The dissimilarity score concept focuses on the amino acid variations of
the highly polymorphic antigen-presenting α1 and α2 domains in HLA class I,
and of the ß1 domain in HLA class II. Residues polymorphic
between donor and recipient are evaluated, and assigned either to regions of major
(peptide-binding groove and/or region contacting the T-Cell receptor) or minor
allogeneic potential (remaining amino acid residues) according to HLA-A2
(Garboczi et al.; Saper et al.) and HLA-DR1 (Brown et al.; Hennecke et al.; Stern et al.).
Furthermore, the dissimilarity between the
single pairs of exchanged amino acids is measured by the amino acid distance
matrix as proposed by Risler et al. |
The basic idea of Risler's score was, that two distinct amino acids are more similar, the more often they substitute each other in functionally related proteins. Accordingly, pairs of amino acids with low substition rates (thus representing functional dissimilarity), yield a higher score, with the maximum value of 100. HistoCheck encorporates Rislter's scores in its dissimilariy score calculation by summing the Rislter scores on each amino acid mismatch in the key domains (in HistoCheck, Rislter scores are divided by 100, putting them in the range 0 to 1). When the mismatch is located at a position with major allogeneic potential, the value 1 is added in order to gain a weighted score for this position. Residues that contribute to both peptide binding and contact with the T-Cell recptor (TCR) are rated as if they possess only one function. The described algorithm results in higher scores even for low mismatch at functionally relevant positions compared to any mismatch at positions that are probably of functionaly minor importance. A mathematical description of the dissimilarity score is shown below:
Based on T-Cell reactivity pattern shared T-Cell epitopes between HLA-DPB1 alleles have been identified that determine HLA-DP-specific alloresponsiveness. Alloreactive T-Cell clones recognizing shared epitopes allowed to classify HLA-DPB1 alleles as a strongly immunogenic group 1, an intermediately immunogenic group 2 and a poorly immunogenic group 3 (2), and is here refered to as Evidence-based T-Cell Epitope algorithm 3, TCE3_EB. In later studies experimental evidence allowed to differentiate the immunogenic group 3 into a smaller immunogenic group 3 consisting of the HLA-DPB1*02 alleles and an immunogenic group 4 consisting of the rest of the alleles of the former immunogenic group 3 (3) (Table 2). This algorithm is herein refered to as Evidence-based T-Cell Epitope algorithm 4, TCE4_EB. This classification of HLA-DPB1 alleles based on the observed T-Cell reactivity pattern could be correlated to some extent to the 6 hypervariable regions A – F of the HLA-DPβ chains (4 - 6). HLA-DPB1 alleles of immunogenic group 1 share the amino acid sequence of regions A, B, D, and F. Alleles from immunogenic group 2 have substitutions in region D, alone or in combination with regions A or C, as compared to group 1 alleles. Alleles from immunogenic group 3 and 4 have substitutions in at least 3 of the 4 regions A, B, D, or F shared by group 1 alleles. In TCE4 the immunogenic group 3 exclusively consists of sequences identical to HLA-DPB1*02 alleles.
This sequence/T-Cell epitope correlation shown in Table 1 has been used to assign all HLA-DPB1 alleles based on their sequence to one
of the four immunogenic groups and has been named Sequence-based T-Cell Epitope algorithm 4, TCE4_SB.
Table 1: Amino acid squence alignment of the hypervariable regions of HLA-DPB1 alleles analyzed in 1.
Table 2: Evidence-based classification of HLA-DPB1 alleles into 3 groups (TCE3), or 4 groups (TCE4), on the basis of T-Cell alloreactivity. HLA-DPB1 alleles were classified into 3 groups (TCE3), or 4 groups (TCE4), on the basis of T-Cell alloreactivity. TCE3 group 1 and TCE4 group 1: Alleles encoding antigens recognized by all T-Cell clones studied by Zino et al. (2). TCE3 group 2 and TCE4 group 2: Alleles encoding antigens recognized by some but not all T-Cell clones studied by Zino et al. (2). TCE3 group 3: Alleles encoding antigens recognized by none of the T-Cell clones studied by Zino et al. (2). “Others” refer to all alleles that can be classified according to the algorithm of Zino et al. (3). TCE4 group 3: DPB1*02 encoding antigens eliciting intermediate levels of MLR reactivity (6-8). TCE4 group 4: All alleles from TCE3 group 3 except of DPB1*02.
Based on T-Cell clones obtained from hematopietic stem cell transplanted patients and based on retrospective clinical studies HLA-DPB1 mismatches between the immunogenic groups were classified as permissive or non-permissive (2, 3). The algorithm of permissiveness is shown in Table 3.
Table 3: Algorithm for non-permissive HLA-DPB1 disparities accoding to TCE3 or TCE4. The 3 or 4 groups of HLA-DPB1 alleles can be present in different combinations in diploid cells. Numbers indicate the group of the first (before the slash) and the second (after the slash) HLA-DPB1 allele of donor or recipient. Classification of HLA-DPB1 group disparities as permissive or non-permissive in GvH or HvG direction is indicated for all possible combinations. Note that all non-permissive TCE3 disparities are also TCE4 non-permissive (gray boxes). In contrast, only a part of the TCE3-permissive disparities are permissive also according to TCE4 (white boxes), whereas the remaining TCE3 permissive disparities score as non-permissive in TCE4 (striped boxes).