An Approach to Predicting Hematopoietic Stem Cell Transplantation Outcome Using HLA-Mismatch Information Mapped on Protein Structure Data

Survival curves for patients with GVHD (gray) and without GVHD (black) receiving transplants from unrelated donors with 2 kinds of HLA-B mismatch, B∗2702/2705 and B∗3501/3503.

Comparison of survival probability for patients from groups distinguished on the basis of donor matching level: Lr match, low-resolution match (allele mismatch); Lr MM, low-resolution mismatch (antigen mismatch); DBMM, double mismatch (in 2 loci); FM, full-match–high-resolution match.

A, Structure substitution scheme: several candidate conformations of EBV peptide–ball-and-stick representation (1) presented by the original MHC B∗3501 ribbon representation (2) and the HLA-B alleles listed in Table 3. B, TCR–MHC contact region. Residues in the ball-and-stick representation were considered during contact energy calculations. Red, presented peptide; yellow, MHC; blue, TCR.

Results of energy minimization for constructed TCR–pMHC complexes for the 5 alleles evaluated. The y-axis represents the calculated energy of TCR–MHC contacts and TCR–-peptide contacts, according to formula (1). The NX5 structure was used as a template. 2702, 2705, 3501 and 3503 are TCR–pMHC complex models discussed in the text. 3508-ELS is a TCR–pMHC complex (B∗3508/EBVp) that does not activate T cells. 3508-NX5pep is a TCR–pMHC complex (B∗3508/EBVp) with peptide presented in conformation specific for B∗3501. X5ORG is a TCR–pMHC complex (B∗3501/EBVp) triggering T cell reaction.

Contact energies for the 5 Å zone without ligand and with only TCR and MHC residues, according to formula (2). Complexes were reconstructed on the template of the 1NX5.pdb file.

The molecular surface of the TCR–MHC contact zone with the presented EBV peptide depicted using a ball-and-stick model. TCR chain A, orange; chain B, blue; HLA chain A, grey

Residues of MHC class I making contact on TCR (sorted by MHC residues) based on the known structures of TCR–pMHC complexes (according to Rudolph et al. [9]) and a proximity parameter of 5 Å. SNP B∗3501/3503 and B∗27-2/2705 also are shown (A105, 104, 101, and A141). The following MHC residues made the most contacts on TCR residues: A58, A59, A62, A65, A66, A69, A69, A70, A72, A73, A75, A76, A79, A146, A 147, A149, A150, A151, A152, A154, A 155, A158, A159, A162, A163, A166, A167, and A170.

Aligned sequences of 4 analyzed alleles of HLA-B. A, Amino acid differences between alleles of the same group (B2702-B2705 [black] and B3501-B3503 [blue]). B, Amino acid differences between alleles belonging to the separate HLA groups (B27 vs B35).

Comparison of survival curves for 2 groups of HSCT recipients who received transplants from B∗3501/3503 mismatched donors (MM 3501/3503; dotted line) and from B∗2702/2705 mismatched donors (MM 2702/2705; solid line) (n = 18).

Comparison of survival probability for patients from groups distinguished on the basis of the mismatched HLA locus: MMA, patients receiving transplants from HLA-A–mismatched donors; FM, patients receiving transplants from fully matched donors; DBMM, patients receiving transplants from donors mismatched at more than 1 locus. A, Curves plotted based on the whole data set. B, Curves plotted based on only the IHWG data. C, Curves plotted for only the Polish patients.

Survival curves for patients receiving transplants from donors mismatched in MHC class I or class II and for the fully matched control group.