in consideration of the situation, it is possible to appropriately determine whether to use a drug that enhances the Th1 biological reaction or to use a drug that suppresses the Th1 biological reaction. In general, at the end of the administration of an anti-Th2 drug, the Th1 biological reaction often decreases, and therefore it is preferable to administer a drug that enhances the reaction. In the present invention, the Th3 biological reaction once adjusted within the normal range is not greatly influenced by the subsequent administration of the anti-Th2 drug or Th1 modulator, and continues within the normal range (or in the vicinity thereof). Retained. Similarly, the Th2 biological reaction once adjusted within the normal range is not greatly affected by subsequent administration of the Th1 regulator, and is continuously maintained within the normal range (or in the vicinity thereof).
On the other hand, when the treatment method of the present invention is to administer an anti-Th3 drug (= anti-TGF drug), a Th1 modulator, and optionally an anti-Th2 drug in this order, specifically, for example, the pathological condition and severeness of atopy Depending on the degree, after the start of the administration of the anti-Th3 drug, it is preferable to administer the Th1 regulator after a decrease in the Th3 biological reaction is observed. It is preferable to administer an anti-Th2 drug after it is observed. Specifically, when the administration of an anti-Th3 drug to a mammal developing atopic dermatitis is started, the Th3 biological reaction is reduced, and thereby the Th3 (%) value (for example, superficial Th3 (%)) ) Is within the normal range, so switching from administration of anti-Th3 drugs to administration of Th1 regulators at that stage. Here, at the end of the administration of the anti-Th3 drug, whether the Th1 biological response is reduced or increased may vary depending on the individual situation. It is possible to appropriately determine whether to use a drug that enhances a biological reaction or a drug that suppresses a Th1 biological reaction. Generally, at the end of the administration of an anti-Th3 drug, the Th1 biological reaction often decreases, and therefore, it is preferable to administer a drug that enhances the reaction. Thus, when the administration of the Th1 modulator is started, the Th1 vital reaction is reduced or enhanced, and thereby the Th1 (%) values (for example, the endogenous Th1 (%) and the superficial Th1 (%)) are in the normal range. Therefore, the administration of the anti-Th1 drug is terminated at that stage. Thereafter, in some cases, the administration can be switched to administration of an anti-Th2 drug. When the administration of the anti-Th2 drug is started, the Th2 vital reaction decreases, and the value of Th2 (%) (for example, superficial Th2 (%)) falls within the normal range. Exit. In the present invention, the Th3 biological reaction once adjusted within the normal range is not greatly affected by subsequent administration of the Th1 regulator or anti-Th2 drug, and continues within the normal range (or in the vicinity thereof). Retained. Similarly, the Th1 vital reaction once adjusted within the normal range is not greatly affected by the subsequent administration of the anti-Th2 drug, and is continuously maintained within the normal range (or in the vicinity thereof).
Here, the normal range of each Th (%) is not limited, and a known range that is known for each type of mammal to be treated may be adopted. In the case of Th (%), Th3 (%) is preferably 2.0 to 10.0%, Th2 (%) is preferably 0.20 to 1.2%, and Th1 (%) is It is preferably 20 to 60%.
The method for calculating the value of each Th (%) (for example, each of the superficial Th (%)) is as described in 2. This is the same as the calculation method described in the section.
In addition, when the treatment method of the present invention is applied to a mammal developing severe atopic dermatitis, the following administration modes are particularly preferable. That is, after administration of an anti-Th3 drug is started, it is preferable to administer by switching from an anti-Th3 drug to an anti-Th2 drug after a decrease in the Th3 biological response and an increase in the Th2 biological reaction are observed. After the start of administration, after a decrease in the Th1 biological reaction is observed together with a decrease in the Th2 biological reaction, the anti-Th2 drug may be switched to a Th1 adjusting drug for administration.
When the treatment method of the present invention is to administer an anti-Th3 drug, an anti-Th2 drug, and optionally a Th1 regulator in this order, the anti-Th3 drug is preferably administered while monitoring a Th3 vital reaction. Biological reaction monitoring may also be performed. By monitoring Th3 biological reaction and Th2 biological reaction in parallel with administration of anti-Th3 drug, administration of anti-Th3 drug using the value of Th3 (%) etc. (for example, superficial Th3 (%) etc.) as an index It is possible to easily set and judge the control of the period and the dose, and the switching timing of the administration from the anti-Th3 drug to the anti-Th2 drug, and the therapeutic effect of atopic dermatitis can be further enhanced.
Similarly, the administration of the anti-Th2 drug after the administration of the anti-Th3 drug is preferably performed while monitoring the Th2 biological reaction, and the monitoring of the Th1 biological reaction may also be performed. By monitoring the Th2 biological reaction and the Th1 biological reaction in parallel with the administration of the anti-Th2 drug, administration of the anti-Th2 drug using the value of Th2 (%) etc. (for example, superficial Th2 (%) etc.) as an index Easily control the period and dose, especially when to stop administration of anti-Th2 drugs (ie, it may be time to achieve drug withdrawal), and when to switch from anti-Th2 drugs to Th1 regulators It can be set and judged, and the therapeutic effect of atopic dermatitis can be further enhanced.
Further, similarly, the administration of the Th1 regulator performed after the administration of the anti-Th2 drug is preferably performed while monitoring the Th1 vital reaction, and more preferably performed while monitoring the test value and score score (CL) of the Th test. . Moreover, you may perform monitoring of the test value and score score (CL) of Th test | inspection of Th2 biological reaction and / or Th3 biological reaction together. By monitoring Th1 biological reaction etc. in parallel with the administration of Th1 regulator, Th1 regulator using Th test value and score score (CL) of Th1 biological reaction or TGF-β1 or IL-5 as an index Administration period and dose control, especially the end of administration of Th1 regulator (ie, drug withdrawal achievement time) can be easily set and judged, and the therapeutic effect of atopic dermatitis can be further enhanced. . In particular, since TGF-β1 (plasma concentration) can be used as a parameter for evaluating the pathology of atopic dermatitis, the above setting and determination can be performed more easily and simply.
When the treatment method of the present invention is to administer an anti-Th3 drug (anti-TGF drug), a Th1 regulator, and optionally an anti-Th2 drug in this order, the anti-Th3 drug should be administered while monitoring the Th3 vital reaction. Preferably, monitoring other than Th1 biological reaction may be performed together. By monitoring Th3 biological reaction and Th1 biological reaction in parallel with administration of anti-Th3 drug, administration of anti-Th3 drug using the value of Th3 (%) etc. (for example, superficial Th3 (%) etc.) as an index It is possible to easily set and judge the control of the period and the dose, and further the switching timing of administration from the anti-Th3 drug to the Th1 regulator, and the therapeutic effect of atopic dermatitis can be further enhanced.
Similarly, the administration of the Th1 regulator performed after the administration of the anti-Th3 drug is preferably performed while monitoring the Th1 biological reaction, and the Th2 biological reaction may also be monitored. By monitoring Th1 biological reaction and Th2 biological reaction in parallel with the administration of Th1 regulator, Th1 adjustment is performed using the value of Th1 (%) etc. (for example, endogenous type and superficial Th1 (%) etc.) as an index. Control of drug administration period and dose, especially the timing of the end of administration of a Th1 regulator (ie, it may be the time to achieve drug withdrawal), and the timing for switching from a Th1 regulator to an anti-Th2 drug depending on circumstances Can be easily set and judged, and the therapeutic effect of atopic dermatitis can be further enhanced.
Similarly, the administration of the anti-Th2 drug performed after the administration of the Th1 regulator is preferably performed while monitoring the Th2 vital reaction, and more preferably performed while monitoring the test value and score score (CL) of the Th test. . Moreover, you may perform monitoring of the test value and score score (CL) of Th test | inspection of Th1 biological reaction and / or Th3 biological reaction together. By monitoring Th2 biological reaction in parallel with administration of anti-Th2 drug, anti-Th2 drug using Th test value and score (CL) of Th2 biological reaction or TGF-β1 or IL-5 as an index Administration period and dose control, especially when anti-Th2 drug administration is completed (ie, when drug withdrawal is achieved) can be easily set and judged, and the therapeutic effect of atopic dermatitis can be further enhanced. . In particular, TGF-β1 (concentration in plasma ng / ml) can be used as a parameter for evaluating the pathological condition of atopic dermatitis, so that the above setting and determination can be performed more easily and simply.
In the monitoring described above, the blood concentration of TGF-β1, which is a Th3 cytokine, may be monitored instead of or concurrently with the Th3 biological reaction, and the Th2 cytokine instead of or concurrently with the Th2 biological reaction. The blood concentration of certain IL-4 may be monitored, and the blood concentration of INF-γ, which is a Th1 cytokine, may be monitored instead of or concurrently with the Th1 vital reaction.
In the treatment method of the present invention, the monitoring method is not limited, and can be performed using, for example, flow cytometry, FACS (fluorescence-activated cell sorter), a simple kit, etc. Alternatively, the blood concentration can be evaluated by calculating the abundance ratio.
Regarding the administration days, dosage forms, dosages, etc. of the anti-Th3 drug, anti-Th2 drug and Th1 regulator used in the treatment method of the present invention, refer to 2. The explanations in the sections are equally applicable.
Note that the present invention relates to an anti-Th3 drug and an anti-Th2 drug (including a Th1-adjusting drug as the case may be) for producing a kit or a drug for treating atopic dermatitis in a mammal (human or non-human mammal). The use as well as the use of anti-Th3 and anti-Th2 drugs (and optionally Th1 modulators) to treat atopic dermatitis in mammals (human or non-human mammals) are also included. In another aspect, the present invention provides an anti-Th3 drug and a Th1 modulator (optionally anti-Th2) for producing a kit or a drug for the treatment of atopic dermatitis in a mammal (human or non-human mammal). As well as the use of anti-Th3 drugs and Th1 modulators (optionally including anti-Th2 drugs) to treat atopic dermatitis in mammals (human or non-human mammals). .
4). Detection kit for atopic dermatitis
In the present invention, a kit for detecting atopic dermatitis characterized by comprising an anti-TGF-β antibody can also be provided. The present inventor measured TGF-β value (TGF-β concentration) from the plasma of a patient group diagnosed as atopic dermatitis by a dermatologist and a non-atopic group (healthy person), and there was a significant difference between the two groups. Confirmed that there is. Specifically, the patient group diagnosed with atopic dermatitis was found to have a significantly higher TGF-β value than the non-atopic group. The kit for detecting atopic dermatitis of the present invention has been completed based on such findings.
The detection kit of the present invention can also be used as a diagnostic kit for atopic dermatitis. The present invention also relates to a pharmaceutical composition for detecting and diagnosing atopic dermatitis comprising an anti-TGF-β antibody, a method for detecting and diagnosing atopic dermatitis using an anti-TGF-β antibody, and atopic skin. It also includes the use of anti-TGF-β antibodies to produce drugs for detecting and diagnosing flame.
In the detection kit of the present invention, the anti-TGF-β antibody is preferably provided in a dissolved state in consideration of stability (preservability) and ease of use.
The detection kit of the present invention can contain other components in addition to the anti-TGF-β antibody. Examples of other components include primary antibody detection reagents, chromogenic substrates, various buffers, various devices and containers for collecting plasma, various containers that can be used for antigen-antibody reactions, and usage manuals.
In particular, when the detection kit of the present invention is a kit for detecting TGF-β1 using ELISA, other components include a primary antibody detection reagent, a chromogenic substrate, and the like. Can do. In addition, in the case of a kit for detecting TGF-β using Western blotting, other components may further include a primary antibody detection reagent, a chromogenic substrate, and the like. In addition, in the case of a kit for detecting TGF-β using an immunochromatography method (gold colloid method), in addition to a colloidal gold labeled antibody and various solid-phased antibodies, a nitrocellulose membrane, a sample pad, and a conjugate pad And a test stick equipped with the above.
The detection kit of the present invention only needs to have at least the anti-TGF-β antibody described above as a component. Therefore, all of the components essential for the detection and diagnosis of atopic dermatitis may be provided together with the anti-TGF-β antibody or not, and there is no limitation.
The production method of the anti-TGF-β antibody (anti-TGF-β1 antibody) used in the detection kit of the present invention is not limited, and known polyclonal antibody and monoclonal antibody production methods can be used. The anti-TGF-β antibody is not limited, but is preferably a monoclonal antibody.
When detecting atopic dermatitis using the detection kit of the present invention, the concentration of TGF-β1 in plasma is 1.5 ng / ml or more, preferably 2.0 ng / ml or more in humans. It can be evaluated that atopic dermatitis has developed significantly. Similarly, in the case of cats, when TGF-β1 plasma concentration is 1.7 ng / ml or more and in dogs 2.0 ng / ml or more, it is evaluated that atopic dermatitis is significantly developed. be able to.
As described above, the detection kit of the present invention has shown that atopic dermatitis can be detected using the concentration of TGF-β1 in plasma as an index. In addition to being able to be used for drug use decision making to administer anti-Th3 drugs in the treatment method of, it is also used for the determination of drug withdrawal achievement (judgment of therapeutic effect such as whether or not complete cure) in medication treatment for atopic dermatitis be able to.
In the present invention, for example, by using the above detection kit, it is also possible to provide a method for detecting TGF-β in the plasma of a test mammal and evaluating the pathological condition of atopic dermatitis using the detection result as an index. it can. That is, TGF-β in plasma is detected and measured at any stage before, during or after treatment of atopic dermatitis, or at any stage where the onset of atopic dermatitis is unknown By doing so, the degree of symptoms of atopic dermatitis and the degree of therapeutic effect can be easily evaluated.
Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
In this example, a novel atopic dermatitis treatment method “Anti-Th3, anti-Th2, adjustment-Th1 / P. Therapy” (step method) using a drug kit was appropriately used. Anti-Th3, anti-Th2, adjustment-Th1, and P.I. The definition and description of Therapy are as follows.
Anti-Th3: anti-Th3 drug
Anti-Th2: anti-Th2 drug
Adjustment-Th1: Th1 regulator (suppresses superficial Th1 and enhances endogenous Th1, both of which are defined as regulators because they are both simultaneous)
・ P. Therapy: pulse therapy (performed when pruritus remains): 100 to 200 mg of itraconazole is orally taken once a day immediately after meals. The dosage may be adjusted according to age and symptoms. However, in the case of switching from itraconazole injection, 200 mg is taken orally twice a day (daily dose 400 mg) immediately after meals. In animals, the appropriate amount of this drug is 8 mg / kg / SIG, but a range of 3 to 30 mg is preferred.

Treatment of severe atopic dermatitis (1)
Severe atopic dermatitis is characterized by the fact that the test value of the Th2 vital reaction rebounds (the number suddenly becomes high). In severe atopic dermatitis, all steps of the drug (Anti-Th3, anti-Th2, adjustment-Th1 / P. Therapy) will be applied, and the decision to use the drug, such as the dose of each Th drug and itraconazole, will be based on the Th test. There is a need to implement.
Case: A 45-year-old male. From childhood, he had atopic dermatitis (AD), and he was desteroidalized at the age of 30 years. The rash exacerbated once every three years and often settled after resting at home for two months.
Current medical history and present symptom: The skin rash should have been relieved normally, but he did not relieve, so he consulted. The skin of the whole body was reddish black, scarring scars occurred frequently, and skin infiltration was remarkable. IPD (Taisho Pharmaceutical) was used as an anti-Th2 drug, and further treated with Onon etc. for 2 months, but it did not improve during the past 35 years.
Treatment: As a treatment method, a step method (Anti-Th3, anti-Th2, adjustment-Th1 / P. Therapy) was performed. Actually, as a step 1, as a reference to TGF-β1 biomarker, phenotype Th3 biological response (drug determinant of drug administration period) and endogenous biological reaction (drug determinant of drug administration), I took herbal medicine Ganoderma (Nissan Chemical). About 2 months after taking the anti-Th3 drug, the pruritus was remarkably reduced, and the atopy infiltration (mossification / skin thickening) in the skin was also improved. Thereafter, IPD (Taisho Pharmaceutical Co., Ltd.) was administered for about 2 months as an anti-Th2 drug that improves the enhancement of Th2 biological reaction (IgE production). Thereafter, an oral IFN-inducing agent (a Chinese medicine / herbal medicine mixture consisting mainly of Western Nanpo and Nanshige: Interferon Herb Research Institute, Snow Dream) was taken for about 1 month as a Th1 regulator. As shown in the figure, in Step 3, the Th1 vital reaction was adjusted within the normal value range (adjustment-Th1), and the oral IFN inducer described above was administered.
In this example, the patient was able to withdraw from oral administration in about 108 days, and all Th biological responses and TGF-β1 biomarkers were adjusted to approximate normal values as clinical symptoms improved (see FIG. 3). . TGF-β1 was also statistically more significant as a therapeutic marker for atopic dermatitis than IgE or TARC (Th2 chemokine).
The results and effects of the above treatment are shown in FIGS.
As can be seen from FIG. 1 and FIG. 2, in severe atopic dermatitis (AD), Th2 rebound (increased Th2 biological response) is observed by administration of an anti-Th3 drug from a situation predominantly Th2 biological reaction It was a feature. On the other hand, Th2 rebound was not observed in pediatric atopic dermatitis patients for reference. The Th2 biological reaction means that the evaluation value Th% of the efficacy when a Th2 agonist is administered fluctuates. Here, the Th2 biological reaction of an atopic patient is normal value 0.2 by administration of an anti-Th2 agent. This is referred to as shortening of the Th2 biological response in terms of treatment.
Moreover, although the external appearance of the skin of the upper arm part of a patient was shown in FIG.3 and FIG.4, the symptom score (SCORAD) of atopic dermatitis improved remarkably. The treatment method of this example did not improve during the past 35 years for severe AD showing resistance to normal treatment, but it was possible to achieve remission for the first time.

Treatment of severe atopic dermatitis (2)
Female adults with atopic dermatitis develop a transient increase in the Th2 vital reaction (rebound) and latex fruit syndrome (also animal dogs and cats). There was a need to do.
Case: A 39-year-old woman. Clinical course and present symptoms: Both upper limbs, both lower legs, chest, neck and face were rough and reddish (see the left figure in FIG. 5B). These symptoms were not effective after topical steroid ointment.
Treatment: Basically, the same treatment as that of the male adult severe atopic dermatitis of Example 1 was performed. First, as a step 1, actually, as an anti-Th3 drug based on TGF-β1 biomarker, phenotype Th3 biological reaction (drug determinant of drug administration period), and endogenous biological reaction (drug determinant of drug administration) I took 5 tablets of Chinese medicine and herbal medicine Reishi (Nissan Chemical). The pruritus decreased dramatically two weeks after administration. 45 days after taking the tablets, the medicine was changed to taking herbal medicines and herbal ganoderma pills from the tablets every other day (2.5g). 33 days after taking the anti-Th3 drug powder, IPD and ONON (ONON DS: ONON dry syrup), which are anti-Th2 drugs, were completed. Step 3 was changed to take 1 g of an IFN inducer that is a Th1 regulator.
The results and effects of the above treatment are shown in FIGS. 5A and 5B. Although it was resistant to the treatment so far, it responded well to this step, and erythroderma of the skin disappeared (findings in the right figure of FIG. 5B).

Treatment of childhood atopic dermatitis Childhood atopy is up to the second step of anti-Th3 and anti-Th2 agents, and atopic dermatitis may be completely cured. All of them made a decision to use the drug based on the test results and biomarkers from the Th test, and were treated after planning the treatment.
Case: 9 year old female.
Clinical course (current medical history) and current symptom: 5 days after first visit, 2 allegra (30) tablets and pediatric protopic (face and neck) moderately strong locoid ointment, and strong antebate ointment and moisturizer I was treated with. However, the improvement effect was not seen. The present condition was severe atopic dermatitis in which the skin of the whole body was scratched (red and black infiltrating lichen).
Treatment: Adult type severe atopic dermatitis (threshold of TGF-β1 10-100 ng / ml) in relation to the actual amount of TGF-β1 (defined as 5-10 ng / ml. Th3 cytokine / Th3 vital response) Before treatment, there is a statistically significant difference, and naturally, it exhibits a high value with a statistically significant difference from the average value (1.23 ng / ml (n = 105)) of healthy individuals. Therefore, the TARC value was 7109, and treatment was performed based on the diagnosis of a dermatologist with atopic dermatitis and the result of the Th test.
Specifically, when Ganoderma (Nissan Chemical) was taken as an anti-Th3 drug for 37 days, anti-Th2 action was also observed thereafter, and withdrawal from the internal medicine was possible on the 40th day. The reason for this is pointed out that the TGF-β1 marker value is lower than that of adult patients, and that the increase in Th2 biological response (Th2 significance) is not so high.
The results of the above treatment and the effects on the 37th day (findings before withdrawal from the drug) are shown in FIG.
Seven days after taking, redness of the body disappeared incredibly. The patient's visit improved on taking irregular visits and taking anti-Th3 drugs.

Treatment of canine atopic dermatitis (clinical overview of treatment and extrapolation to human treatment)
As shown in Table 1 below, the treatment using the hygiene hypothesis (the balance between Th1 and Th1 balance by subcutaneous administration of IFN, a Th1 cytokine) is about 90 days, and the cure rate is about 70%. (N = 8). In addition, an increase in Th3 vital reaction was observed in incurable dog cases. It was also statistically judged that TGF-β1 was a therapeutic inhibitor of atopy in Th3 or Th3 cytokines. From this evidence, treatment of atopic dermatitis using TGF-β1 as a therapeutic marker and administering an anti-Th3 drug kit (Anti-Th3, anti-Th2, adjustment-Th1 / P. Therapy; step method ) Was invented. As compared to the conventional method using the hygiene hypothesis, a new treatment method drug kit was applied (implemented the step method) for animal atopy. As shown in Table 1 below, the treatment days averaged 45.0 days. The remission rate was 97.0%, indicating a significant shortening of the treatment period and an improvement in the remission rate (%) (n = 49). When the conventional Th1 / Th2 balance therapy was used (n = 8), the drug administration average period was 92.4 days, and the drug withdrawal achievement rate was 75.0%.

FIG. 8 shows an average effect example of 49 cases that were maintained using a novel therapeutic drug kit as a basic human research. As shown in the left figure (Before) of FIG. 8, atopic dermatitis was treated in a dog (miniature dachshund adult dog) with hair loss and lichenized erythroderma.
The dosing method in treatment is a three-step step method as shown in FIG. 7, and Anti-Th3, anti-Th2, adjustment-Th1 / P. Using therapeutics, Kampo and herbal medicine Reishi (Nissan Chemical) as the anti-Th3 drug in Step 1, IPD (Taisho Pharmaceutical) as the anti-Th2 drug, and oral intestinal solvent INF-γ (CD4 / 8 ratio is high as the Th1 regulator) In the pathology of anergy, intraoral IFN-α) was administered to dogs as test animals.
The results and effects of the above novel treatment are shown as average effect examples in FIGS.
It was found that the atopic dermatitis with hair loss was almost completely cured by the treatment of this example. Regarding the treatment of canine atopic dermatitis, when the step method shown in this example was used (n = 49), as described above, the average period of drug administration was 45.0 days, and drug withdrawal was achieved. The rate was 98.0%, indicating a very excellent therapeutic effect (see Table 1).

Detection method of atopic dermatitis Plasma is collected from atopic dermatitis patient group (Atopy) and non-atopic group (Healthy person: Control), and the amount of TGF-β1 is measured using immunochromatography method (gold colloid method) did.
Specifically, TGF-β1 for human or animal was used as an antigen, and the concentration of TGF-β1 in the collected plasma was measured using various antibodies and pads shown in FIG. Specifically, in this method, when plasma passes through the membrane by capillary action, a TGF-β1 complex is formed by three members of TGF-β1, labeled anti-TGF-β1 antibody and capture antibody, and the labeled product. It is a measuring method which confirms accumulation | storage of this. Measurement time can be shortened by using two strips (about 10 minutes). In addition, cryopreservation is necessary until measurement.
The results of measuring the concentration of TGF-β1 in plasma by the immunochromatography method are shown in FIG. In the case of humans, it has been found that if the concentration of TGF-β1 in plasma is 1.5 ng / ml or more, it can be evaluated that atopic dermatitis has developed significantly. In the same manner, as a result of measurement for cats and dogs, cats with a TGF-β1 concentration of 1.7 ng / ml or more and dogs of 2.0 ng / ml or more significantly developed atopic dermatitis. It was found that it can be evaluated (not shown).
In this example, it was shown that atopic dermatitis can be detected using the concentration (amount) of TGF-β1 in plasma as an index, but the result of the concentration measurement is that the intention to use the drug for administering the anti-Th3 drug In addition to being used for determination, it can also be used to determine the achievement of drug withdrawal in medication treatment for atopic dermatitis.

Treatment of severe atopic dermatitis (3)
Among severe atopy patients, especially those with the most severe atopy have a high Th2 biological response, but unlike other atopies, the Th1 biological response is low (anergy) and the Th3 biological response is also low. (See FIG. 15). Here, the most severe atopy was defined as a state having skin erythema in 36% or more of the body surface area in the severity classification of atopy. Clinically, most patients with wet lichenification after desteroidalization fall into this severity category.
Data showing the clinical effect on adult-type most severe atopic dermatitis in the most severe atopic patients are shown in FIG. In addition, using plasma collected from the patient as a test sample and using a simple kit for detecting atopic dermatitis (for humans) containing the anti-TGF-β1 antibody exemplified in FIG. As shown in FIG. 14, it was positive for activated TGF-β1. However, in the most severe atopy, as a result of considering the disease state and Th3 biological reaction, etc., it was determined that administration of a Th3 biological reaction enhancer (Th3 enhancer) was more appropriate than administration of anti-Th3 drugs, and atopic dermatitis It clearly showed the complexity of the treatment when put together.
At the first visit (0th disease day), all high values were observed, and in particular, IgE was 49,370 IU / ml. Since the Th3 vital reaction was low in the most severe atopy, a Th3 enhancer (zinc-containing material: oyster shell powder) was administered. About 30 days after administration (09/11/11), a significant improvement was observed. Subsequently, when an anti-Th2 agent (IPD) was administered for 30 to 50 days, the activated TGF-β1 (result of the above-described simple detection kit) significantly decreased in good agreement with clinical symptoms.
From the above, it has been clarified that activated TGF-β1 measured by the simple detection kit is consistent with the clinical symptoms of atopy and with the therapeutic effect.
Next, the effect on each Th biological reaction to adult-type most severe atopic dermatitis is shown in FIG.
Although it was positive with the activated TGF-β1 simple kit for humans, the Th3 vital reaction was remarkably low immediately before dosing two months later, and when a Th3 enhancer was administered instead of an anti-Th3 agent, 2009 was obtained. On November 11, 2012 (30th day of administration), the Th3 vital reaction (%) was significantly improved from 0.3 to 7.6. However, an increase in Th2 biological response was observed in the atopy and the adult type most severe or severe type. Therefore, an anti-Th2 agent (IPD) was administered over the administration period of 30 to 50 days, clinical symptoms were brought to the face, and sensation was drastically reduced. However, seizures remained.
Subsequently, clinical symptoms improved and TGF-β1 was significantly improved. This indicates that TGF-β1 is consistent with the therapeutic effect as a marker consistent with clinical symptoms and drug withdrawal (stimulation).
Fig. 16 shows skin abnormalities (atopy infiltration) of the most severe atopic patients in this example before treatment (left figure: at the first visit) and after the final examination (right figure: appearance on the 74th day after the first examination). Respectively.
At the first visit, a characteristic dark red fading due to skin ulcers and the like was seen, and the skin color returned to normal. From the appearance on the 74th day after the first visit, the genital pruritus and skin ulcer (cracking) seen at the first visit disappeared completely, and the lichenification was remarkably improved.
Scarring: The ulcer caused by scratching at the first visit is scarring and healed on the appearance on the 74th day. In addition, in the appearance findings on the 74th day, a large scar was found in the center of the back of the hand, but it was a scratch that was not seen at the first visit, and was judged to be a healing scar when Th3 potentiator (SD: Snow Dream) was administered. . It shows clinically that the healing promotion effect by the growth of keratinoid is remarkable.
Pruritus: With all the data improvements, sensation improved with the recovery of skin barrier function.
Lichenization (skin thickening): Lichenization was observed throughout the body, but it decreased dramatically overall. However, genital malaise tended to remain. The disappearance of ulcer and subsequent increase in vascular permeability were suppressed, skin thickening was significantly rotated, and functional recovery of the hand was also observed. In addition, the edema-like changes on the back of the hand disappeared, and the ligament and the blood vessels on the back were clearly observed. Furthermore, it was observed when the finger became thinner due to the improvement of lichenification (FIG. 16).

According to the present invention, a kit for treating atopic dermatitis and a method for treating atopic dermatitis can be provided. Moreover, according to the present invention, a kit for detecting atopic dermatitis and a method for evaluating the pathological condition of atopic dermatitis can be provided.
The treatment kit and treatment method of the present invention are, for example, a patient who has been suffering from atopic dermatitis for 45 years (patients who have not developed onset for the previous 3 years: severe atopic treatment first treated by the present inventor. (Dermatitis) can be completely cured by epoch-making healing, and once all of the test figures are normalized, no recurrence has been observed, so it is extremely useful as a treatment for atopic dermatitis. Is something.
Further, the detection kit for atopic dermatitis of the present invention is capable of easily and quickly determining whether the subject and the test animal have developed atopic dermatitis as a test for the presence of an atopic treatment inhibitor. As shown in FIG. 11, a statistically significant difference was observed (FIG. 11: risk level of 5%). Furthermore, using the concentration of TGF-β1 in plasma detected by the kit as an indicator, making a drug use decision for administering the anti-Th3 drug in the AD treatment method of the present invention, and administering a drug for atopic dermatitis The AD detection kit of the present invention is extremely useful in that it can determine whether or not drug withdrawal has been achieved in treatment and can evaluate the pathology of AD.

Claims

A kit for treating atopic dermatitis comprising an anti-Th3 drug and an anti-Th2 drug, wherein an anti-Th3 drug is administered to a mammal, and then an anti-Th3 drug is administered instead of the anti-Th3 drug The kit, which is used.
The kit according to claim 1, further comprising a Th1 regulator, wherein the Th1 regulator is administered in place of the anti-Th2 drug after administration of the anti-Th2 drug.
The kit according to claim 1 or 2, wherein the anti-Th2 drug is administered after the start of administration of the anti-Th3 drug and a decrease in Th3 biological response is observed.
The kit according to claim 3, wherein the anti-Th2 drug is administered after the start of administration of the anti-Th3 drug and after a decrease in the Th3 biological response and an increase in the Th2 biological response are observed.
After the start of the administration of the anti-Th3 drug, the anti-Th2 drug is administered after normalization of the Th3 biological reaction is observed, and after the start of the administration of the anti-Th2 drug, a decrease in the Th2 biological reaction is observed and then the Th1 regulator is administered. The kit according to claim 2, which is used as described above.
After the start of administration of the anti-Th3 drug, the anti-Th2 drug is administered after the decrease of the Th3 biological reaction and the increase of the Th2 biological reaction are observed. After the start of the administration of the anti-Th2 drug, the decrease of the Th2 biological reaction and the decrease of the Th1 biological reaction The kit according to claim 5, which is used so that a Th1 adjusting agent is administered after admitted.
A kit for treating atopic dermatitis comprising an anti-Th3 drug and a Th1 modulator, wherein an anti-Th3 drug is administered to a mammal, and then a Th1 modulator is administered in place of the anti-Th3 drug The kit, which is used.
The kit according to claim 1, further comprising an anti-Th2 drug, wherein the anti-Th2 drug is administered instead of the Th1 drug after administration of the Th1 drug.
The kit according to claim 7 or 8, which is used so that a Th1 regulator is administered after a decrease in Th3 biological response is observed after the start of administration of an anti-Th3 drug.
The kit according to claim 9, which is used so that a Th1 regulator is administered after a decrease in Th3 biological response and a decrease or enhancement in Th1 biological response are observed after the start of administration of an anti-Th3 drug.
After the start of administration of the anti-Th3 drug, the Th1 biological reaction is reduced and then the Th1 adjustment drug is administered. After the start of administration of the Th1 adjustment drug, the Th1 biological reaction is promoted or decreased and then the anti-Th2 drug is administered. The kit according to claim 8, which is used as described above.
After the start of administration of the anti-Th3 drug, the Th1 biological reaction is decreased and the Th1 biological reaction is decreased or enhanced, and then the Th1 modulator is administered. After the start of the administration of the Th1 modulator, the Th1 biological reaction is enhanced or decreased and the Th2 The kit according to claim 11, which is used so that an anti-Th2 drug is administered after enhancement of a biological reaction is observed.
The kit according to any one of claims 1 to 12, wherein the anti-Th3 drug is a drug and / or Lindsay that contains ganoderma or an extract thereof as an active ingredient.
The kit according to any one of claims 1 to 13, which is used so that the dose of the anti-Th3 drug is 1 to 120 mg / kg body weight per day.
15. The kit according to any one of claims 1 to 6 and 8 to 14, wherein the anti-Th2 drug is a drug containing IPD and / or ganoderma or an extract thereof as an active ingredient.
The kit according to any one of claims 1 to 6 and 8 to 15, which is used so that the dose of the anti-Th2 drug is 0.1 to 10 mg / kg body weight per day.
The Th1 modulator is a drug containing, as an active ingredient, at least one selected from the group consisting of interferon-γ, interferon-α, nanban seeds or extracts thereof, nanbanata or extracts thereof, and cinnamon or extracts thereof. The kit according to any one of claims 2 to 16.
The kit according to any one of claims 2 to 17, which is used so that the dosage of the Th1 regulator is 1 to 30 MU per day.
The kit according to any one of claims 1 to 18, wherein the administration is oral administration, subcutaneous administration, intravenous administration, buccal administration, buccal administration, sublingual administration, gingival application, mucosal administration or spray administration. .
The kit according to any one of claims 1 to 19, wherein the mammal is a human or non-human mammal.
21. The kit according to claim 20, wherein the non-human mammal is a dog, cat, cow, horse, pig, sheep, goat, mouse, rat, rabbit, guinea pig or hamster.
A method for treating atopic dermatitis, comprising administering an anti-Th3 drug to a non-human mammal that develops atopic dermatitis, and then administering an anti-Th2 drug instead of the anti-Th3 drug .
23. The method according to claim 22, further comprising administering a Th1 modulator instead of the anti-Th2 drug after the anti-Th2 drug.
24. The method according to claim 22 or 23, wherein after the start of administration of the anti-Th3 drug, the anti-Th2 drug is administered after a decrease in Th3 vital reaction is observed.
25. The method according to claim 24, wherein after starting administration of the anti-Th3 drug, the anti-Th2 drug is administered after a decrease in Th3 biological response and an increase in the Th2 biological response are observed.
After the start of administration of the anti-Th3 drug, the anti-Th2 drug is administered after a decrease in the Th3 biological reaction is observed, and after the start of administration of the anti-Th2 drug, after the decrease in the Th2 biological reaction is observed, a Th1 adjustment drug is administered. 24. The method of claim 23.
After the start of administration of the anti-Th3 drug, the anti-Th2 drug is administered after the decrease in the Th3 biological reaction and the increase in the Th2 biological reaction are observed. 27. The method of claim 26, wherein a Th1 modulator is administered after the is found.
The method according to any one of claims 22 to 27, wherein the administration of the anti-Th3 drug is performed while monitoring a Th3 vital reaction.
Furthermore, the method of Claim 28 performed while monitoring Th2 vital reaction.
The method according to any one of claims 22 to 29, wherein the administration of the anti-Th2 drug is performed while monitoring a Th2 vital reaction.
Furthermore, the method of Claim 30 performed while monitoring Th1 vital reaction.
The method according to any one of claims 23 to 31, wherein the anti-Th1 modulator is administered while monitoring a Th1 vital reaction.
A method for treating atopic dermatitis, comprising administering an anti-Th3 drug to a non-human mammal that develops atopic dermatitis, and then administering a Th1 regulator instead of the anti-Th3 drug .
34. The method according to claim 33, further comprising administering an anti-Th2 drug after the Th1 modulator in place of the Th1 modulator.
35. The method according to claim 33 or 34, wherein after the start of administration of the anti-Th3 drug, a Th1 regulator is administered after a decrease in Th3 biological response is observed.
36. The method according to claim 35, wherein after the start of administration of the anti-Th3 drug, a Th1 regulator is administered after a decrease in Th3 biological response and a decrease or enhancement in Th1 biological response are observed.
After the start of administration of the anti-Th3 drug, a Th1 adjustment drug is administered after a decrease in the Th3 biological reaction is observed. After the start of administration of the Th1 adjustment drug, an anti-Th2 drug is administered after the increase or decrease in the Th1 biological reaction is observed. 35. The method of claim 34.
After the start of the administration of the anti-Th3 drug, the Th1 biological reaction is decreased and the decrease or enhancement of the Th1 biological reaction is observed, and then the Th1 modulator is administered. After the start of the administration of the Th1 modulator, the Th1 biological reaction is enhanced or decreased and the Th2 38. The method according to claim 37, wherein the anti-Th2 drug is administered after an enhanced vital reaction is observed.
The method according to any one of claims 33 to 38, wherein the administration of the anti-Th3 drug is performed while monitoring a Th3 vital reaction.
Furthermore, the method of Claim 39 performed while monitoring Th1 vital reaction.
The method according to any one of claims 33 to 40, wherein the administration of the anti-Th1 modulator is performed while monitoring a Th1 vital reaction.
Furthermore, the method of Claim 41 performed while monitoring Th2 vital reaction.
The method according to any one of claims 34 to 42, wherein the administration of the anti-Th2 drug is performed while monitoring a Th2 vital reaction.
44. The method according to any one of claims 22 to 43, wherein the dose of the anti-Th3 drug is 1 to 120 mg / kg body weight per day.
45. The method according to any one of claims 22 to 44, wherein the anti-Th3 drug is a drug and / or Lindsay that contains ganoderma lucidum or an extract thereof as an active ingredient.
The method according to any one of claims 22 to 32 and 34 to 45, wherein the dose of the anti-Th2 drug is 0.1 to 10 mg / kg body weight per day.
46. The method according to any one of claims 22 to 32 and 34 to 45, wherein the anti-Th2 drug is a drug containing IPD and / or ganoderma or an extract thereof as an active ingredient.
The method according to any one of claims 23 to 47, wherein the dose of the Th1 modulator is 1 to 30 MU per day.
The Th1 modulator is a drug containing, as an active ingredient, at least one selected from the group consisting of interferon-γ, interferon-α, nanban seeds or extracts thereof, nanbanata or extracts thereof, and cinnamon or extracts thereof. 48. The method according to any one of claims 23 to 47.
The method according to any one of claims 22 to 49, wherein the administration is oral administration, subcutaneous administration, intravenous administration, buccal administration, buccal administration, sublingual administration, gingival application, mucosal administration or spray administration. .
The method according to any one of claims 22 to 50, wherein the non-human mammal is a dog, cat, cow, horse, rabbit, guinea pig or hamster.
A kit for detecting atopic dermatitis, comprising an anti-TGF-β antibody.
A method of detecting TGF-β in plasma of a test mammal and evaluating the pathological condition of atopic dermatitis using the detection result as an index.
54. The method of claim 53, wherein the mammal is a human or non-human mammal.
55. The method of claim 54, wherein the non-human mammal is a dog, cat, cow, horse, pig, sheep, goat, mouse, rat, rabbit, guinea pig or hamster.