title: 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.
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.
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Max
authors.initials: M
authors.lastname: Jameson-Lee
authors.affiliation: The Center for the Study of Biological Complexity, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Koparde
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Griffith
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Allison F
authors.initials: AF
authors.lastname: Scalora
authors.affiliation: The Center for the Study of Biological Complexity, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Juliana K
authors.initials: JK
authors.lastname: Sampson
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Haniya
authors.initials: H
authors.lastname: Khalid
authors.affiliation: The Center for the Study of Biological Complexity, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Nihar U
authors.initials: NU
authors.lastname: Sheth
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Batalo
authors.affiliation: The Center for the Study of Biological Complexity, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Myrna G
authors.initials: MG
authors.lastname: Serrano
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Roberts
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hess
authors.affiliation: The Center for the Study of Biological Complexity, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Buck
authors.affiliation: Department of Psychiatry and Statistical Genomics, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Neale
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.affiliation: Stem Cell Transplant Program, Massey Cancer Center, Virginia Commonwealth University , Richmond, VA , USA.
authors.forename: Amir Ahmed
authors.initials: AA
authors.lastname: Toor
keywords: HLA; alloreactivity potential; minor histocompatibility antigen; stem-cell transplant; whole exome sequencing