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In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Jameson-Lee M, Koparde V, Griffith P, Scalora AF, Sampson JK, Khalid H, Sheth NU, Batalo M, Serrano MG, Roberts CH, Hess ML, Buck GA, Neale MC, Manjili MH, Toor AA - Front Immunol (2014)

Bottom Line: All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms.A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm.The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.

ABSTRACT
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

No MeSH data available.


Related in: MedlinePlus

Unique peptide-HLA complexes (GVH vector) with IC50 < 500 nM predicted by both SMM and NetMHCpan. Scatter plots depict the IC50 for unique polymorphic peptide-HLA complexes predicted by the two different algorithms studied. Each circle corresponds to a unique peptide-HLA complex, with color depicting specific HLA. A large number of patient-HLA-specific strong-binding peptides identified by both programs, using SNP data derived from exome sequencing. Only shared peptide-HLA complexes predicted to have an IC50 < 500 nM by both algorithms included.
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Figure 5: Unique peptide-HLA complexes (GVH vector) with IC50 < 500 nM predicted by both SMM and NetMHCpan. Scatter plots depict the IC50 for unique polymorphic peptide-HLA complexes predicted by the two different algorithms studied. Each circle corresponds to a unique peptide-HLA complex, with color depicting specific HLA. A large number of patient-HLA-specific strong-binding peptides identified by both programs, using SNP data derived from exome sequencing. Only shared peptide-HLA complexes predicted to have an IC50 < 500 nM by both algorithms included.

Mentions: To confirm the IEDB-SMM algorithm findings, a second peptide-HLA binding affinity prediction tool, NetMHCpan was used to interrogate the variant peptide libraries from the unique DRP and its output compared with the IEDB SMM. The NetMHCpan yielded a median of 3,962 peptides categorized as presented and 989 peptides as strongly presented in the nine DRP studied (MRD versus URD, P = 0.063 and 0.11, respectively, Mann–Whitney U test) (Table 3). The IEDB-SMM and NetMHCpan datasets were then combined and unique peptide-HLA complexes predicted to be presented by both algorithms determined (shared peptides). The median number of shared unique peptides presented/DRP was 2,065 (range: 417–4,881) (Table 3). A representative data table depicting peptide sequences and respective IC50 values for binding to a single HLA locus, in a patient, predicted by both algorithms is given in Table S1 in Supplementary Material. Plotting the IC50 of unique presented peptide-HLA complexes derived utilizing both algorithms, demonstrated not only a very large number of complexes identified by both algorithms, but also that a large proportion of these complexes were categorized as strongly presented (Figure 5). Furthermore, a weak, but significant correlation was identified between the IC50 predictions for both the algorithms in the shared peptide-HLA complex datasets (N = 9, median Pearson’s correlation coefficient R = 0.62, P < 0.01). Additionally, when the distribution of peptides presented on the three class I HLA loci was examined, no discernable preference for particular HLA loci was observed in terms of likelihood of peptide presentation (Figure S2A,B in Supplementary Material), except for a possible HLA-C dominance in URD recipients in the SMM algorithm.


In silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem-Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation.

Jameson-Lee M, Koparde V, Griffith P, Scalora AF, Sampson JK, Khalid H, Sheth NU, Batalo M, Serrano MG, Roberts CH, Hess ML, Buck GA, Neale MC, Manjili MH, Toor AA - Front Immunol (2014)

Unique peptide-HLA complexes (GVH vector) with IC50 < 500 nM predicted by both SMM and NetMHCpan. Scatter plots depict the IC50 for unique polymorphic peptide-HLA complexes predicted by the two different algorithms studied. Each circle corresponds to a unique peptide-HLA complex, with color depicting specific HLA. A large number of patient-HLA-specific strong-binding peptides identified by both programs, using SNP data derived from exome sequencing. Only shared peptide-HLA complexes predicted to have an IC50 < 500 nM by both algorithms included.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222229&req=5

Figure 5: Unique peptide-HLA complexes (GVH vector) with IC50 < 500 nM predicted by both SMM and NetMHCpan. Scatter plots depict the IC50 for unique polymorphic peptide-HLA complexes predicted by the two different algorithms studied. Each circle corresponds to a unique peptide-HLA complex, with color depicting specific HLA. A large number of patient-HLA-specific strong-binding peptides identified by both programs, using SNP data derived from exome sequencing. Only shared peptide-HLA complexes predicted to have an IC50 < 500 nM by both algorithms included.
Mentions: To confirm the IEDB-SMM algorithm findings, a second peptide-HLA binding affinity prediction tool, NetMHCpan was used to interrogate the variant peptide libraries from the unique DRP and its output compared with the IEDB SMM. The NetMHCpan yielded a median of 3,962 peptides categorized as presented and 989 peptides as strongly presented in the nine DRP studied (MRD versus URD, P = 0.063 and 0.11, respectively, Mann–Whitney U test) (Table 3). The IEDB-SMM and NetMHCpan datasets were then combined and unique peptide-HLA complexes predicted to be presented by both algorithms determined (shared peptides). The median number of shared unique peptides presented/DRP was 2,065 (range: 417–4,881) (Table 3). A representative data table depicting peptide sequences and respective IC50 values for binding to a single HLA locus, in a patient, predicted by both algorithms is given in Table S1 in Supplementary Material. Plotting the IC50 of unique presented peptide-HLA complexes derived utilizing both algorithms, demonstrated not only a very large number of complexes identified by both algorithms, but also that a large proportion of these complexes were categorized as strongly presented (Figure 5). Furthermore, a weak, but significant correlation was identified between the IC50 predictions for both the algorithms in the shared peptide-HLA complex datasets (N = 9, median Pearson’s correlation coefficient R = 0.62, P < 0.01). Additionally, when the distribution of peptides presented on the three class I HLA loci was examined, no discernable preference for particular HLA loci was observed in terms of likelihood of peptide presentation (Figure S2A,B in Supplementary Material), except for a possible HLA-C dominance in URD recipients in the SMM algorithm.

Bottom Line: All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms.A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm.The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.

ABSTRACT
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.

No MeSH data available.


Related in: MedlinePlus