JPH10139800A - Therapeutic agent for sjogren's syndrome - Google Patents

Therapeutic agent for sjogren's syndrome

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Publication number
JPH10139800A
JPH10139800A JP8304949A JP30494996A JPH10139800A JP H10139800 A JPH10139800 A JP H10139800A JP 8304949 A JP8304949 A JP 8304949A JP 30494996 A JP30494996 A JP 30494996A JP H10139800 A JPH10139800 A JP H10139800A
Authority
JP
Japan
Prior art keywords
sjogren
syndrome
peptide
glu
leu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
JP8304949A
Other languages
Japanese (ja)
Inventor
Kusuki Nishioka
久寿樹 西岡
Takayuki Sumita
孝之 住田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SEI MARIANNA IKA UNIV
Santen Pharmaceutical Co Ltd
Original Assignee
SEI MARIANNA IKA UNIV
Santen Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SEI MARIANNA IKA UNIV, Santen Pharmaceutical Co Ltd filed Critical SEI MARIANNA IKA UNIV
Priority to JP8304949A priority Critical patent/JPH10139800A/en
Publication of JPH10139800A publication Critical patent/JPH10139800A/en
Withdrawn legal-status Critical Current

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

PROBLEM TO BE SOLVED: To obtain a new peptide comprising T cell epitope having base constituting components of specific amino acids and derived from Sjogren's syndrome patient, capable of providing an antibody inhibiting the binding thereof to the binding site of the T cell and an analogue peptide thereof useful as a therapeutic agent, etc., for the Sjogren's syndrome. SOLUTION: This new peptide is T cell epitope derived from Sjogren's syndrome patient and having amino acids of Gly, Leu, Ile, Asp, Glu, Gln and Arg as base constituting components and including an amino acid sequence represented by the formula, etc. An antibody inhibiting the binding of the T cell epitope to the biding site of the T cell and an analogue peptide of the T cell analogue are useful as a therapeutic agent, etc., for the Sjogren's syndrome. The peptide is obtained by discovering that the peptide comprising 190-245 amino acid sequence of Ro/SS-A52kD protein of saliva of the Sjogren's syndrome patient is an autoantigen recognized by an autoreactive T cell, and synthesizing a peptide having the amino acid sequence.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【発明の属する技術分野】本発明は、シェーグレン症候
群のＴ細胞エピトープの同定、ならびに該Ｔ細胞エピト
ープがＴ細胞の結合部位に結合することを阻止し、シェ
ーグレン症候群治療剤として有用である抗体やアナログ
ペプチドに関するものである。TECHNICAL FIELD The present invention relates to the identification of T cell epitopes of Sjogren's syndrome, and to antibodies and analogs which prevent the T cell epitope from binding to the binding site of T cells and are useful as therapeutic agents for Sjogren's syndrome. It relates to peptides.

【０００２】[0002]

【従来の技術】シェーグレン症候群はドライアイや口腔
乾燥症を引き起こす涙腺や唾液腺へのリンパ球浸潤を特
徴とする自己免疫疾患である。リンパ球浸潤は腎、肺、
甲状腺および肝臓にも認められる。免疫組織の研究にお
いて、唾液腺、涙腺および腎の周囲の浸潤リンパ球はほ
とんどＣＤ4 陽性のαβＴ細胞である。最近のポリメラ
ーゼ連鎖反応（ＰＣＲ）による研究によって、ＣＤ4 陽
性αβＴ細胞にＴ細胞受容体ＶβとＶαの遺伝子が存在
していることが明らかとなった。ＣＤＲ3 領域の塩基配
列検索はいくつかの保存されたアミノ酸モチーフを示し
ており、浸潤Ｔ細胞が自己抗原の関連したいくつかのエ
ピトープを認識していることを支持している。2. Description of the Related Art Sjogren's syndrome is an autoimmune disease characterized by lymphocyte infiltration into the lacrimal glands and salivary glands that causes dry eye and xerostomia. Lymphocyte infiltration occurs in the kidneys, lungs,
It is also found in the thyroid and liver. In studies of immunohistochemical, salivary gland, infiltrating lymphocytes surrounding the lacrimal gland and kidney are αβT cells of most CD 4-positive. Studies by the recent polymerase chain reaction (PCR), it was revealed that the gene of the T cell receptor Vβ and Vα the CD 4-positive αβT cells are present. CDR 3 base sequence search region shows several conserved amino acid motifs, infiltrating T cells supports that are aware of several epitopes associated autoantigens.

【０００３】シェーグレン症候群における自己反応性Ｔ
細胞によって認識される自己抗原については、細胞タン
パク、Epstein-Bar ウィルス、または内因性もしくは外
因性レトロウィルスが考えられている。Namekawaらはシ
ェーグレン症候群患者の唾液腺にＲｏ／ＳＳ−Ａ ５２
ｋＤ タンパク（以下、タンパクＡと略記する）の１９
０〜２４５のアミノ酸配列からなるペプチドに反応する
Ｔ細胞が多く存在していることを報告している（J. Rhe
umatol., 22, 2092 -2099 (1995)）。このことはタンパ
クＡが涙腺や唾液腺で自己反応性Ｔ細胞に対して自己抗
原の役割を担っていることを示唆している。タンパクＡ
は細胞質に分布しているリボ核酸タンパクであるが、細
胞表面にも出現する。したがって、インシュリン依存性
糖尿病患者のグルタミン酸カルボキシル基分解酵素や混
合性結合組織病患者の自己抗原であるｓｎＲＮＰのよう
な、自己反応性Ｔ細胞によって認識される自己抗原であ
る。Self-reactive T in Sjogren's syndrome
For self-antigens recognized by cells, cellular proteins, Epstein-Bar virus, or endogenous or exogenous retroviruses are considered. Namekawa et al. Added Ro / SS-A52 to the salivary glands of Sjogren's syndrome patients.
19 of kD protein (hereinafter abbreviated as protein A)
It has been reported that there are many T cells that respond to a peptide having an amino acid sequence of 0 to 245 (J. Rhe
umatol., 22 , 2092-2099 (1995)). This suggests that protein A plays a role of an autoantigen for self-reactive T cells in lacrimal glands and salivary glands. Protein A
Is a ribonucleic acid protein distributed in the cytoplasm, but also appears on the cell surface. Therefore, it is an autoantigen recognized by autoreactive T cells, such as glutamate carboxylase in insulin-dependent diabetes patients and snRNP which is an autoantigen in patients with mixed connective tissue disease.

【０００４】[0004]

【発明が解決しようとする課題】シェーグレン症候群患
者の唾液のタンパクＡからシェーグレン症候群のＴ細胞
エピトープを同定し、そのＴ細胞エピトープがシェーグ
レン症候群患者由来のＴ細胞の結合部位に結合すること
を阻止する抗体やアナログペプチドを見いだすことは興
味ある課題であった。SUMMARY OF THE INVENTION A T cell epitope of Sjogren's syndrome is identified from protein A in saliva of a patient with Sjogren's syndrome, and the T cell epitope is prevented from binding to a binding site of a T cell derived from a patient with Sjogren's syndrome. Finding antibodies and analog peptides has been an interesting issue.

【０００５】[0005]

【課題を解決するための手段】シェーグレン症候群のＴ
細胞エピトープを明らかにするために、タンパクＡの１
８８〜２３７のアミノ酸配列のうち１５のアミノ酸配列
からなる合成ペプチドを用いて、タンパクＡ反応性Ｔ細
胞の増殖能への作用を検討した。その結果、タンパクＡ
の２０３〜２１２のアミノ酸配列であるＡｓｐ−Ｇｌｕ
−Ａｒｇ−Ｇｌｕ−Ｇｌｎ−Ｌｅｕ−Ａｒｇ−Ｉｌｅ−
Ｌｅｕ−Ｇｌｙが、シェーグレン症候群患者由来の自己
反応性Ｔ細胞によって認識されるシェーグレン症候群の
Ｔ細胞エピトープの１つであることが判明した。Means for Solving the Problems T of Sjogren's Syndrome
To identify cellular epitopes, one of protein A
Using a synthetic peptide consisting of 15 amino acid sequences of the 88 to 237 amino acid sequences, the effect on the proliferation ability of protein A-reactive T cells was examined. As a result, protein A
Asp-Glu, which is the amino acid sequence of
-Arg-Glu-Gln-Leu-Arg-Ile-
Leu-Gly was found to be one of the Sjogren's syndrome T cell epitopes recognized by autoreactive T cells from Sjogren's syndrome patients.

【０００６】したがって、Ａｓｐ−Ｇｌｕ−Ａｒｇ−Ｇ
ｌｕ−Ｇｌｎ−Ｌｅｕ−Ａｒｇ−Ｉｌｅ−Ｌｅｕ−Ｇｌ
ｙがシェーグレン症候群患者由来のＴ細胞の結合部位に
結合することを阻止する抗体やアナログペプチドは、シ
ェーグレン症候群の治療剤として有用であることが期待
される。Therefore, Asp-Glu-Arg-G
lu-Gln-Leu-Arg-Ile-Leu-Gl
Antibodies and analog peptides that prevent y from binding to the binding site of T cells derived from Sjogren's syndrome patients are expected to be useful as therapeutic agents for Sjogren's syndrome.

【０００７】[0007]

【発明の実施の形態】以下に薬理試験の結果を示すが、
この例は本発明をよりよく理解するためのものであり、
本発明の範囲を限定するものではない。BEST MODE FOR CARRYING OUT THE INVENTION The results of pharmacological tests are shown below,
This example is for a better understanding of the invention,
It does not limit the scope of the invention.

【０００８】[0008]

【実施例】【Example】

［薬理試験］タンパクＡの１８８〜２３７のアミノ酸配
列のうち１５のアミノ酸配列からなる合成ペプチドの作
用を、［ 3Ｈ］チミジンの取り込み量を指標としたシェ
ーグレン症候群患者から得られたタンパクＡ反応性Ｔ細
胞の増殖の程度で検討した。 （実験方法）シェーグレン症候群患者５５名から得られ
たタンパクＡ反応性Ｔ細胞（１０5ｃｅｌｌｓ／ｍｌ）
を、１５のアミノ酸からなる下記８種の被験合成ペプチ
ド（２５μｇ／ｍｌ）と３７℃・５％ＣＯ2 ／ａｉｒの
条件下、７２時間インキュベーションした。抗原提示細
胞として放射線照射（３０００ｒａｄ）処理した抹消血
リンパ球（２．５×１０5 ｃｅｌｌｓ／ｍｌ）を加え
た。最後の１６時間は［3Ｈ］チミジン（０．５μＣｉ
／ｗｅｌｌ）を加えておき、［ 3Ｈ］チミジンの取り込
み量を液体シンチレーションカウンターで測定した。[Pharmacological test] Protein A reactivity obtained from a patient with Sjögren's syndrome using the effect of a synthetic peptide consisting of 15 amino acid sequences out of the 188 to 237 amino acid sequences of protein A as an index of [ 3 H] thymidine incorporation. The degree of T cell proliferation was examined. (Experimental method) Protein A-reactive T cells (10 5 cells / ml) obtained from 55 patients with Sjogren's syndrome
Was incubated with the following eight test synthetic peptides (25 μg / ml) consisting of 15 amino acids under conditions of 37 ° C. and 5% CO 2 / air for 72 hours. Irradiated (3000 rad) -treated peripheral blood lymphocytes (2.5 × 10 5 cells / ml) were added as antigen-presenting cells. [ 3 H] thymidine (0.5 μCi
/ Well) was added and [ 3 H] thymidine incorporation was measured with a liquid scintillation counter.

【０００９】用いた８種の被験合成ペプチドは次の通り
である。The eight test synthetic peptides used are as follows.

【００１０】[0010]

【表１】FLVEEEQRQLQELEK ( すなわちPhe-Leu-Val-Glu-Glu-Glu-Gln-Arg-Gln-Leu-
Gln-Glu-Leu-Glu-Lys) タンパクＡ中の位置１８８〜２０２ EQRQLQELEKDEREQ ( すなわちGlu-Gln-Arg-Gln-Leu-Gln-Glu-Leu-Glu-Lys-
Asp-Glu-Arg-Glu-Gln) タンパクＡ中の位置１９３〜２０７ QELEKDEREQLRILG ( すなわちGln-Glu-Leu-Glu-Lys-Asp-Glu-Arg-Glu-Gln-
Leu-Arg-Ile-Leu-Gly) タンパクＡ中の位置１９８〜２１２ DEREQLRILGEKEAK ( すなわちAsp-Glu-Arg-Glu-Gln-Leu-Arg-Ile-Leu-Gly-
Glu-Lys-Glu-Ala-Lys) タンパクＡ中の位置２０３〜２１７ LRILGEKEAKLAQQS ( すなわちLeu-Arg-Ile-Leu-Gly-Glu-Lys-Glu-Ala-Lys-
Leu-Ala-Gln-Gln-Ser) タンパクＡ中の位置２０８〜２２２ EKEAKLAQQSQALQE ( すなわちGlu-Lys-Glu-Ala-Lys-Leu-Ala-Gln-Gln-Ser-
Gln-Ala-Leu-Gln-Glu) タンパクＡ中の位置２１３〜２２７ LAQQSQALQELISEI ( すなわちLeu-Ala-Gln-Gln-Ser-Gln-Ala-Leu-Gln-Glu-
Leu-Ile-Ser-Glu-Ile) タンパクＡ中の位置２１８〜２３２ QALQELISEIDRRCH ( すなわちGln-Ala-Leu-Gln-Glu-Leu-Ile-Ser-Glu-Ile-
Asp-Arg-Arg-Cys-His) タンパクＡ中の位置２２３〜２３７[Table 1] FLVEEEQRQLQELEK (that is, Phe-Leu-Val-Glu-Glu-Glu-Gln-Arg-Gln-Leu-
Gln-Glu-Leu-Glu-Lys) position 188-202 in protein A EQRQLQELEKDEREQ (i.e.Glu-Gln-Arg-Gln-Leu-Gln-Glu-Leu-Glu-Lys-
Asp-Glu-Arg-Glu-Gln) Positions 193-207 in Protein A QELEKDEREQLRILG (i.e. Gln-Glu-Leu-Glu-Lys-Asp-Glu-Arg-Glu-Gln-
Leu-Arg-Ile-Leu-Gly) positions 198-212 in protein A DEREQLRILGEKEAK (i.e. Asp-Glu-Arg-Glu-Gln-Leu-Arg-Ile-Leu-Gly-
Glu-Lys-Glu-Ala-Lys) Positions 203-217 in protein A LRILGEKEAKLAQQS (i.e.Leu-Arg-Ile-Leu-Gly-Glu-Lys-Glu-Ala-Lys-
Leu-Ala-Gln-Gln-Ser) Positions 208-222 in Protein A EKEAKLAQQSQALQE (i.e.Glu-Lys-Glu-Ala-Lys-Leu-Ala-Gln-Gln-Ser-
Gln-Ala-Leu-Gln-Glu) positions 213-227 in protein A LAQQSQALQELISEI (i.e. Leu-Ala-Gln-Gln-Ser-Gln-Ala-Leu-Gln-Glu-
Leu-Ile-Ser-Glu-Ile) positions 218-232 in protein A QALQELISEIDRRCH (ie Gln-Ala-Leu-Gln-Glu-Leu-Ile-Ser-Glu-Ile-
Asp-Arg-Arg-Cys-His) Positions 223-237 in Protein A

【００１１】なお、陽性対照としてタンパクＡの１９０
〜２４５のアミノ酸配列からなるペプチドとβ−ガラク
トシダーゼの組み換え融合タンパク（以下、Ａ１と略記
する）を、陰性対照としてβ−ガラクトシダーゼ（以
下、β−ｇａｌと略記する）を用いた。As a positive control, protein A of 190
A recombinant fusion protein (hereinafter abbreviated as A1) of a peptide having an amino acid sequence of -245 and β-galactosidase was used as a negative control, and β-galactosidase (hereinafter abbreviated as β-gal) was used as a negative control.

【００１２】（結果）図１に結果の一例を示す。タンパ
クＡの１９８〜２１２のアミノ酸配列である合成ペプチ
ドおよびタンパクＡの２０３〜２１７のアミノ酸配列
である合成ペプチドで細胞増殖の促進が認められた。
すなわち、これらの合成ペプチドに共通している、
タンパクＡの２０３〜２１２のアミノ酸配列であるＡｓ
ｐ−Ｇｌｕ−Ａｒｇ−Ｇｌｕ−Ｇｌｎ−Ｌｅｕ−Ａｒｇ
−Ｉｌｅ−Ｌｅｕ−Ｇｌｙが、シェーグレン症候群患者
由来の自己反応性Ｔ細胞によって認識されるシェーグレ
ン症候群のＴ細胞エピトープであることが明らかとなっ
た。(Results) FIG. 1 shows an example of the results. Promotion of cell proliferation was observed with the synthetic peptide having the amino acid sequence of 198 to 212 of protein A and the synthetic peptide having the amino acid sequence of 203 to 217 of protein A.
That is, common to these synthetic peptides,
As which is the amino acid sequence of 203 to 212 of protein A
p-Glu-Arg-Glu-Gln-Leu-Arg
-Ile-Leu-Gly was found to be a Sjogren's syndrome T cell epitope recognized by autoreactive T cells from Sjogren's syndrome patients.

【００１３】[0013]

【発明の効果】上記の薬理試験の結果、タンパクＡの２
０３〜２１２のアミノ酸配列であるＡｓｐ−Ｇｌｕ−Ａ
ｒｇ−Ｇｌｕ−Ｇｌｎ−Ｌｅｕ−Ａｒｇ−Ｉｌｅ−Ｌｅ
ｕ−Ｇｌｙがシェーグレン症候群のＴ細胞エピトープの
１つであることが判明し、このペプチドがシェーグレン
症候群患者由来のＴ細胞の結合部位に結合することを阻
止する抗体やアナログペプチドは、シェーグレン症候群
の治療剤として有用であることが示唆された。As a result of the above pharmacological test, protein A 2
Asp-Glu-A having the amino acid sequence of Nos. 03 to 212
rg-Glu-Gln-Leu-Arg-Ile-Le
u-Gly was found to be one of the T cell epitopes of Sjogren's syndrome, and antibodies and analog peptides that prevent the peptide from binding to the binding site of T cells from Sjögren's syndrome patients have been shown to treat Sjögren's syndrome. It was suggested to be useful as an agent.

【図面の簡単な説明】[Brief description of the drawings]

【図１】 細胞の増殖応答を示すグラフである。FIG. 1 is a graph showing the proliferative response of cells.

フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ Ａ６１Ｋ 38/00 ＡＣＫ Ａ６１Ｋ 39/395 ＡＢＬＮ 39/00 ＡＥＤＤ 39/395 ＡＢＬ 37/02 ＡＢＡ ＡＥＤ ＡＣＫ Continued on the front page (51) Int.Cl. 6 Identification code FI A61K 38/00 ACK A61K 39/395 ABLN 39/00 AEDD 39/395 ABL 37/02 ABA AED ACK

Claims (4)

【特許請求の範囲】[Claims] 【請求項１】 シェーグレン症候群患者由来のＴ細胞エ
ピトープであり、Ｇｌｙ、Ｌｅｕ、Ｉｌｅ、Ａｓｐ、Ｇ
ｌｕ、Ｇｌｎ、Ａｒｇのアミノ酸を基本構成成分とする
ペプチド。1. A T cell epitope derived from a patient with Sjogren's syndrome, which is Gly, Leu, Ile, Asp, G
A peptide containing amino acids lu, Gln, and Arg as basic components. 【請求項２】 アミノ酸配列がＡｓｐ−Ｇｌｕ−Ａｒｇ
−Ｇｌｕ−Ｇｌｎ−Ｌｅｕ−Ａｒｇ−Ｉｌｅ−Ｌｅｕ−
Ｇｌｙである請求項１記載のペプチド。2. The amino acid sequence is Asp-Glu-Arg.
-Glu-Gln-Leu-Arg-Ile-Leu-
The peptide according to claim 1, which is Gly. 【請求項３】 シェーグレン症候群患者由来のＴ細胞の
結合部位に、抗原である請求項２記載のペプチドが結合
することを阻止する抗体。3. An antibody that blocks binding of the peptide according to claim 2, which is an antigen, to a binding site of a T cell derived from a patient with Sjogren's syndrome. 【請求項４】 シェーグレン症候群患者由来のＴ細胞の
結合部位に、抗原である請求項２記載のペプチドが結合
することを阻止する請求項２記載のペプチドのアナログ
ペプチド。4. An analog peptide of the peptide according to claim 2, which blocks binding of the peptide according to claim 2, which is an antigen, to a binding site of a T cell derived from a patient with Sjogren's syndrome.
JP8304949A 1996-11-15 1996-11-15 Therapeutic agent for sjogren's syndrome Withdrawn JPH10139800A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP8304949A JPH10139800A (en) 1996-11-15 1996-11-15 Therapeutic agent for sjogren's syndrome

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP8304949A JPH10139800A (en) 1996-11-15 1996-11-15 Therapeutic agent for sjogren's syndrome

Publications (1)

Publication Number Publication Date
JPH10139800A true JPH10139800A (en) 1998-05-26

Family

ID=17939259

Family Applications (1)

Application Number Title Priority Date Filing Date
JP8304949A Withdrawn JPH10139800A (en) 1996-11-15 1996-11-15 Therapeutic agent for sjogren's syndrome

Country Status (1)

Country Link
JP (1) JPH10139800A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004512824A (en) * 2000-07-11 2004-04-30 コリクサ　コーポレイション Compositions and methods for treatment and diagnosis of lung cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004512824A (en) * 2000-07-11 2004-04-30 コリクサ　コーポレイション Compositions and methods for treatment and diagnosis of lung cancer

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