JPH07206896A - Immunosuppressive agent containing oligolpeptide having affinity for hla - Google Patents

Abstract

PURPOSE:To obtain a new oligopeptide useful as an active ingredient for an immunosuppressive agent, effective for treating autoimmune diseases, allergic diseases, etc., comprising a specific amino acid sequence, having affinity for an antigen with compatibility with human main tissue. CONSTITUTION:This new immunosuppressive agent having affinity for an antigen (HLA) HLA-DRBI*0405 with compatibility with human main tissue has an amino acid sequence of the formula (X1 is an amino acid such as W, F, L, M, Y or I; X2 is an amino acid such as F, L, I, Y, W, C, V, M or A; X3 is N, D, T, I, V, S, F, M or W; Y1 to Y3 are arbitrary L-amino acid) and is useful as an immunosuppressive agent for treating autoimmune diseases, allergic diseases, etc. This oligopeptide is obtained by establishing a lymphocyte obtained from a patient having DRBI* 0405 with an EB virus, treating the cell strain B with a solution of a cell, centrifuging the solution of a cell, treating the supernatant liquid with an enzyme and purifying by adsorption and separation by an anti-DR antibody immobilized column.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to HLA-binding oligopeptides, pharmaceutical compositions containing them as active ingredients, and their use in human and veterinary medicine.

[0002]

BACKGROUND OF THE INVENTION The human major histocompatibility complex (HLA) gene region is located on the short arm of human chromosome 6 and has class I (HLA-A, B, C,
E, F, G) and Class II (HLA-DR, DQ, D)
P) is roughly classified into genes. Class II genes consist of genes encoding class II molecules (antigens). Class II molecules are composed of α chain and β chain, and are expressed on the cell membrane surface of antigen presenting cells (macrophages, dendritic cells, etc.), B cells and activated T cells. Class II molecules are antigen peptides (antigen presenting cells take up the antigen taken up from the extracellular fluid,
It binds to a peptide produced by degrading with a proteolytic enzyme contained in lysosomes), is expressed on the cell surface, and is presented to CD4 ⁺ helper T cells. Helper T cells that have been activated by recognizing both the antigen peptide and the class II molecule secrete various lymphokines and promote B-cell antibody production.

A characteristic of HLA is the presence of a high degree of individual variation (polymorphism) in the human population. Since T cells recognize individual differences in HLA molecules and show a strong immune response, HLA agreement in organ transplantation is an important factor for avoiding rejection. Furthermore, HLA polymorphisms also determine individual differences in the immune response to specific antigen peptides by limiting the types of antigen peptides that can bind to them and affecting the differentiation process of T cells.

The etiology of diseases includes environmental factors and genetic factors. Diseases caused by immune disorders such as autoimmune diseases and allergies are probably multifactorial diseases that are caused by complicated intertwining of multiple environmental factors and genetic factors. As a genetic factor, the correlation between many autoimmune diseases and HLA has been clarified. That is, in rheumatoid arthritis, in white people, DR
B1 ^* 0401 and DRB1 ^* 0404 show a positive correlation with DRB1 ^* 0405 in Japanese. Insulin-dependent diabetes mellitus is DQA1 ^{* in} Caucasians, Blacks, and Japanese ^.
0301-DQB1 ^* 0302 and DQA1 ^* 050
It shows a positive correlation with 1-DQB1 ^* 0201. Furthermore, HLA is known to have a positive correlation with diseases such as Graves disease and Behcet's disease.

[0005] As described above, it is known that HLA plays an important role in the onset of disease as a genetic factor, and that an antigenic peptide binds to a class II molecule and is separated (Buus, et al, Science). 242, 1045
1988), nothing was described or suggested in relation to DRB1 ^* 0405, and the presence of other HLA-binding oligopeptides and the effect of the substance on the immune response were only slightly reported (Cottens). , et al., W
O93 / 05011, Chicz, et al., J. Exp. Med.,
178, 27, 1993, Hammer, et al, Cell 74,
197-203, July 16, 1993). Therefore, the present inventors have isolated and purified HLA-oligopeptide conjugates from established human B cells, further isolated and purified oligopeptides bound to HLA, and as a result of earnestly examining the binding ability to HLA. The present inventors have surprisingly discovered that an oligopeptide having a certain amino acid sequence has an HLA-binding action, and arrived at the present invention.

[0006]

That is, the present invention provides the following formula (Ia) X ₁ -Y ₁ -Y ₂ -X ₂ -Y ₃ -X ₃ (Ia) [wherein X ₁ is Represents an amino acid selected from the group consisting of W, F, L, M, Y and I, and X ₂ is F, L, I, Y,
Represents an amino acid selected from the group consisting of W, C, V, M and A, X ₃ represents an amino acid selected from the group consisting of N, D, T, I, V, S, F, M and W, and Y ₁ , Y
₂ and Y ₃ each represent an arbitrary L-amino acid. ]
It is a human major histocompatibility complex (HLA) HLA-DRB1 ^* 0405 binding oligopeptide having an amino acid sequence represented by.

Among the above X ₁ , X ₁ is preferable because W, F, and M are in this order because of high affinity with the DR molecule, and among X ₂ , X ₂ , F, L, and I are It is also preferable in order, and X ₃ is also preferable among X _3. Specifically, as an oligopeptide having such a combination of N, X ₁ , X ₂ and X ₃ , the following formula W—Y ₁ —Y ₂ -L-Y ₃ -N (I-a-1) F-Y ₁ -Y ₂ -L-Y ₃ -N (I-a-2) F-Y ₁ -Y ₂ -F -Y ₃ -N ( I-a-3) M-Y _1- Y _2- L-Y _3- N (I-a-4) F-Y _1- Y ₂ -I-Y ₃ -N (I-a-5) (Formula In the above, the definitions of Y ₁ , Y ₂ and Y ₃ include those having an amino acid sequence selected from those in formula (Ia). From the above formula (Ia-1) to
In (Ia-5), Y ₁ , Y ₂ and Y 3 are the same as those in the above formula (Ia), but among them, Y ₁ , Y ₂ and Y ₃ are all A, or Y ₁ =
Those in which D, Y ₂ = N and Y ₃ = P can be mentioned as preferable ones.

The above formulas (Ia-1) to (Ia-
5) N-terminal side and / or C of the oligopeptide represented by
Further, 0 to 15 amino acid residues can be present on the end side, for example, GSTV, AA and AAAA on the N side.
Preferable ones are those having 2 to 6 amino acid residues selected from, and those having PE or AA amino acid residues on the C-terminal side.

In the above combination of X ₁ , X ₂ and X ₃ , X ₁ is W or Y, X ₂ is F, Y or W, and X ₃
Where D is DRB1 ^* 0406
It is preferable because it has a stronger affinity for the DR molecule (DRB1 ^* 0405) than the molecule. In this case, as Y ₁ , Y ₂ and Y ₃ , Y ₁ to Y ₃ are all A or Y ₁ = D, Y ₂ = N, Y ₃ = P, and further N end side and / or C Those in which the same amino acid residue as above is present on the end side are also preferable.

In the above formula (Ia) and the like, each alphabet represents a one-letter abbreviation of an amino acid corresponding to each L-amino acid as shown in Table 1 below.

[0011]

[Table 1]

As long as the oligopeptide of the present invention has the HLA-binding property of the present invention, one or more amino acids of the amino acids constituting the oligopeptide of the present invention are deleted, or other amino acids are substituted. Oligopeptides obtained by substitution or insertion of other amino acids are also included.

Further, the HLA-DRB1 ^* 040 of the present invention
Examples of 5-binding oligopeptides include Y-Y ₁ -Y ₂ -L -Y ₃ -N (Ia-6) Y -Y ₁ -Y ₂ -V -Y ₃ -V (Ia-7) L-Y ₁ -Y ₂ -I-Y ₃ -S (Ia-8) F-Y ₁ -Y ₂ -MY ₃ -S (Ia-9) Oligo having an amino acid sequence Peptides are also preferred.

The oligopeptide of the present invention can be obtained as follows. As a naturally-derived substance, for example, lymphocytes are obtained from a patient having DRB1 ^* 0405, and the lymphocytes are established with EB virus to obtain a predetermined amount of B cell line. Then, the DR molecule-oligopeptide conjugate is fractionated from the whole cell lysate obtained by treating this B cell line with a buffer solution using an anti-DR antibody column. HLA collected
The oligopeptide conjugate is acid-eluted and incubated to release the target oligopeptide, and the target oligopeptide is isolated by ultrafiltration / column chromatography.
It can be purified. Alternatively, for example, the above formula (I-
It can be obtained by synthesizing oligopeptides having the amino acid sequences represented by a-1) to (Ia-9) by a peptide synthesizer or the like by a conventionally known method. The HLA-binding oligopeptide of the present invention includes those oligopeptides thus obtained from cells and those produced by conventional publicly known peptide synthesis.

In order to maintain the maximum activity of the thus obtained peptide, the oligopeptide of the present invention should be fresh or stored at 4 ° C. within about 5 days after storage. preferable. Alternatively, the oligopeptide of the present invention can be lyophilized and stored frozen. Furthermore, the solution of the oligopeptide of the present invention may be frozen.

The present invention also relates to HLA-DRB1 ^* 0405 having an amino acid sequence represented by the above formula (Ia).
A pharmaceutical composition containing a binding oligopeptide as an active ingredient and an immunosuppressive agent containing a therapeutically effective amount of the oligopeptide as an active ingredient.

The pharmaceutical composition of the present invention comprises the fillers, fillers, binders, moisturizers, disintegrants, surface-active agents,
It can be prepared using a diluent such as a lubricant or an excipient, for example, a preparation for oral administration such as tablets, powders, solutions, capsules, suppositories, injections, etc., or a preparation for parenteral administration. be able to. As the excipients, diluents and the like in such preparations, conventionally known ones can be used. For example, in the case of tablets, lactose, starch, glucose,
In the case of an injection such as crystalline cellulose, water, propylene glycol, etc. may be mentioned, and if necessary, an absorption enhancer, a preservative, a coloring agent, a solubilizing agent, an interfering agent, a soothing agent may be added. it can.

In the present invention, the immunosuppressive agent of the present invention can be prepared by a known method by combining a peptide as such an active ingredient and a known appropriate excipient. Preferably, the immunosuppressive agent of the present invention is administered as a parenteral administration preparation, especially as a drip or single-dose (bolus) intravenous or local administration preparation. In the case of intravenous preparations, physiological saline, 5% dextrin-containing water, Ringer's solution, and other commercially available intravenous perfusion physiological buffer may be used depending on the patient's symptoms.

The effective amount of the HLA-binding oligopeptide of the present invention in humans or animals varies depending on, for example, the age and weight of the subject, symptoms and severity, the dosage form, the form and potency of the oligopeptide used, and the like. Yes, and it will eventually change depending on the intention of the doctor or veterinarian. An effective amount of the oligopeptide of the present invention is, for example, about 1 to 100 mg / kg body weight / day, preferably about 5 to 20 mg / kg body weight / day, administered by local injection such as intravenous, intramuscular, intraperitoneal or intraarticular. To be done.

Thus, the HLA-binding oligopeptide of the present invention and a pharmaceutical composition containing the HLA-binding oligopeptide of the present invention as an active ingredient can be obtained. The HLA-binding oligopeptide of the present invention is obtained by treating an antigen peptide with an antigen-presenting cell. In the process of binding to class II molecules and being expressed on the cell membrane, it substitutes for an antigen peptide, and antigen presenting cells and helper T
It inhibits or modifies information transmission with cells, and eventually suppresses antibody production, delayed-type allergic reaction and the like.

[0021]

The present invention will be described in detail with reference to the following Reference Examples and Examples, but these Examples do not limit the scope of the present invention.

Reference Example 1 The method of Buus et al. (Science 24
2, 1045, 1988) according to DRB1 ^* 0405
Lymphocytes obtained from patients with EB virus were established with EB virus, B cell lines were established, and the cells were proliferated until the number of cells reached about 10 ¹⁰ . Next, this B cell line thus established was treated with a buffer solution (1% nonidet P-40, 5 mM Na-orthovanadate,
25 mM iodoacetamide, 1 mM PMSF (phenylmethanesulfonyl fluoride) -containing phosphate buffer p
H7.2) to obtain whole cell lysate. This whole cell lysate was centrifuged (10,000 rpm, 1 hour), and the supernatant was 0.45 μm membrane filter (Millipore).
After passing through the column, it was treated with mouse γ-globulin-Sepharose (Pharmacia) and protein A-Sepharose column (Pierce). The eluate obtained by the treatment as described above is subjected to anti-DR antibody-immobilized column (anti-DR monoclonal antibody HU-4 (reference: Hirayama, K. et el. 1
986, J. Immunol. 137, 924-)-immobilized column made by Pierce) was used to fractionate DRB1 ^* 0405 molecule-oligopeptide conjugate (wash: 0.1% SD).
S, 0.5% NP-40-containing phosphate buffer pH 7.2,
Phosphate buffer solution containing 1% n-octyl glucoside pH 7.
2. Elution: buffer solution containing 1% n-octyl glucoside pH
10.5). Furthermore, the precipitate produced with 75% acetonitrile was dissolved in 2.5 M acetic acid and incubated at 37 ° C. for 30 minutes to release the oligopeptide, which was subjected to ultrafiltration (molecular weight cutoff: 10 kDa), and the flow-through fraction was concentrated. Then, the desired oligopeptide was obtained. The filtration residue is free DRB1 ^* 0
It was stored as 405 molecules (free DR molecule) and used in the binding experiment of Reference Example 2. HPLC of the obtained oligopeptide
(C18 column manufactured by Waters; Bondasphere 5 μm, 100
A, 2.1 × 150 mm) was used for separation (flow rate:
0.25 ml / min, elution condition: 120 minute gradient elution using 0.06% TFA aqueous solution and 0.052% TFA acetonitrile solution) (FIG. 1). Based on the results obtained by subjecting each peak to a peptide sequencer using Edman degradation, a homology search was performed to determine the amino acid sequence of each peak.

Table 2 shows the amino acid sequence corresponding to each HPLC peak of the oligopeptide acid-eluted from the HLA-oligopeptide conjugate and the homology relationship.

[0024]

[Table 2]

Based on these homology information, oligopeptides (I) having the amino acid sequences shown in Table 3
(VII) was postulated as an HLA-binding oligopeptide.

The cases in which these oligopeptides (I) to (VII) are represented by using three-letter abbreviations are shown in SEQ ID NOs: 1 to 7 in the sequence listing below.

[0027]

[Table 3]

Hereinafter, in Reference Examples and Examples, oligopeptides having the peak numbers 295.17 and the like shown in Table 3 are abbreviated as "295.17 oligopeptides".

Reference Example 2 (1) The 295.36 oligopeptides shown in Table 3 were synthesized by a peptide synthesizer. It was confirmed that each of the obtained synthetic oligopeptides had the amino acid sequence shown in Table 3, and the following examples were carried out using these synthetic oligopeptides.

(2) The solvent of the free DR molecule obtained in Reference Example 1 was 1 mM PMSF, 0.05% NP40, 5% DM.
SO, phosphate buffer containing 0.1% NaN ₃ (pH 7.
0) and then a protease inhibitor (final concentration: 1.3
mM 1,10-phenanthroline, 73 μM pepstatin A, 8 mM EDTA, 6 mM N-ethylmaleimide, 200 μM N, α-p-tosyl-L-lysine chloromethyl ketone) was added. To 1 μM of DR molecule, 10 nM of synthetic oligopeptide labeled with iodine 125 (labeled with 295.36, 295.24, 295.17 oligopeptide shown in Table 3) was added and allowed to stand at room temperature for 48 hours for reaction.

As a negative control, irrelevant M12 peptide (YNELSGEAHKDALKGKLIDN)
Was reacted in the same manner. Then Sephadex G
-50 columns (Pharmacia, 4 × 120 mm) were used for separation and counting was performed using a gamma counter, and the (radioactivity bound to DR molecule / total radioactivity) × 100 was determined and defined as the binding rate (%).

Table 4 shows the binding rate of the labeled synthetic oligopeptide to the DR molecule.

[0033]

[Table 4]

From Table 4, labeled 295.36 and 295.24 oligopeptides and 295.17 oligopeptides were labeled with free DR molecules and 7.
5, 12.7 and 8.2% bound. On the contrary,
The negative control only bound 0.7%.

Reference Example 3 At the time of the binding reaction of Reference Example 2, unlabeled synthetic oligopeptide was added at a molar concentration ratio of 10 to 1,000.
A double amount was added to determine the binding inhibition rate (%). At this time, as a negative control, an oligo peptide (irrelevantM12 peptide) that does not bind to the DR molecule was added in a large excess amount to serve as a negative control.

In FIG. 2, unlabeled 2 at various molar ratios of labeled 295.24 oligopeptide to free DR molecule binding.
9 shows the inhibitory action of 95.24 oligopeptides.

From FIG. 2, it can be seen that the unlabeled 295.24 oligopeptide inhibited the binding between the labeled 295.24 oligopeptide and the free DR molecule in a concentration-dependent manner.

Table 5 shows the inhibitory effect of various unlabeled oligopeptides listed in Table 3 on the binding between labeled 295.24 oligopeptide and free DR (DRB1 ^* 0405) molecule.

295.24, 295.36, 295.1
7, 295.29, 295.26, 295.32 and 295.21 oligopeptides inhibited the binding of labeled 295.24 oligopeptides to free DR molecules at 1000-fold concentration. In contrast, the negative control (irrele
vantM12 peptide) showed no effect.

[0040]

[Table 5]

Example 1 (1) Peak number 295.2 as shown in FIG.
We synthesized 15 kinds of peptides in which the hydrophilic amino acid residue of 4 was replaced with alanine and the hydrophobic amino acid residue was replaced with serine, and the effect on the binding between the ¹²⁵ I-labeled substance of 295.24 and the free DR molecule was examined. The results are shown in FIG.

From the N-terminal of FIGS. 3 to 295.24, 5,
Labeled 295.24 by substitution of amino acids at positions 8 and 10.
It can be seen that the inhibitory effect on the binding between the free DR molecule and As a result, it was inferred that the motif represented by ---- F--L--N-- (-indicates the presence of an arbitrary amino acid) is an important motif for binding to the DR molecule.

(2) From the motif inferred in (1),
A, which is an alanine-substituted form of the 295.24 oligopeptide
A F A A L A N A A and F , L , N of this peptide
Was synthesized by sequentially substituting other amino acid residues,
The affinity with the free DR molecule was examined in the same manner as in Reference Example 2. In the same manner as in Reference Example 1, free DRB1 ^* 04 from EB virus strain DRB1 ^* 0406-positive B cells was used.
06 molecules were obtained and used as a control in binding experiments.

The results are shown in FIGS. 4- (a), (b) and (c).
It was shown to.

FIG. 4- (a) shows an alanine-substituted product of the 295.24 oligopeptide and F among them as shown in FIG.
The result of the binding experiment using the alanine substitution product obtained by substituting various amino acids described on the horizontal axis of (a) is shown.

Further, FIGS. 4- (b) and 4- (c) show alanine substitution products obtained by substituting L and N with various amino acids shown on the abscissas of both figures. The results of the binding experiments used are shown.

From FIG. 4, the oligopeptide AA F A A L A
N AA inhibits the binding of the labeled 295.24 oligopeptides and DR molecules and DRB1 ^* 0406 molecule, was shown to have an affinity for each. In particular, W, F, M, Y, I is at the 3rd position from the N-terminal, and F, L, I, Y, at the 6th position.
W, C, V, M, A, N, D, T, I, V
It was shown to have a high affinity for DR molecules in the presence of S, F, M, W. Among them, W is third.
It can be seen that the combination of F or M, the 6th position being L, F or I, and the 8th position being N has excellent affinity. DRB1 ^* 0
For 406 molecules, F, I, M, W at position 3, L, I, M, V, F, A, T at position 6, S, N, I at position 8
Q showed a particularly high affinity. Also, W, Y, 6 in 3rd place
A stronger affinity for the DR molecule was observed when the position was replaced with F, Y, W and D at position 8.

(3) From these results, the HLA-binding oligopeptides ((I), (II), synthesized in Reference Example 1)
(IV), (VII), etc.), as shown in Table 6,
The possibility of binding at points was suggested.

[0049]

[Table 6]

From the above, it is considered that the motifs obtained in these Examples provide important information for identifying self-antigens in autoimmune diseases such as rheumatoid arthritis (RA), and peptides having this motif are It is considered to be useful as an immunosuppressant.

[0051] [Example 2] The injectable solutions motif conducted during manufacture 1ml of injection Example 1 (1) to (oligopeptide) containing 0.3mg was prepared by the following formulation.

Motif of Example 1 (1) 30 mg Salt 900 mg Distilled water for injection 100 ml

[0053]

[Sequence list]

SEQ ID NO: 1 Sequence length: 15 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Val Pro Ile Gln Arg Ala Val Tyr Gln Asn Val Val Val Asn Asn 1 5 10 15

SEQ ID NO: 2 Sequence length: 12 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Ser Pro Gly Thr Gly Ala Tyr Tyr Val Leu Leu Asn 1 5 Ten

SEQ ID NO: 3 Sequence length: 20 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Gly Ser Thr Val Phe Asp Asn Leu Pro Asn Pro Glu Ile Asp Gly Asp 1 5 10 15 Tyr Tyr Gly Trp 20

SEQ ID NO: 4 Sequence length: 20 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Glu Gly Gln Leu Val Ser Ile His Ser Pro Glu Glu Gln Asp Phe Leu 1 5 10 15 Thr Lys His Ala 20

SEQ ID NO: 5 Sequence length: 20 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Gly Pro Lys Pro Leu Phe Arg Arg Met Ser Ser Leu Val Gly Pro Thr 1 5 10 15 Gln Ser Phe Phe 20

SEQ ID NO: 6 Sequence length: 20 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Gly Lys Pro Pro Gln Tyr Ile Ala Val His Val Val Pro Asp Gln Leu 1 5 10 15 Met Ala Phe Gly 20

SEQ ID NO: 7 Sequence length: 19 Sequence type: Amino acid Topology: Linear Sequence type: Peptide Fragment type: Intermediate fragment Sequence: Ser Asp Pro Ile Leu Tyr Arg Pro Val Ala Val Ala Leu Asp Thr Lys 1 5 10 15 Gly Pro Glu

[Brief description of drawings]

FIG. 1 shows the results of HPLC in Reference Example 1.

FIG. 2 shows the inhibitory effect of an unlabeled oligopeptide on the binding between an oligopeptide (labeled) and a free DR molecule in Reference Example 3.

FIG. 3 is a label 295.2 in Example 1 (1).
4 shows the inhibitory effect of the oligopeptide of the present invention on the binding between 4 oligopeptides and DR molecule.

FIG. 4 shows an affinity spectrum of an oligopeptide of the present invention and a DR molecule in Example 1 (2). Figure, (a) shows the AA F AA L A N AA polyalanine peptides and 1 residue substitution polyalanine peptides and F are substituted with another amino acid residue, (b) is likewise one residue substituted poly alanine L Peptide, (c) similarly shows the case where N- residue-substituted polyalanine peptide was used.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Keiji Komoritani 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Limited Tokyo Research Center

Claims (4)

[Claims] 1. The following formula (Ia) X ₁ -Y ₁ -Y ₂ -X ₂ -Y ₃ -X ₃ (Ia) [wherein X ₁ is W, F, L, M, Y] And I represents an amino acid selected from the group consisting of, and X ₂ is F, L, I, Y,
Represents an amino acid selected from the group consisting of W, C, V, M and A, X ₃ represents an amino acid selected from the group consisting of N, D, T, I, V, S, F, M and W, and Y ₁ , Y
₂ and Y ₃ each represent an arbitrary L-amino acid. ]
A human major histocompatibility complex (HLA) HLA-DRB1 ^* 0405 binding oligopeptide having an amino acid sequence represented by: 2. The following formulas (Ia-1) to (Ia-5) W-Y ₁ -Y _2- L-Y ₃ -N (I-a-1) F-Y ₁ -Y ₂ -L-Y ₃ -N (I-a-2) F-Y ₁ -Y ₂ -F-Y ₃ -N (I-a-3) M-Y ₁ -Y ₂ -L -Y ₃ -N ( Ia-4) F-Y ₁ -Y ₂ -I-Y ₃ -N (Ia-5) (wherein Y ₁ , Y ₂ and Y ₃ are defined in formula (Ia)) The same as the above.), The oligopeptide according to claim 1, which has an amino acid sequence represented by any of 3. A pharmaceutical composition containing the oligopeptide according to claim 1 as an active ingredient. 4. An immunosuppressive agent containing a therapeutically effective amount of the oligopeptide according to claim 1 as an active ingredient.