Efficient discovery of immune response targets by cyclical refinement of QSAR models of peptide binding.

Peptides that induce and recall T-cell responses are called T-cell epitopes. T-cell epitopes may be useful in a subunit vaccine against malaria. Computer models that simulate peptide binding to MHC are useful for selecting candidate T-cell epitopes since they minimize the number of experiments required for their identification. We applied a combination of computational and immunological strategies to select candidate T-cell epitopes. A total of 86 experimental binding assays were performed in three rounds of identification of HLA-A11 binding peptides from the six preerythrocytic malaria antigens. Thirty-six peptides were experimentally confirmed as binders. We show that the cyclical refinement of the ANN models results in a significant improvement of the efficiency of identifying potential T-cell epitopes.

[1]  V. Apostolopoulos,et al.  MUC1 peptide epitopes associated with five different H‐2 class I molecules , 1997, European journal of immunology.

[2]  Marie-Paule Lefranc,et al.  IMGT, the international ImMunoGeneTics database , 1997, Nucleic Acids Res..

[3]  S. Clementi,et al.  The importance of secondary anchor residue motifs of HLA class I proteins: a chemometric approach. , 1994, Molecular immunology.

[4]  P. Travers,et al.  The MHC class I-restricted immune response to HIV-gag in BALB/c mice selects a single epitope that does not have a predictable MHC-binding motif and binds to Kd through interactions between a glutamine at P3 and pocket D. , 1998, Journal of immunology.

[5]  R. J. Stonier,et al.  Complex Systems: Mechanism of Adaptation , 1994 .

[6]  F. Marincola,et al.  Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. , 1999, Journal of immunology.

[7]  L C Harrison,et al.  MHCPEP: a database of MHC-binding peptides. , 1994, Nucleic acids research.

[8]  Mark Lindsey,et al.  Complexity among constituents of the HLA-B*1501 peptide motif , 1998, Immunogenetics.

[9]  M F del Guercio,et al.  Definition of an HLA-A3-like supermotif demonstrates the overlapping peptide-binding repertoires of common HLA molecules. , 1996, Human immunology.

[10]  E. Huarte,et al.  Specific and general HLA-DR binding motifs: comparison of algorithms. , 2000, Human immunology.

[11]  K. Parker,et al.  Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. , 1994, Journal of immunology.

[12]  R Elber,et al.  Knowledge-based structure prediction of MHC class I bound peptides: a study of 23 complexes. , 1998, Folding & design.

[13]  Z. Nagy,et al.  Precise prediction of major histocompatibility complex class II-peptide interaction based on peptide side chain scanning , 1994, The Journal of experimental medicine.

[14]  L. Szekely,et al.  Identification of wild‐type and mutant p53 peptides binding to HLA‐A2 assessed by a peptide loading‐deficient cell line assay and a novel major histocompatibility complex class I peptide binding assay , 1994, European journal of immunology.

[15]  P. Cresswell,et al.  Assembly, transport, and function of MHC class II molecules. , 1994, Annual review of immunology.

[16]  R W Chesnut,et al.  Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. , 1997, Immunity.

[17]  V. Brusic,et al.  Neural network-based prediction of candidate T-cell epitopes , 1998, Nature Biotechnology.

[18]  Vladimir Brusic,et al.  Prediction of MHC class II-binding peptides using an evolutionary algorithm and artificial neural network , 1998, Bioinform..

[19]  Vladimir Brusic,et al.  MHCPEP, a database of MHC-binding peptides: update 1996 , 1997, Nucleic Acids Res..

[20]  M. Vaillant,et al.  Immune responses against Plasmodium falciparum asexual blood-stage antigens and disease susceptibility in Gabonese and Cameroonian children. , 1999, The American journal of tropical medicine and hygiene.

[21]  R. Henderson,et al.  Identification of an HLA-A11-restricted epitope from the tandem repeat domain of the epithelial tumor antigen mucin. , 1995, Journal of immunology.

[22]  S Walters,et al.  T-cell immunity to peptide epitopes of liver-stage antigen 1 in an area of Papua New Guinea in which malaria is holoendemic , 1997, Infection and immunity.

[23]  P. Cresswell,et al.  Mechanisms of MHC class I--restricted antigen processing. , 1998, Annual review of immunology.

[24]  P. Miller.  Medical informatics in clinical medicine and the biosciences , 1995, Nature Medicine.

[25]  S. Hoffman,et al.  Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. , 1998, Science.

[26]  S. H. van der Burg,et al.  Identification of peptide sequences that potentially trigger HLA‐A2.1‐restricted cytotoxic T lymphocytes , 1993, European journal of immunology.

[27]  Cvi Scotland,et al.  Newsletter Issue 1 , 1970 .

[28]  T. Elliott,et al.  A method to quantify binding of unlabeled peptides to class I MHC molecules and detect their allele specificity. , 1993, Journal of immunological methods.

[29]  Hans-Georg Rammensee,et al.  MHC Ligands and Peptide Motifs , 1998, Molecular Biology Intelligence Unit.

[30]  P. Cresswell,et al.  Impaired assembly and transport of HLA‐A and ‐B antigens in a mutant TxB cell hybrid. , 1986, The EMBO journal.

[31]  H Mamitsuka,et al.  Predicting peptides that bind to MHC molecules using supervised learning of hidden markov models , 1998, Proteins.

[32]  S. H. van der Burg,et al.  Peptide‐pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA‐A*0201‐binding peptides from the Melan‐A/MART‐1 self antigen , 1996, European journal of immunology.

[33]  R. R. Mallios,et al.  Class II MHC quantitative binding motifs derived from a large molecular database with a versatile iterative stepwise discriminant analysis meta- algorithm , 1999, Bioinform..