title: A proposed algorithm predictive for cytotoxic T cell alloreactivity.
abstract: Previously, we showed that with an increasing number of amino acid differences in single HLA class I-mismatched molecules, the probability of T cell alloreactivity decreases. It is unlikely that every amino acid difference will affect T cell alloreactivity in a similar way; we hypothesized that the effect of an amino acid difference may be dependent on its position and/or physicochemical properties. We selected 131 patient/donor pairs with either a single HLA-A or -C mismatch in the graft-versus-host direction and that were compatible for HLA-B, -DRB1, and -DQB1. The alloreactive CTL precursor (CTLp) frequency was determined and associated with the amino acid differences between the single HLA class I mismatches. In the β sheet, only amino acids that are noncompatible in their physicochemical properties affect T cell alloreactivity, whereas in the α helices, both compatible and noncompatible amino acids affect CTLp outcome. Positions 62, 63, 73, 76, 77, 80, 99, 116, 138, 144, 147, and 163 were bivariately associated with CTLp outcome, irrespective of the total number of amino acid differences. In multivariate analysis, positions 62, 63, 73, 80, 116, 138, 144, and 163 were found to be most predictive for negative CTLp outcome. These results formed the basis for a weighted predictive mismatch score; pairs with the highest mismatch scores are estimated to be 13 times more likely to have a negative CTLp. This new algorithm may be a tool in donor selection for hematopoietic stem cell transplantation.
authors.affiliation: Europdonor Foundation, Leiden 2333 BZ, The Netherlands. joris@europdonor.nl
authors.forename: Monique M
authors.initials: MM
authors.lastname: Jöris
authors.forename: Jon J
authors.initials: JJ
authors.lastname: van Rood
authors.forename: Dave L
authors.initials: DL
authors.lastname: Roelen
authors.forename: Machteld
authors.initials: M
authors.lastname: Oudshoorn
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D046148:Donor Selection; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006650:Histocompatibility Testing / Q000379:methods*; D006801:Humans; D020539:Sequence Analysis, Protein; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I