Figure 1.
The biological models and their theoretical and relative contributions to T-cell alloreactivity against HLA-DPB1 incompatibilities. Schematic view of HSCT involving a recipient and a 10/10 MUD carrying at least one HLA-DPB1 allele mismatch. Matched HLA class I and II molecules are shown in green; the mismatched HLA-DPB1 molecules in donor and recipient are shown in red and blue, respectively. The donor and recipient differ genetically at genes encoding minor histocompatibility antigens that can be derived into antigenic peptides presented in the peptide-binding groove of HLA molecules (represented by different shades of gray). They can also present some peptides in common (ie, shared peptidome shown in the same gray tone). The 3 biological models for predicting permissive HLA-DPB1 mismatches are illustrated, each one differing in the type of T-cell allorecognition possibly involved (ie, direct and/or indirect) and in the vector of incompatibility (ie, in both directions for TCEs or GvH for expression and PIRCHE). Furthermore, the expression model is limited to situations in which the donor and recipient differ by only one HLA-DPB1 mismatch with an incompatibility in the GvH direction (ie, also including bidirectional mismatches). The expression model was not designed for double mismatches, which were considered unacceptable given the high risk of severe grade 3 to 4 aGVHD. The TCE model is determined by immunogenic variations called TCEs that are located within the peptide-binding region of HLA molecules. These epitopes can be directly recognized by alloreactive T cells. TCE permissiveness and differential immunopeptidome presentation have been proposed to be mediated by HLA-DM peptide editing, thus also potentially involving the indirect pathway of allorecognition in the TCE model. In the expression model, high cell surface expression of the mismatched HLA-DPB1 molecule in the recipient can favor two types of allorecognition, either direct, notably through the TCEs, or indirect, in cases of allopeptides derived from minor histocompatibility antigens and presented in the peptide-binding groove of the mismatched (but also of the matched) HLA-DPB1 molecule. Finally, indirect allorecognition is also expected in cases of allopeptides derived from mismatched HLA-DPB1 molecule(s) that can be presented in the peptide-binding groove of shared HLA class I or II molecules. This type of recognition is described by the PIRCHE model. D, donor; R, recipient.

The biological models and their theoretical and relative contributions to T-cell alloreactivity against HLA-DPB1 incompatibilities. Schematic view of HSCT involving a recipient and a 10/10 MUD carrying at least one HLA-DPB1 allele mismatch. Matched HLA class I and II molecules are shown in green; the mismatched HLA-DPB1 molecules in donor and recipient are shown in red and blue, respectively. The donor and recipient differ genetically at genes encoding minor histocompatibility antigens that can be derived into antigenic peptides presented in the peptide-binding groove of HLA molecules (represented by different shades of gray). They can also present some peptides in common (ie, shared peptidome shown in the same gray tone). The 3 biological models for predicting permissive HLA-DPB1 mismatches are illustrated, each one differing in the type of T-cell allorecognition possibly involved (ie, direct and/or indirect) and in the vector of incompatibility (ie, in both directions for TCEs or GvH for expression and PIRCHE). Furthermore, the expression model is limited to situations in which the donor and recipient differ by only one HLA-DPB1 mismatch with an incompatibility in the GvH direction (ie, also including bidirectional mismatches). The expression model was not designed for double mismatches, which were considered unacceptable given the high risk of severe grade 3 to 4 aGVHD. The TCE model is determined by immunogenic variations called TCEs that are located within the peptide-binding region of HLA molecules. These epitopes can be directly recognized by alloreactive T cells. TCE permissiveness and differential immunopeptidome presentation have been proposed to be mediated by HLA-DM peptide editing, thus also potentially involving the indirect pathway of allorecognition in the TCE model. In the expression model, high cell surface expression of the mismatched HLA-DPB1 molecule in the recipient can favor two types of allorecognition, either direct, notably through the TCEs, or indirect, in cases of allopeptides derived from minor histocompatibility antigens and presented in the peptide-binding groove of the mismatched (but also of the matched) HLA-DPB1 molecule. Finally, indirect allorecognition is also expected in cases of allopeptides derived from mismatched HLA-DPB1 molecule(s) that can be presented in the peptide-binding groove of shared HLA class I or II molecules. This type of recognition is described by the PIRCHE model. D, donor; R, recipient.

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