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PubMed2002

Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23.

There is evidence that amino acids 9-23 of the insulin B chain are a major target of anti-islet autoimmunity in type 1 diabetes. Administration of this peptide to NOD mice prevents diabetes, and phase I trials of an altered peptide ligand of B:9-23 are underway in humans. We were interested in long-term subcutaneous therapeutic administration of B:9-23 without adjuvant. To our initial surprise, the peptide consistently induced fatal anaphylaxis in NOD mice after 6 weeks of administration. Anaphylaxis could be blocked by a combination of antihistamine and platelet-activating factor antagonist (but neither alone) or by a combination of anti-IgG receptor and anti-IgE antibodies. High titers of anti-B:9-23 antibodies were induced within 3-4 weeks of immunization with the peptide. Peptide B:13-23 also induced anaphylaxis and was more potent than peptide B:9-23. Antibodies induced by peptide B:9-23 and peptide B:13-23 did not cross-react with each other. Thus, the insulin peptides B:9-23 and B:13-23, even when administered subcutaneously in the absence of adjuvant, can induce a dramatic humoral response leading to fatal anaphylaxis in NOD mice.

Anaphylaxis↗
PubMed1995

Hydrolytic cleavage of pyroglutamyl-peptide bond. I. The susceptibility of pyroglutamyl-peptide bond to dilute hydrochloric acid.

The susceptibility of the pyroglutamyl-peptide bond in some biologically active peptides, dog neuromedin U-8 fragment (pGlu-Phe-Leu-Phe-Arg-Pro-Arg-OH), human big gastrin fragment (pGlu-Leu-Gly-Pro-OH) and thyrotropin releasing hormone (TRH) fragments (pGlu-His-Pro-OH, pGlu-His-OH), to 1 N HCl under mild conditions and/or at 60 degrees C was studied. It was found that the N-terminal portion of pGlu-peptides is extremely labile to acid hydrolysis, giving not only the ring-opened product of the pyrrolidone moiety of the pGlu residue, but also the cleavage product of the pGlu-peptide linkage. The ring-opening reaction predominated over the cleavage reaction in hydrolysis of the four peptides in 1 N HCl at 60 degrees C. The ring-opening reaction and the cleavage reaction of pGlu-peptide linkage proceeded faster than the cleavage of internal peptide bonds. The rate of hydrolysis was affected by the reaction temperature, and the ring-operating reaction was greatly diminished at 4 degrees C in comparison with the cleavage reaction. Thus, the phenomenon that the pGlu-peptide bond is susceptible to dilute HCl as compared to the other peptide bond appears to be a general one.

Amino Acid Sequence↗
PubMed2001

Facile solid-phase synthesis of sulfated tyrosine-containing peptides: Part II. Total synthesis of human big gastrin-II and its C-terminal glycine-extended peptide (G34-Gly sulfate) by the solid-phase segment condensation approach.

Application of the fluoren-9-ylmethoxycarbonyl (Fmoc)-based solid-phase segment condensation approach to the preparation of sulfated peptides was investigated through the synthesis of human big gastrin-II, a 34-residue sulfated tyrosine [Tyr(SO3H)]-containing peptide. Highly acid-sensitive 2-chlorotrityl resin (Clt resin) was exclusively employed as an anchor-resin for the preparation of the three peptide segments having the C-terminal Pro residue as well as of the Tyr(SO3H)-containing resin-bound segment. By using the PyBOP-mediated coupling protocol [PyBOP=benzotriazolyloxytris(pyrrolidino)phosphonium hexafluorophosphatel, we successively condensed each segment and constructed the 34-residue peptide-resin without any difficulty. The final acid treatment of the fully protected peptide-resin at low temperature (90% aqueous TFA, 0 degree C for 8 h), which can detach a Tyr(SO3H)-containing peptide from the resin and remove the protecting groups concurrently with minimum deterioration of the sulfate, afforded a crude sulfated peptide. After one-step HPLC purification, a highly homogeneous human big gastrin-II was easily obtained in 14% yield from the protected peptide-resin. The sulfate form of the C-terminal glycine-extended gastrin (G34-Gly sulfate), a posttranslational processing intermediate of gastrin-II, was also successfully prepared with the segment condensation approach (11% yield). These results demonstrated the usefulness of the segment condensation protocol for preparing large Tyr(SO3H)-containing peptides.

Gastrins↗
PubMed1975

Studies on polypeptides. V. Improved synthesis of human proinsulin C-peptide and its benzyloxycarbonyl derivative. Circular dichroism and immunological studies of human C-peptide.

An improved synthesis of human C-peptide is described. Five fragments: 33-39, 40-46, 47-49, 50-54 and 55-63 were used in the total synthesis. In the fully protected C-peptide the N-terminal alpha-amino function was blocked by a benzyloxycarbonyl group and the carboxyl and serine hydroxyl functions were blocked by t-butyl protection. The latter protecting groups were removed by trifluoroacetic acid to obtain N-alpha-benzyloxycarbonyl human C-peptide which, on catalytic hydrogenation, yielded human C-peptide. The immunoreactivity of the prepared human C-peptide was tested and found to deviate slightly from the human C-peptide synthesized earlier by another route. When tested in the immunoassay, human pancreatic extracts containing natural C-peptide (or fragments thereof) showed dilution patterns identical to that of the new synthetic C-peptide but different from that of the previously synthesized batch of C-peptide. The possible explantation for the observed differences in the immunoreactivity is discussed.

Benzyl Compounds↗
PubMed2000

Kinetics of peptide uptake and tissue distribution following a single intranasal dose of peptide.

We have previously used intranasal (i.n.) peptide application to induce mucosal tolerance in experimental autoimmune encephalomyelitis (EAE). This strategy, however, appeared to give rise to similar phenomena of tolerance observed as a result of systemic administration of soluble antigenic peptide. We were interested, therefore, in the uptake and tissue distribution of peptide following i.n. treatment. In the H-2u mouse model of EAE, the highly tolerogenic peptide analogue Ac1-9[4Y] of myelin basic protein (MBP) displays high affinity binding to Au MHC class II. For the purpose of the present study this peptide was synthesised to contain a tritiated acetyl group and a protocol was developed to recover radioactivity in solubilised tissues taken at various times after [3H]Ac1-9[4Y] i.n.. Radiolabel loads of the lung and gastro-intestinal tract were initially high but declined rapidly. Radiolabel uptake by blood and lymphoid tissues followed similar kinetics with peak levels around 2.5-4 hours after i.n. administration. Concentrations were high in the draining cervical lymph nodes (CLN) but also reached significant levels in the spleen and 'nondraining' inguinal lymph nodes. The presence of intact antigenic peptide was demonstrated in spleens and CLN from Ac1-9[4Y] i.n. treated mice. Cell suspensions prepared from these tissues at selected time points after peptide i.n. were able to stimulate peptide-specific T cell lines up to at least one day after peptide i.n., suggesting long lasting formation of stable Au-Ac1-9[4Y] complexes in vivo.

Administration, Intranasal↗
PubMed2004

Coupling in silico and in vitro analysis of peptide-MHC binding: a bioinformatic approach enabling prediction of superbinding peptides and anchorless epitopes.

The ability to define and manipulate the interaction of peptides with MHC molecules has immense immunological utility, with applications in epitope identification, vaccine design, and immunomodulation. However, the methods currently available for prediction of peptide-MHC binding are far from ideal. We recently described the application of a bioinformatic prediction method based on quantitative structure-affinity relationship methods to peptide-MHC binding. In this study we demonstrate the predictivity and utility of this approach. We determined the binding affinities of a set of 90 nonamer peptides for the MHC class I allele HLA-A*0201 using an in-house, FACS-based, MHC stabilization assay, and from these data we derived an additive quantitative structure-affinity relationship model for peptide interaction with the HLA-A*0201 molecule. Using this model we then designed a series of high affinity HLA-A2-binding peptides. Experimental analysis revealed that all these peptides showed high binding affinities to the HLA-A*0201 molecule, significantly higher than the highest previously recorded. In addition, by the use of systematic substitution at principal anchor positions 2 and 9, we showed that high binding peptides are tolerant to a wide range of nonpreferred amino acids. Our results support a model in which the affinity of peptide binding to MHC is determined by the interactions of amino acids at multiple positions with the MHC molecule and may be enhanced by enthalpic cooperativity between these component interactions.

Amino Acid Sequence↗
PubMed2000

Depletion of natriuretic peptide C receptors eliminates inhibitory effects of C-type natriuretic peptide on evoked neurotransmitter efflux.

Natriuretic peptides suppress evoked catecholamine efflux by a mechanism attributed to activation of the natriuretic peptide receptor (NPR)-C, but this designation relies on the absolute specificity of truncated natriuretic peptide analogs for the NPR-C. The NPR-C involvement in evoked catecholamine efflux was defined better in this study by selectively ablating the NPR-C in pheochromocytoma cells with antisense oligodeoxynucleotides. This treatment suppressed NPR-C levels by 52 +/- 4% relative to missense treatment. The reduction of NPR-C levels suppressed evoked catecholamine efflux 33 +/- 6% and eliminated the effect of C-type natriuretic peptide to suppress evoked catecholamine efflux. The native peptide, C-type natriuretic peptide, reduced evoked catecholamine efflux 39 +/- 3% in cells with a normal complement of NPR-C. The NPR-C reduction failed to alter neuromodulatory effects of N-nitro-L-arginine methyl ester or an active fragment of the NPR-C receptor administered in permeabilized cells. Furthermore, the NPR-C reduction did not prevent guanylyl cyclase activation in response to C-type natriuretic peptide. These latter experiments indicate that the antisense treatment resulted in a specific suppression of the NPR-C and did not affect alternative neuromodulatory pathways or guanylyl cyclase receptors. The novel aspects of this study include both the inhibitory effect of NPR-C reduction on basal-evoked neurotransmitter efflux and the ablation of natriuretic peptide effects on neurotransmitter efflux by NPR-C reduction. The results are consistent with the notion of a key signal-transducing role of the NPR-C in mediating inhibitory effects of natriuretic peptides on neurotransmitter efflux.

Amino Acid Sequence↗
PubMed1992

Immunization with synthetic peptides containing a defined malaria epitope induces a highly diverse cytotoxic T lymphocyte response. Evidence that two peptide residues are buried in the MHC molecule.

In the present study, we have explored ways of inducing a CTL response to a previously defined H-2Kd MHC class I restricted epitope in the circumsporozoite (CS) protein of Plasmodium berghei, and studied in detail the fine specificity of the response. We found that the s.c. injection of a variety of synthetic peptides emulsified in Freund's adjuvant efficiently induced a specific CTL response in (BALB/c x C57BL/6)F1 (H-2d x H-2b) mice. In contrast, BALB/c mice responded only marginally, consistent with the possible requirement for a concomitant Th response that would be provided by the C57BL/6 strain. Similar to our previous observations in analyzing CTL clones from sporozoite-immunized mice, the CTL response induced by peptide immunization was in part cross-reactive with an epitope from the Plasmodium yoelii species. The minimal P. berghei CS epitope, the octapeptide PbCS 253-260, was studied in detail by the analysis of a series of variant CS peptides containing single Ala substitutions. The relative antigenic activity for each variant peptide was calculated for 28 different CTL clones. Overall, the response to this P. berghei CTL epitope appeared to be extremely diverse in terms of fine specificity. This was evident among the CTL derived from sporozoite-immunized mice, as well as among those from peptide-immunized animals. The heterogeneity found at the functional level correlates with the highly diverse TCR repertoire that we have found for the same series of CTL clones in a study that is reported separately. The relative competitor activity for each Ala-substituted peptide was also determined in a quantitative functional competition assay. For the residues (Tyr253 and Ile260) within the 8-mer CS peptide, substitution with Ala reduced competitor activity by at least 40-fold, and for two others the reduction was 5- to 10-fold. When the relative antigenic activity for each CTL/peptide combination was normalized to the relative competitor activity of the peptide, a striking pattern emerged. The two residues that most affected competitor activity showed no additional effect on recognition beyond that observed for competition. In marked contrast, Ala substitutions at the other five positions tested varied widely, depending on the CTL/peptide combination. This pattern not only supports a model whereby the Tyr253 and Ile260 residues anchor the peptide to the Kd molecule, but also implies that they are virtually inaccessible to the TCR.

Amino Acid Sequence↗
PubMedDate not supplied

Influenza virus haemagglutinin-derived peptides inhibit T-cell activation induced by HLA-DR4/1 specific peptides in rheumatoid arthritis.

OBJECTIVE: To investigate whether influenza virus haemagglutinin (HA)-derived altered peptide ligands (APLs) could abrogate T-cell responses to wild type HA308-317 or type II collagen (CII) 263-272 peptides and explore the potential inhibitory effects of the altered HA308-317 peptides on T-cell activation in rheumatoid arthritis (RA). METHODS: Altered HA308-317 peptides containing substitutions of T-cell receptor (TCR)-contact residues were synthesized. Peripheral blood mononuclear cells (PBMC) were obtained from 27 HLA-DR4/1-positive RA patients. Impact of the altered HA308-317 peptides on T-cell responses and the inhibitory effects on T-cell activation were determined by using PBMC from RA. RESULTS: The results showed that the altered HA308-317 peptides could bind to HLA-DR4/1 on cell surface and had no effects on T-cell proliferation and CD25 expression. Moreover, all the altered HA308-317 peptides inhibited T-cell proliferative responses to wild type HA308-317 or CII263-272. In addition, Th1 type cytokine profile was found when PBMC were cultured with wild type HA308-317 or CII263-272, but not the altered HA 308-317 peptides. CONCLUSIONS: It is suggested that altered HA308-317 peptides bind to the RA-associated HLA-DR4/1 with no stimulating effects on T cells and might be potentially important in inhibition of T-cell activation in RA.

Adult↗
PubMed1991

Recognition of peptides that are immunopathogenic but cryptic. Mechanisms that allow lymphocytes sensitized against cryptic peptides to initiate pathogenic autoimmune processes.

Interphotoreceptor retinoid binding protein (IRBP) is a glycoprotein that localizes in the retina and induces inflammatory changes in this tissue in immunized animals. Certain IRBP-derived peptide determinants are also immunopathogenic, and we have previously shown that these determinants could be either immunodominant or cryptic. Lymphocytes sensitized against the cryptic peptides do not recognize whole IRBP in vitro, and yet these lymphocytes must recognize the protein in vivo to initiate the autoimmune pathogenic process. We have examined here two hypothetical explanations for this dissociation: 1) It is possible that when IRBP is processed in vitro, immunodominant peptide determinants compete with the cryptic ones and inhibit their interaction with the MHC molecules on the APC. This explanation was ruled out here by the finding that the immunodominant peptide 1179-1191 ("W10") did not inhibit the response to a cryptic one, 1158-1180 ("R4"), when added at equivalent and even moderately higher concentrations. 2) The second hypothesis proposes that the cryptic antigenic sites are not generated from IRBP by the APC in vitro, whereas enzymes in the retina digest the protein to yield fragments that generate these antigenic sites upon processing by the APC. In line with this hypothesis, we have found that cleavage of IRBP by certain endoproteinases (Asp-N, Glu-C, or V-8) produced molecules that were recognized in culture by lymphocytes sensitized to the immunopathogenic but cryptic peptide R4. This study, therefore, describes a putative Ag processing mechanism that results in IRBP recognition and, consequently, the initiation of an autoimmune process by lymphocytes sensitized against a cryptic peptide. Furthermore, experiments with R4 and other cryptic peptides have shown that cleavage fragments of up to 38 residues in length can be presented by APC, to stimulate lymphocytes sensitized against these peptides. No responses were stimulated, however, by fragments of 75 or more residues. The data thus provide new insights into the processing and presentation of cryptic peptide determinants by APC.

Amino Acid Sequence↗
PubMed1990

[Molecular cloning and expression of Mycobacterium tuberculosis Aoyama B peptide antigen genes in Escherichia coli--a gene encoding 60 kD antigen (AT201) and immunological activity of recombinant peptides (15 and 60 kD)].

To obtain recombinant peptides related to PPDs, we constructed a genomic library from the DNA of Mycobacterium tuberculosis Aoyama B, a standard strain in Japan to manufacture PPDs, using plasmid vectors pUC18 series. Seven clones reacting the anti-PPDs-rabbit-serum on immunoblotting were obtained, and restriction map was analysed. A nucleotide sequence and a putative open reading frame (ORF) of pAT01, encoding 15kD peptide, as well as the mode of expression was reported previously). In this study, nucleotide sequence of 60 kD peptide gene was determined, and the comparative database analysis (GENBANK) revealed a striking level of homology to so called mycobacterial heat shock protein. The expression mode of pAT201 encoding 60 kD, as well as pAT01 encoding 15 kD peptide, indicated that these peptides were not hybrid proteins with the lacZ gene product, but they were consisted of peptides only mycobacterial source. Therefore, 15 kD and 60 kD directly were subjected to immunological studies. The peptides were extracted from E. coli, carrying pAT01 or pAT201, purified through series of DEAE chromatography and followed by Detoxi-Gel to remove LPS. 15 kD peptide behaved almost similar to PPDs both in the DTH skin reaction and the lymphocyte proliferation response on guinea pigs or rats in respect to sensitivity. However, 60 kD was unique in that, and it behaved like a general mitogen. We discussed role of 60 kD peptide, comparing with the common antigen, generally found in most species of bacteria as the heat shock protein.

Antigens, Bacterial↗
PubMed1989

A novel peptide, vasoactive intestinal contractor, of a new (endothelin) peptide family. Molecular cloning, expression, and biological activity.

A new peptide family (endothelin (ET] consisting of three members in mammals appears to be present in mice according to genomic Southern blot analysis. Two ET-related genes were identified by cloning and sequence analysis of a mouse genome. One encoded a peptide identical to porcine and human vasoconstrictor peptide ET, and the other encoded a novel peptide differing from ET in 3 amino acid residues, with 4 cysteines in the same positions as in ET. This novel peptide was synthesized and confirmed to have in vivo pressor activity similar to that of ET. Northern blot analysis, however, indicated the gene of this novel peptide to be expressed only in the intestine, and not in other tissues or cell lines, or endothelial cells. Furthermore, the peptide evoked a strong contractile response in the guinea pig ileum. This peptide may thus be reasonably classified as a gastrointestinal peptide, vasoactive intestinal contractor.

Amino Acid Sequence↗
PubMed1985

Antigen presentation of lysozyme: T-cell recognition of peptide and intact protein after priming with synthetic overlapping peptides comprising the entire protein chain.

Recently, using synthetic overlapping peptides which encompass the entire protein chain of hen egg lysozyme, the full submolecular profile of continuous regions on the protein recognized by T cells (T sites) was localized. In the present report, we have examined in two mouse strains the proliferative response to peptides and to native protein of lymph node cells from mice primed with synthetic overlapping peptides, either individually or as a mixture. It was found that the pattern of T-cell recognition observed after priming with peptides differs from that obtained when the native protein is used as the immunogen. Some, but not all, of the T-site containing peptides were effective in priming for an anti-lysozyme T-cell response. Several peptides which were highly immunogenic as free synthetic peptides were not associated with any of the known protein T sites. Further, some peptides were effective in priming for T cells that respond in vitro to the priming peptide, but not to the whole protein. If antigen processing proceeds via fragmentation, then only those regions containing T sites would be expected to be effective in priming for a T-cell response to the intact protein. Since this was not found to be the case, it is unlikely that fragmentation of lysozyme is a prerequisite for antigen presentation. Rather, we suggest that the critical aspects in the presentation of a protein antigen predominantly involve recognition of an intact protein, the interaction of which with the cell membrane triggers cellular activating events.

Animals↗
PubMed1984

The characterization of high-affinity binding sites in rat brain for the mast cell-degranulating peptide from bee venom using the purified monoiodinated peptide.

The preparation of a pure, monoiodinated derivative of mast cell-degranulating peptide (MCD peptide), the mast cell-degranulating peptide from bee venom, has enabled us to identify binding sites in rat brain membranes that have a high affinity and specificity for this peptide. These binding sites are evenly distributed throughout the brain and copurify with synaptic membranes. Saturation-binding curves, determined by rapid centrifugation or filtration assays, indicate a single population of sites with a concentration of 200 fmol/mg membrane protein in partially fractionated, lysed brain membranes. Dissociation constants of 150 and 140 pM were calculated for the iodinated and native peptides, respectively. These binding sites are probably associated with the neurotoxic action of MCD peptide in the central nervous system. No similar binding sites have been identified in peripheral tissue preparations, and other polycationic mast cell-degranulating agents including compound 48/80 show no such specificity. Specific modification of the primary amines, arginine residues, or disulfide bridges of MCD peptide results in a complete loss of binding activity. Other components of bee venom show specificity for the MCD peptide-binding site, suggesting that a class of neurotoxins in bee venom (possibly including secapin and tertiapin, but not apamin) share the specific action of MCD peptide on the central nervous system.

Amino Acid Sequence↗
PubMed1981

Isolation of the membrane-binding peptide of NADPH-cytochrome P-450 reductase. Characterization of the peptide and its role in the interaction of reductase with cytochrome P-450.

A peptide identified as the membrane-associated segment of NADPH-cytochrome P-450 reductase has been generated by steapsin protease treatment of vesicle-incorporated reductase and isolated by preparative gel electrophoresis. This peptide remains associated with vesicles when steapsin protease digests of vesicle-incorporated reductase were fractionated by Sepharose 4B chromatography, confirming its identity as the membrane-binding peptide. The molecular weight of the membrane-binding peptide was 6400 as determined by gel filtration in 8 M guanidine hydrochloride, and its amino acid content was not especially hydrophobic. The activity of reconstituted hydroxylation systems consisting of reductase, cytochrome P-446, and dilauroyl phosphatidylcholine was not inhibited by large molar excesses of purified membrane-binding peptide. Moreover, when purified reductase and cytochrome P-446 were added to liposomes which contained the membrane-binding peptide, it was determined that mixed function oxidase activity was reconstituted as effectively as when vesicles without the membrane-binding peptides were used. Similar results were obtained with reductase, cytochrome P-450, and detergent-solubilized liposomes (with or without the membrane-binding peptide). Thus, the membrane-binding peptide does not appear to interact with either of these two forms of the hemoprotein in a site-specific manner to prevent reconstitution of hydroxylation activity.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1980

[Basic peptides from bee venom, IV. Synthesis of the mast cell-degranulating peptide by liquid-phase fragment condensation (author's transl)].

The synthesis of the mast cell-degranulating peptide by liquid-phase fragment condensation is described. After the carboxyterminal of the peptide is condensated with polyethylene-glycol (Mr 10000) the following fragments are coupled stepwise on the polymer, a soluble carrier in dichloromethane by the dicyclohexylcarbodiimide/hydroxybenzotriazole-method. Pos. 17-21 Boc-Lys(Z)-Ile-Cys(SiPr)-Gly-Lys(Z) (I) Pos. 12-16 Boc-Pro-His(Trt)-Ile-Cys(Trt)-Arg(Tos) (II) Pos. 8-11 Boc-His(Trt)-Val-Ile-Lys(Z) (III) Pos. 5-7 Boc-Cys(SiPr)-Lys(Z)-Arg(Tos) (IV) Pos. 1-4 Boc-Ile-Lys(Z)-Cys(Trt)-Asn(Mbh) (V) It is practical to crystallize the polyethyleneglycol peptide-coupling products from ethanol after each step. Most of the protecting groups can be removed by treatment of the complete polyethylene-glycol-peptide in trifluoroacetic acid/HBr. In methanol, saturated with ammonia, the peptide is removed in the amid-form from the carrier. The guanidyl-blocking group disappears by solving the peptide in liquid HF. The crude peptide is converted into the tetra-S-sulfonate derivate by oxidative sulfitolysis and purified by ion-exchange and gel chromatography. After reduction by mercaptoethanol a cautious air-reoxidation of the SH- to the SS-peptide followed. Rechromatography on ion-exchange and dextran gels yields a peptide with good biological activity in rat cell histamin-liberation and inflammation inhibition compared with the natural recombinated product.

Amino Acid Sequence↗
PubMed1993

Characterization of cytotoxic T lymphocyte epitopes of a self-protein, p53, and a non-self-protein, influenza matrix: relationship between major histocompatibility complex peptide binding affinity and immune responsiveness to peptides.

We previously described a motif prediction of major histocompatibility complex allele-specific peptides and an in vitro assay for actual measurement of peptide binding to human leukocyte antigen HLA-A2.1 molecules. Using this method we have identified candidate cytotoxic T lymphocyte (CTL) epitopes derived from a non-self-protein (influenza matrix) and self-protein (p53). We now show that results of binding assays performed over a range of peptide concentrations indicate that distinct differences in HLA-A2.1 peptide binding affinities exist between the influenza matrix and p53 protein. The results for the influenza matrix protein indicate that the peptide that shows the highest binding affinity to HLA-A2.1 is identical to the known immunodominant peptide recognized by influenza virus-specific CTLs. The results for p53 indicate that one of the peptides with a low binding affinity is capable of inducing specific CTL responses, but CTLs recognizing the highest affinity binding peptides were not obtained. These findings are discussed in terms of the distinct implications for induction of cellular immune responses directed against peptides with different binding affinities for HLA-A2.1 of proteins that constitute attractive targets for tumor immunotherapy.

Amino Acid Sequence↗
PubMed1994

Immunity to TCR peptides in multiple sclerosis. I. Successful immunization of patients with synthetic V beta 5.2 and V beta 6.1 CDR2 peptides.

Immunization with disease-associated TCR V region peptides is an effective treatment for experimental autoimmune encephalomyelitis. Myelin basic protein-specific T cells, which induce experimental autoimmune encephalomyelitis in many animal strains, may be important in the pathogenesis of multiple sclerosis. Myelin basic protein-specific T cell clones from some multiple sclerosis patients preferentially use TCR V genes from the V beta 5.2 and V beta 6.1 families. To assess the safety and immunogenicity of TCR V beta 5.2 and V beta 6.1 peptides, we injected 11 multiple sclerosis patients with varying doses of two synthetic peptides, TCR V beta 5.2(39-59) and V beta 6.1(39-59), encompassing the CDR2 region of these V gene families. Low doses (100 to 300 micrograms) of peptide induced T cell immunity in 7 of 11 patients to one or both peptides. Delayed type hypersensitivity skin responses to the peptides were observed in three of seven responders, and TCR peptide-specific Ab occurred in two of seven T cell responders. Low doses of TCR peptides produced no side effects and did not cause broad spectrum immunosuppression. Synthetic TCR V region peptides can induce T cell immunity safely in humans and may prove useful in treating human autoimmune diseases.

Adult↗