New peptides for use in immunotherapy of autoimmune diseases


The invention relates to new peptides having the amino acid sequence of the 9-55 amino acid residues, comprising the amino acid sequence FTLASAETT (SEQ ID NO:l), pharmaceutical compositions for treatment of autoimmune diseases, containing one or more of these peptides and a pharmaceutically acceptable carrier. 2 S. and 4 C.p. f-crystals, 5 tab., 6 Il.

The invention relates to new peptides, to their use for the treatment of chronic destruction of the cartilage of the joints in autoimmune diseases, to pharmaceutical compositions containing the specified peptide, and to a method of diagnosis, aimed at the definition of self-reactive T cells in the tested sample.

The immune system is based on the principle of discrimination between foreign antigens (not their antigens and autoantigens (their antigens, which is the affiliation of an individual organism), achieved in the development of tolerance in relation to their antigens.

The immune system protects individuals from foreign antigens and when meeting with the foreign antigen is responsible of the activation of specific cells, such as T - and b-lymphocytes, and PR is giruet immune system, undergo degradation with antigen-presenting cells (APCs), and a fragment of the antigen associated with the glycoprotein major histocompatibility complex (MHC) class II is expressed on the cell surface. Complex MHC-glycoprotein-fragment antigen is presented to T cells via their T-cell receptors recognize a fragment of the antigen together with protein MHC class II, with which they are associated. T-cell becomes activated, i.e., proliferate and/or produces interleukins, which leads to the expansion of activated lymphocytes to the antigen against which the immune attack is aimed (Grey et al., Sci. Am., 261:38-46, 1989).

Autoantigens are also constantly subjected to the processing and presentation of antigen fragments with MHC glycoproteins T cells (Jardetsky et al., Nature 353:326-329, 1991). Thus, samorasprostranenie is a property inherent in the immune system. In normal conditions, the immune system tolerance to autoantigens, and activation of the immune response by autoantigens is not implemented.

When tolerance to autoantigens is lost, the immune system can be activated against one or more proteins, leading to activation of self-reactive T-clede is destructive, i.e. implies the destruction of invasive alien antigen, an autoimmune response can cause tissue destruction of his own body.

The contribution of T cells in the development of autoimmune diseases has in several studies. In mice with experimental autoimmune encephalomyelitis (EAE) is mediated by a very limited group of T cells that are grouped according to their specificity in relation to one epitope of the basic protein of myelin (ICBMs) in complex with the molecule MHC class II. In rats, Lewis, lines with high susceptibility to various autoimmune diseases, the disease, as shown, is mediated by T-cells. In human autoimmune diseases are also believed to be associated with the induction of autoaggressive T cells.

Destructive autoimmune response involved in the development of various diseases, such as rheumatoid arthritis (RA), in which the integrity of the joint cartilage is destroyed by the chronic inflammatory process resulting from the presence of large numbers of activated lymphocytes and cells expressing MHC class II. The presence of cartilage seems to be necessary to maintain local inflammatory response: it is assumed that the destruction of cartilage include the c. Trans. 18:796, 1990; Burmester et al., Rheumatoid arthritis Smolen, Kalden, Maini (Eds) Springer-Verlag Berlin Heidelberg, 1992). Moreover, the destruction of cartilage in RA patients surgically, as shown, leads to a reduction of the inflammatory process (R. S. Laskin, J. Bone Joint Surgery (Am) 72:529, 1990). Proteins of cartilage, therefore, considered autoantigens target that is competent in relation to the stimulation of T cells. Activation of these self-reactive T cells leads to the development of autoimmune diseases. However, the identification of autoimmune components that play a role in the development of rheumatoid arthritis, still remains unclear.

Inflammatory response, leading to the destruction of cartilage, can be treated with several drugs, such as steroid drugs. However, these drugs are often such drugs immunosuppressants, which are nonspecific and have toxic side effects. The disadvantage of non-specific immunosuppression makes them extremely unfavorable for treatment.

Antigen-specific non-toxic immunosuppressive therapy creates a very attractive alternative to non-specific immunosuppression. This antigen-specific therapy includes treatment of patients autoantigen These synthetic peptides correspond to the epitopes of the antigen to T cells and can be used for the induction of specific tolerance of T cells as ourselves, and to the antigen. Although desensitization of the immune system with the same antigen, which is responsible for activating the immune system seems paradoxical, controlled introduction (auto)target antigen can be very effective against data demonstrate that differently modulated the immune system. Desensitization, or immune tolerance, immune system based on the long-observed phenomenon, namely, that animals that were given with food or through inhalation of an antigen or epitope that is less prone to development of systemic immune response against the specified antigen or epitope, when the specified antigen or epitope comes with the systemic administration.

Glycoprotein-39 cartilage person (HC gp-39) previously identified as the autoantigen target in rheumatoid arthritis (RA) (Verheijden et al., Arthritis Rheum. 40:1115-1125, 1997). The strategy, which is followed by the identification of the relevant epitope NS gp-39, was based on the assumption that the molecule DR4 or DR1 predispose to the development of RA (Gao et al., Arthritis Rheum. 33:939-946, 1990; Nelson et al., Rheumatoid Arthritis, In Proceedings of the Eleventh International Histocompatibility Workshop and Conference. Vol 1, Tsuji et al Ed, Oxford University Press, 1991) at two levels, firstly by defining a set of T-cells and, secondly, determining their selection. UPA peptides for presentation to T cells (Gregerson et al., Arthritis Rheum. 30:1205-1213, 1987). Putative binding sequence in the primary structure of the NA gp-39 were identified when using binding motif peptide DR4 (B1*0401) (Verheijden et al., Arthritis Rheum. 40:1115-1125, 1997). NS gp-39 protein, consisting of 362 amino acids, not including signal sequence (Hakala et al., J. Biol. Chem. 268:25803-25810, 1993), contains six areas containing this motif. Selected four peptides were synthesized and tested for binding with options DR1 and DR4 (B1*0401 and 0404) associated with RA. Everything is based on the motif peptides comprising residues 103-116, 259-275, 263-275 and 326-338 NS gp-39, has been found to bind with relatively high affinity to molecules DRB1*0401. It was then investigated the recognition of these peptides to T-cells in peripheral blood of RA patients and healthy donors. Everything is based on the motif peptides were easily recognizable in patients with RA, resulting in the expected high incidence of specific NA gp-39 T-cells in RA. Response to 263-275 was most pronounced; 8 of 18 RA patients responded to this peptide (Verheijden et al., Arthritis Rheum. 40:1115-1125, 1997). Thus, HC gp-39 is a target for immune recognition in the joint.

The importance of this protein for arthritis was galerucinae cells microgram quantities of protein mixed with IFA (incomplete adjuvant's adjuvant), causing chronic inflammation of a joint, resembling RA (Verheijden et al., Arthritis Rheum. 40:1115-1125, 1997).

Was recently isolated and described a novel protein chondrocytes human YKL-39 (Hu et al., J. Biol. Chem. 271: 19415-19420, 1996). The protein shows significant sequence identity with NA gp-39 (YKL-40). Another homologue of NA gp-39 is secreted by human macrophages and is denoted as chitotriosidase (Boot et al., J. Biol. Chem. 270: 26252-26256, 1995). The sequence corresponding to the peptide RSFTLASSETGVG NS gp-39 (263-275) (SEQ ID N0:3), identified as HSFTLASAETTVG (SEQ ID NO:2) in the protein YKL-39 (266-278) and as RSFTLASSSDTRVG (SEQ ID NO: 4) in chitotriosidase macrophages (269-282), respectively (table 1).

The peptide chitotriosidase Chi (269-282) contains a binding motif peptide DRB1*0401, which previously used for selection of epitopes for T-cells in proteins. In contrast, the peptide YKL-39 (266-278) does not contain this 0401 motive.

It should be clear that the emergence of tolerance reactive to NS gp-39 (263-275) T cells may be beneficial for RA patients. Similarly, mimikriya epitopes NS gp-39 (263-275) can perform a similar function and can be used for the induction of tolerance. Preferably, such mimikriya epitopes had at least the same capacity vyzyvaet the decision cartilage, mediated by T-cells, there is a significant need to identify reactive against T-cell peptides that can desensitizing patients to the action of autoantigen, which activates the T-cells responsible for the inflammation.

Although the peptide YKL-39 does not contain the motif 0401, it has been unexpectedly found that the epitope YKL-39 (266-278) is mimicries epitope NS gp-39 (263-275).

This epitope, therefore, is applicable for the induction of tolerance self-reactive T cells with activity directed by HC gp-39 (263-275), YKL-39 (266-278) or mimikriya epitopes in patients with rheumatoid arthritis.

The aim of the invention is to propose peptides that can induce systemic immune tolerance, more specifically, the tolerance of specific T-cells, preferably in relation to reactive antigen cartilage in patients suffering mediated T-cell destruction of cartilage. The peptides of the present invention are characterized in that they comprise one or more amino acid sequences FTLASAETT (SEQ ID NO:l). More specifically, the peptide according to the invention includes HSFTLASAETTVG (SEQ ID NO:2).

In the scope of the invention also includes multimeric peptides according to the invention, some of gammera, consisting of many identical peptides or heteromers consisting of various peptides.

Typical amino acid sequences of the peptides according to the invention can join a random amino acid sequences. Preferred are the flanking sequences, which have a stabilizing effect on the peptides, thereby increasing their bioavailability.

Glycoprotein 39 cartilage person is autoantigen target in patients with RA, which activates specific T cells, thereby causing or Poreba inflammatory process. The peptides of the NA gp-39 was mainly recognizable self-reactive T-cells of patients with RA, but rarely T-cells of healthy donors, indicating, therefore, that NA gp-39 is autoantigens with RA. Causes arthritis nature NA gp-39 was subsequently confirmed in mice of Balb/c. A single subcutaneous injection of the indicated protein in mice of Balb/c was able to cause symptoms of arthritis in animals. Stroke induced NA gp-39 of the disease was characterized by a periodically occurring relapses in four legs and/or hind legs and gradually evolved from arthritis moderate to more severe illness is based recurring relapses resembles the disease of arthritis, especially RA.

Unexpectedly it was found that the peptide YKL-39 266-278 effective as of the inductor tolerance. For professionals, it should be clear that the peptides can be extended from either side of the peptide or both sides and will be the same immunological function. This extender can be an amino acid sequence similar to the natural sequence of the protein YKL-39.

The peptides according to the invention can be obtained by well known methods of organic chemistry for peptide synthesis, such as solid-phase peptide synthesis as described, for example, in J. Amer. Chem. Soc. 85:2149 (1963) and Int. J. Petide Protein Res. 35:161-214 (1990). The peptides according to the invention can also be obtained using methods of recombinant DNA. The sequence of a nucleic acid encoding a peptide according to the invention or multimer these peptides insert into expressing vector. Suitable expressing vectors contain the necessary control replication and expression. Expressing the vector may be transferred for expression in the cell of the host. Appropriate cell hosts are, for example, bacteria, yeast cells and mammalian cells. Such methods are well known can be stabilized using a C - and/or N-terminal modifications, that should reduce catalyzed ectopeptidases hydrolysis. Modifications may include C-terminal acylation (for example, acylation = AC-peptide), the introduction of N-terminal amide (for example, peptide-NH2), the combination of acylation and the introduction of amide (for example, AC-peptide-NH2and the introduction of D-amino acids instead of L-amino acids (Powell et al., J. Pharm. Sci., 81:731-735, 1992).

Other modifications focused on preventing hydrolysis of endopeptidase. Examples of such modifications are the following: the introduction of D-amino acids instead of L-amino acids, modified amino acids, cyclization within the peptide, the introduction of modified peptide bonds, for example, the recovered peptide bonds[CH2NH] and, for example, peptoids (N-alkyl derivatives of glycine) (Adang et al, Reel. Trav. Chim. Pays-Bas, 113:63-78, 1994; Simon et al, Proc. Natl. Acad. Sci. USA, 89:9367-9371, 1992).

The peptides according to the invention are epitopes of T cells that recognize self-reactive T-cells and can stimulate. These self-reactive T cells can be detected, for example, in the blood of patients suffering from autoimmune diseases.

Thus, according to the invention the peptides, these peptides resembling restricti is whether SEQ ID NO:2, are highly suitable for use in therapy for the induction of specific tolerance of T cells to the specified autoantigen in mammals, specifically humans, suffering from mediated T-cell destruction of cartilage, such as arthritis, specifically rheumatoid arthritis. Optional this treatment can be combined with the introduction of other drugs, such as DMARDs (disease modifying antirheumatoid drugs), for example, sulfasalazin, antimalarials (chloroquine, hydroxychloroquine), injected or applied oral gold, methotrexate, D-penicillamine, azathioprine, cyclosporine, mycophenolate), NSAIDs (non-steroidal anti-inflammatory drugs), corticosteroids or other medications that are known to affect the course of disease in patients with autoimmune disease.

The peptides according to the invention can also be used for modulation of lymphocytes that are reactive against antigens other than the specified autoantigen, but which are present in the same fabric as autoantigen, i.e. proteins or parts thereof, comprising the peptide according to SEQ ID NO:l or SEQ ID NO: 2. By induction specific antigen tolerance of T cells mo the Ki are hematopoietic cells. In General, in order to function as inductor tolerance, the peptide must satisfy at least two conditions, i.e., he must possess immunomodulatory ability and he will be expressed locally as part of a larger protein.

Thus, the present invention features a method of treating patients suffering from inflammatory autoimmune diseases, by introducing a pharmaceutical preparation comprising a peptide in accordance with the invention. Such patients may suffer from diseases such as graves disease, juvenile arthritis, primary glomerulonephritis, osteoarthritis, Sjogren syndrome, myasthenia gravis, rheumatoid arthritis, Addison's disease, primary biliary sclerosis, uveitis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis or diabetes. Peptides in accordance with the present invention, therefore, can be applied for the preparation of drugs for the induction of tolerance in patients suffering from these diseases.

The treatment of autoimmune disorders peptides according to the invention allows to use the fact that the observed suppression is called nerds antigen type pleiotropic proteins, such as cytokines that can suppress the immune response.

According to the invention, patients suffering from mediated T-cell destruction of the joint cartilage can be treated with therapeutic compositions containing one or more peptides according to the invention and a pharmaceutically acceptable carrier. Introduction the pharmaceutical compositions according to the invention should cause systemic immunological tolerance, in particular tolerance specific self-reactive T cells of these patients in relation to autoantigen proteins of the cartilage of the joint is exposed to their attack, and other proteins that exhibit identified epitopes MHC class II associated T-cells, and which amino acid sequences characterize or mimic one or more peptides according to the invention. Called in this way, the tolerance must lead to the decrease of the local inflammatory response in the exposed attack the cartilage of the joint.

Very suitable peptides for use in the pharmaceutical compositions according to the invention are peptides, including peptide YKL-39 (268-276) or YKL-39 (266-278), with flanking sequences up to a total length of 55 amino acids. Butalmost peptides represents FTLASAETT or HSFTLASAETTVG.

The peptides according to the invention have advantages in that they have a specific effect on self-reactive T cells and thereby leaving intact the other components of the immune system compared with nonspecific suppressive effect of immunosuppressive drugs. The treatment with the peptides according to the invention should be safe and not have toxic side effects.

Systemic immunological tolerance can be achieved by the introduction of high or low doses of the peptides according to the invention. The number of peptide should depend on the method of administration, time of administration, patient age, and General condition of health and diet.

In General, can be applied dosage from 0.01 to 10000 μg of peptide per kg of body weight, preferably from 0.05 to 500 g, more preferably from 0.1 to 100 μg.

Pharmaceutically acceptable carriers well known in the art and include, for example, sterile saline, lactose, sucrose, calcium phosphate, gelatin, dextrin, agar, pectin, peanut oil, olive oil, sesame oil and water. Other media can be, for example, molecules of MHC class II, if required, are enclosed in liposomes.

Groothedde adjuvants include, among others, aluminum hydroxide, aluminum phosphate, amphigen, tocophenol, monophosphoryl lipid A, a dipeptide muramira and saponins, such as Quill A. Preferably, the adjuvants used in the treatment of inducing tolerance, according to the invention, were mucosal, such as the B-subunit of cholera toxin or carbomer that are associated with the epithelial mucosa. The amount of adjuvant depends on the nature of the adjuvant.

Moreover, the pharmaceutical composition according to the invention may include one or more stabilizers, such as carbohydrates, including sorbitol, mannitol, starch, shortenstring and glucose, proteins such as albumin or casein, and buffers such as phosphates of alkali metals.

Suitable routes of administration are, for example, intramuscular injection, subcutaneous injection, intravenous injection or intraperitoneal injection, oral administration and intranasal introduction, such as sprays.

Another aim of the invention is to provide a method of determining self-reactive T cells involved in the destruction of the joint cartilage, and test set for use in a specified way. Thus, the peptides according to the present invention is reactive T cells, involved in chronic inflammation and destruction of the joint cartilage.

The diagnostic method according to the invention includes the following stages:

a) isolation of mononuclear cells in peripheral blood (RVMS) from a blood sample of an individual,

b) culturing these RUMS in suitable conditions,

c) incubation of this culture RUMS in the presence of one or more peptides according to the invention, and

d) determining the response of T-cells, for example proliferative response, indicating the presence of activated self-reactive T cells from the individual.

Determination of the proliferative response of T-cells can be carried out, for example, by the inclusion of3H-thymidine.

In the scope of the invention also includes the testing kits that include one or more peptides according to the invention. These test kits suitable for use in the diagnostic method according to the invention.

The following examples serve to illustrate the invention, and in no way should be interpreted as limiting the scope of invention.


Fig.1, 2, 3. Cross-reaction of three different specific NA gp-39 hybrid (8 ÷ 12, 14G11, N) with YKL-39 (266-278)

(CVR0271B = HLA-DRB1*0401 hybridoma, specific NA gp-39 (263-275). Activation of T-cell hybridomas expressed in terms of the production of IL-2.

Fig.4. The addition of tolerance in vivo using NS gp-39 (263-275) or YKL-39 (266-278)

In mice of Balb/c caused tolerance via the intranasal route 50, 10 or 2 micrograms NA gp-39 (263-275) or YKL-39 (266-278) followed by immunization NS gp-39 (263-275). As controls used mouse treated as a pre-treatment with saline, or the intact mouse.


Example 1. Comparison of sequences

Protein YKL-39 chondrocytes person exhibits significant sequence identity with NA gp-39 (YKL-40). Another homologue of NA gp-39 is secreted by human macrophages and is called chitotriosidase (Boot et al., 1995). Sequence corresponding to RSFTLASSETGVG (HC gp-39 (263-275), SEQ ID NO:3), were identified as HSFTLASAETTVG in the protein YKL-39 (266-278) and RSFTLASSSDTRVG (SEQ ID NO:4) in chitotriosidase macrophages (269-282), respectively (table 1). Chi (269-282) contains a binding motif peptide HLA-DRB1*0401, which previously used for selection of epitopes for T-cells in proteins. In contrast, the peptide YKL-39 (266-278) does not contain this motif. All peptides were synthesized.

Example 2. Concerns about the uly HLA-DR4 (DRB1*0401) was purified from homozygous EBV transformed B-lymphoblastoid cell lines (human Huly138IC2 and conducted competitive analysis of the binding of peptide-HLA-DR, basically as described Verheijden et al., 1997. The affinity of this peptide in relation linking encoded by DRB1*0401 molecules correlated with competition marker peptide. This relative affinity of binding was defined as the concentration of peptide at which the signal was decreased by 50% (IC50). Peptide HA-F is a positive control (ha 307-319; PKFVKQNTLKLAT; position 309 Y is replaced by F; SEQ ID NO:5). It is known that the peptide has a high affinity to molecules DRB1*0401.

As expected, it was found that the peptide Chi (269-282) associated with DBB1*0401 with high affinity (see table 2). Peptide YKL-39 (266-278), which does not contain an effective motif binding peptide DRB1*0401, was associated with DR4(B1*0401) with very high affinity.

Example 3. Stimulation of T-cell hybridomas

Specific NA gp-39 (263-275) hybridoma tested for the recognition of the respective sequences.

To test cross-reactions 3 different specific NA gp-39 (263-275) hybridoma cell lines by peptide YKL-39 or chitotriosidase 5104hybridoma cells and 2105irradiated (12000 RAD) (0,12 j/g) EBV-transformed bearing spectrally antigen (HC gp-39 (263-275), YKL-39 (266-278), chitotriosidase (269-282) or control peptide) were added to the wells in a volume of 50 μl in two Parallels. Forty-eight hours 100 µl of culture supernatant was analyzed for the formation of IL-2 using a sandwich ELISA with antibodies from Pharmingen, specific IL-2 mouse.

It was found that the synthetic peptide YKL-39 (266-278) causes a response similar to the response for the NS gp-39 (263-275), whereas Chi (269-282) does not cause a response. The results suggest that three different TCRs used in three different hybridomas, do not distinguish between NS gp-39 (263-275) and YKL-39 (266-278) when they are molecules encoded by DRB1*0401 (Fig.1, 2, 3), but there are NS gp-39 (263-275) and Chi (269-282). The data suggest that YKL-39 (266-278) is mimicries epitope NS gp-39 (263-275) (Fig.1, 2, 3).

Example 4. Recognition of YKL-39 (266-278) RVMS

Mononuclear cells from peripheral blood (RVMS) were isolated from heparinised peripheral blood using standard centrifugation in Ficoll-Paque (Pharmacia, Uppsala, Sweden). Cells suspended in the wells of 24-well plate at a concentration of 5105cells in 1 ml of Cells were incubated in medium in the absence or in the presence of 10 or 50 μg/ml of peptide antigen (YKL-39 (266-278)). Culture inquire the Lee 150 ál was made in 4 Parallels to the wells of the 96-well plate with holes with a round bottom. The cells were then subjected to pulsed action of 0.5 µci (1,85104Bq (imp./s)) [3H]thymidine ([3H]TdR), and after 18 h were measured included radioactivity. Presented in tables 3A and 3b the results are expressed as stimulation indexes (SI) (specific for the antigen pulses/pulse background).

Based on table 3A, we can conclude that the epitope YKL-39 (266-278) are easily recognized in patients with RA. Table 3b shows that the recognition of YKL-39 (266-278) RVMS coincides with the recognition of the NA gp-39 (263-275) and HC gp-39 and, moreover, that the recognition of YKL-39 (266-278) are generally more pronounced than the recognition of the NA gp-39 (263-275).

SI = specific antigen pulses/pulse background. SI5 considered positive. R - responsible, NR - not responsible.

Example 5. Induction of tolerance

Was developed specific NA gp-39'(263-275) method of analysis DTH suitable for monitoring the induction of tolerance using peptide antigens. It was found that immunization of Balb/c mice NS gp-39(263-275) in incomplete Freund's adjuvant (IFA) efficient induction of DTH response with subsequent load peptide NS gp-39(263-275). This is based on the peptide DTH system was progene, that intranasal application NS gp-39 (263-275) a dose-dependent manner that negatively modulates induced NA gp-39 (263-275) DTH response. Intranasal application YKL-39 (266-278), however, led to a stronger negative modulation of the DTH response, which indicates that YKL-39 (266-278) can effectively induce specific tolerance against peptide response induced NA gp-39 (263-275) (table 4, Fig.4, 5, 6).


1. The peptide having the amino acid sequence of the 9-55 amino acid residues that includes the amino acid sequence FTLASAETT (SEQ ID NO:l).

2. The peptide under item 1, comprising the amino acid sequence HSFTLASAETTVG (SEQ ID NO:2).

3. The peptide under item 1 or 2, having the amino acid sequence of up to 25 amino acid residues.

4. The peptide according to any one of paragraphs.1-3 for use as a therapeutic agent.

5. Peptides on PP.1-3 to obtain a pharmaceutical preparation for the induction of specific tolerance of T cells to autoantigen in patients suffering from autoimmune disorders, more specifically arthritis.

6. Farmaceutici pharmaceutically acceptable carrier.


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