CN113341161A - Application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases - Google Patents

Application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases Download PDF

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CN113341161A
CN113341161A CN202110646772.2A CN202110646772A CN113341161A CN 113341161 A CN113341161 A CN 113341161A CN 202110646772 A CN202110646772 A CN 202110646772A CN 113341161 A CN113341161 A CN 113341161A
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icosl
icos
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skin diseases
allergic skin
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焦晴晴
刘翠平
杨子良
唐敏慧
赵莹
胡筱涵
苏文星
方富民
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First Affiliated Hospital of Suzhou University
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    • A—HUMAN NECESSITIES
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Abstract

The invention discloses application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases, which comprises application of ICOS/ICOSL as a biomarker in preparation of a detection kit for diagnosis and treatment of allergic skin diseases and application of an anti-human ICOSL antibody in preparation of a medicine for treatment of allergic skin diseases. The experimental result shows that the excessive activation of the ICOS/ICOSL signal channel is obviously related to the clinical symptoms and laboratory indexes of atopic dermatitis and chronic urticaria; the ICOSL antibody can specifically recognize and bind ICOSLIg protein, block the interaction between the ICOS protein and the ICOSL, inhibit the proliferation of T cells and the secretion of related cytokines, and remarkably improve the skin damage condition of an atopic dermatitis model mouse and reduce the scratching times. Therefore, the ICOS/ICOSL signal path has important clinical application value in the diagnosis and treatment of allergic skin diseases.

Description

Application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases
Technical Field
The invention belongs to the field of new application, and particularly relates to application of ICOS/ICOSL as a biomarker in a detection kit for diagnosing and treating allergic skin diseases and application of an ICOSL monoclonal antibody in preparation of a medicine for preventing and treating the allergic skin diseases.
Background
Atopic Dermatitis (AD) is a common disease in children, 1/3 accounting for outpatient visits to dermatology in children, and is the primary disease that afflicts the skin health of children. However, there are other dermatologically common diseases or syndromes found in clinical work that also have the cutaneous manifestations of atopic dermatitis, easily leading to confusion. Therefore, there is a need to understand and differentiate related diseases with atopic dermatitis-like manifestations to aid diagnosis and treatment, and the discovery of new laboratory test indices has important clinical application value for differential diagnosis of AD.
Atopic dermatitis is a T cell mediated, severe pruritus, chronic recurrent and inflammatory dermatosis, which is often accompanied with a series of symptoms such as asthma, allergic rhinitis, conjunctivitis and the like, and is mainly characterized by severe pruritus and sleep disorder, the incidence rate of AD is on the rising trend year by year, and the harm is serious and wide. AD has become a serious social problem, placing a large economic burden on the home and society. At present, systemic glucocorticoids and immunosuppressants are mainly used for clinically treating severe AD which is ineffective in conventional treatment, and the side effects and individual differences of the systemic glucocorticoids and immunosuppressants often cause that the treatment cannot achieve satisfactory curative effect, so the discovery of a new immune intervention way has important clinical significance for searching for effective means for treating AD.
Activation of T cells requires dual signals, antigenic peptide-MHC molecule complexes with T cell surface receptors (T)CR) provides a first signal and a second signal is derived from the interaction between Antigen Presenting Cells (APCs) and T cell surface co-stimulatory molecules. ICOS (ICOS)/ICOSL (ligand of ICOS) are an important pair of costimulatory molecules, and we have found in previous studies: atopic Dermatitis (AD) patients with peripheral blood and local lesions of THICOS expression on 22 cell surface is obviously up-regulated, and CD14 is simultaneously applied to peripheral blood and skin lesion of AD patients+Monocyte, CD19+The ICOSL expression on the surface of the B lymphocyte is also obviously increased and is seriously related to the severity of the disease; staphylococcus aureus exotoxin alpha-toxin can significantly up-regulate T H22 cell surface expression of ICOS, activation of the ICOS/ICOSL signaling pathway leads to T patients with AD H22 cells, and thus down-regulation of the expression of the intermediate filament-associated protein, further aggravates the breakdown of the skin barrier function of the patients and contributes to the immune damage process of AD, which is reported in the mainstream Journal of Dermatology, region 1 of British of Journal of Dermatology (2017/2018 IF = 6.129). ICOS/ICOSL also exert important biological effects in the regulation of the immune response in the body as follows:
(ii) the ICOS/ICOSL signal pathway is capable of mediating TH2、T H1、TH17 and differentiation of resident lymphocytes, up-regulating the expression of some cytokines;
ICOS/ICOSL signal can promote the differentiation of B cell into memory cell and plasma cell by co-stimulating T cell to secrete IL-10 and IL-21, and can coordinate IL-10 to increase the secretion of IgE, IgG and the like of B cell;
(iii) ICOS facilitated T/B interactions and initiated Ig class switching was probably achieved through interactions of the CD40/CD40L pathway; thereby participating in a humoral immune response;
ICOS/ICOSL signals play an important role in the course of allergic inflammatory diseases of the airways;
ICOS gene polymorphism is probably related to the pathogenesis of chronic autoimmune urticaria;
the ICOS/ICOSL signal participates in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and autoimmune uveitis. Currently, monoclonal antibody drugs for lupus treatment are available: (Amgen treatment AMG 577) and its main mechanism of action is to inhibit over-activation of ICOS/ICOSL signals.
In addition, the pathogenesis of Chronic idiopathic urticaria (CSU) is not clear, and it is currently believed that a possible factor relates to THl/TH2 cell imbalance: CD4 mediating immune tolerance+、CD25+Regulatory T cells (Tregs) and helper T cells that mediate inflammatory responsesHThe 17-ratio down regulation is closely related to CSU. Further part T H1、TH2、T H1 and THAbnormal levels of 22-associated cytokines are also associated with autoreactivity or allergen sensitivity in the serum of CSU patients; through preliminary experimental study, we found that: the ICOS/ICOSL signal is also involved in the disease progression and is associated with immune damage in CSU patients.
Therefore, the inventor further researches ICOS/ICOSL to find that the mouse anti-human ICOSL antibody can specifically recognize and bind ICOSLIg protein, block the interaction between ICOS protein and ICOSL, can inhibit T cell proliferation and the secretion of IL-4, IL-10, TNF-alpha and IFN-gamma cytokines, and the inhibition effect of the ICOSL antibody is enhanced along with the increase of the antibody concentration. The ICOSL monoclonal antibody can obviously improve the skin damage condition of a mouse and reduce scratching in an atopic dermatitis mouse model, and the research result shows that the ICOSL monoclonal antibody has good potential treatment value on allergic dermatosis. Therefore, based on the above research findings of the subject group, further understanding and development of the ICOS/ICOSL signaling pathway is of great clinical significance for the prevention and treatment of allergic skin diseases.
Disclosure of Invention
In order to solve the diagnosis and treatment problem of allergic skin diseases existing in the current clinical work, the invention aims to provide the application of ICOS/ICOSL as a biomarker in preparing a detection kit for diagnosing and treating the allergic skin diseases and the application of an anti-human ICOSL antibody in preparing a medicament for treating the allergic skin diseases.
In order to achieve the purpose, the invention adopts the technical scheme that:
the ICOS/ICOSL is used as a biomarker for preparing a detection kit for diagnosing and treating allergic skin diseases.
Further, the detection kit comprises a detection reagent based on protein level detection.
Furthermore, the detection reagent is a reagent for flow cytometry analysis, immunoblotting analysis, enzyme-linked immunosorbent assay (ELISA), immunochromatography, radioimmunoassay, immunodiffusion, immunoelectrophoresis, tissue immunostaining or immunoprecipitation analysis.
Further, the detection reagent comprises an antibody, an aptamer, an affinity multimer, a peptide mimetic, or a receptor that specifically recognizes the biomarker.
Use of an anti-human ICOSL antibody in the manufacture of a medicament for the treatment of allergic skin diseases.
A medicament for the treatment of allergic skin diseases, said medicament comprising an effective amount of an anti-human ICOSL antibody and a pharmaceutically acceptable carrier.
Furthermore, the medicine is a tablet, a sustained release agent, an injection, a capsule, a granule or powder.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses application of ICOS/ICOSL as a biomarker in preparing a detection kit for diagnosing and treating allergic skin diseases, and also discloses application of an anti-human ICOSL antibody in preparing a medicament for treating the allergic skin diseases, wherein an ICOS/ICOSL signal channel has good diagnosis and treatment values on the allergic skin diseases.
Drawings
FIG. 1 is an ICOS+ T H22+Cells and ICOSL+Correlation results of B cells with clinically relevant parameters of AD patients.
FIG. 2 shows CD4 in CSU patients+ICOS+Correlation between cells and clinical indices and the results of IL-21 expression in serum from peripheral blood.
FIG. 3 is a graph showing the results of a competitive inhibition assay of antibodies to ICOS/ICOSL binding.
FIG. 4 is a graph showing the results of ICOSL mab inhibiting T cell proliferation and cytokine secretion. Wherein A is a graph of the results of the inhibition of T cell proliferation by the antibody; b is a result graph of the antibody inhibiting the T cells from secreting IL-4, IL-10, TNF-alpha and IFN-gamma; c is a result chart of the inhibitory effect of the monoclonal antibody on the proliferation of the T cells verified by the CCK8 method.
FIG. 5 is a graph showing the results of ICOSL mab significantly alleviating the clinical phenotype of AD model mice.
Detailed Description
The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Examples 1
ICOS/ICOSL signal regulation THAction mechanism and clinical significance of 22 cells in atopic dermatitis immune injury
Study on peripheral blood and local skin lesion T of AD patientsHCorrelation of ICOS expression on 22 cells with age stage and disease severity, detection of ICOS/ICOSL expression, T H22 cell infiltration and secretion of different cytokines in peripheral blood serum, analysis of the potential clinical significance of ICOS/ICOSL signaling for the diagnosis and treatment of AD, to explore T mediated by this costimulatory signaling pathway in the body H22 biological role of cellular immune dysfunction in the development of AD. The results of the study showed that peripheral blood ICOS was present in AD patients+TH22+Cells and ICOSL+B cells were all associated with the severity of the disease and total IgE levels in the patients (figure 1).
Example 2
Action mechanism and clinical significance of ICOS/ICOSL participating in chronic spontaneous urticaria anaphylactic reaction
Comparison of changes in ICOS/ICOSL expression levels with CD40/CD40L expression before and after treatmentCSU subtype, clinical relevant indexes, pathological indexes and the correlation of Ig, cytokine and chemotactic factor levels, and the potential clinical significance of analyzing ICOS/ICOSL signals for diagnosing and treating CSU; results of the study, CSU patient peripheral blood CD4+ICOS+T cell and UAS7 scores, serum total IgE levels, and CD19+ICOSL+B lymphocyte ratios were significantly correlated. IL-21 expression in peripheral serum of CSU patients was also significantly upregulated (FIG. 2).
EXAMPLE 3
Anti-human ICOSL antibodies block ICOS/ICOSL interactions
The results of the competitive inhibition experiments comparing different doses of ICOSL antibody and icosil with L929/ICOSL as the cells of competitive interest show that the antibody inhibits the ICOS/ICOSL interaction with increasing concentration (fig. 3). Therefore, the antibody has certain application value in the aspect of blocking an ICOS/ICOSL positive costimulatory signal pathway.
EXAMPLE 4
Anti-human ICOSL antibody can inhibit T cell proliferation and cytokine secretion
To further study the biological effect of blocking anti-human ICOSL antibody on T cells, the effect of blocking ICOS/ICOSL positive costimulatory signals by the antibody on T cell proliferation was observed in an in vitro T cell proliferation assay, and as shown in fig. 4A, the antibody significantly inhibited T cell proliferation. The ICOSL antibody group cell culture supernatants were collected and tested for cytokine secretion by CBA, and the presence of ICOSL antibodies was also found to inhibit secretion of IL-4, IL-10, TNF- α and IFN- γ by T cells, as compared to the control group (FIG. 4B). We also verified the effect of two monoclonal antibodies on T cell proliferation in vitro by the CCK8 method, which was similar to the CFSE method (FIG. 4C).
EXAMPLE 5
Evaluation of therapeutic Effect of ICOSL monoclonal antibody on AD model mouse
Sensitizing a normal BALB/c mouse by OVA, and evaluating the disease condition and the severity of AD by adopting a SCORAD scoring system according to Hanifin-Rajak diagnostic standard; the ICOSL functional blocking antibody is adopted to treat the sick AD mice, meanwhile, an untreated group is used as a control, an SCORAD scoring system is adopted to evaluate the AD severity, the skin-related immune cell infiltration is detected by immunohistochemistry, the pathological change of AD skin is observed, and the change of inflammatory factors and chemotactic factors at skin lesions is detected by RT-PCR. We observed that ICOSL monoclonal antibody significantly improved the symptoms of skin lesions in diseased AD mice relative to the untreated group (figure 5).

Claims (7)

1. The ICOS/ICOSL is used as a biomarker for preparing a detection kit for diagnosing and treating allergic skin diseases.
2. The use of claim 1, wherein the test kit comprises a test reagent based on protein level detection.
3. The use of claim 2, wherein the detection reagent is a reagent for flow cytometry, immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), immunochromatography, radioimmunoassay, immunodiffusion, immunoelectrophoresis, tissue immunostaining, or immunoprecipitation analysis.
4. The use of claim 3, wherein the detection reagent comprises an antibody, aptamer, affinity multimer, peptide mimetic, or receptor that specifically recognizes the biomarker.
5. Use of an anti-human ICOSL antibody in the manufacture of a medicament for the treatment of allergic skin diseases.
6. A medicament for the treatment of allergic skin diseases, said medicament comprising an effective amount of an anti-human ICOSL antibody and a pharmaceutically acceptable carrier.
7. The medicament of claim 6, wherein the medicament is a tablet, a sustained release agent, an injection, a capsule, a granule or a powder.
CN202110646772.2A 2021-06-10 2021-06-10 Application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases Pending CN113341161A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0302167D0 (en) * 2003-01-30 2003-03-05 Leuven K U Res & Dev T cell phenotype
CN107810198A (en) * 2015-05-29 2018-03-16 艾伯维公司 Anti-CD 40 antibodies and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0302167D0 (en) * 2003-01-30 2003-03-05 Leuven K U Res & Dev T cell phenotype
CN107810198A (en) * 2015-05-29 2018-03-16 艾伯维公司 Anti-CD 40 antibodies and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Q. JIAO等: "T helper 22 cells from Han Chinese patients with atopic dermatitis exhibit high expression of inducible T-cell costimulator", 《BRITISH JOURNAL OF DERMATOLOGY》 *
Z. BRZOZA等: "Inducible T-cell costimulator (ICOS) and CD28 polymorphisms possibly play a role in the pathogenesis of chronic autoreactive urticaria", 《CLINICAL AND EXPERIMENTAL DERMATOLOGY》 *
胡筱涵: "人诱导共刺激分子配体ICOSL单克隆抗体及ELISA试剂盒的研制及应用", 《中国优秀硕士学位论文全文数据库 (医药卫生科技辑)》 *

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CN113341161A (en) Application of ICOS/ICOSL in diagnosis and treatment of allergic skin diseases

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Application publication date: 20210903