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For hematopoietic stem cell transplantation (HSCT) HLA identical sibling donors or HLA matched unrelated donors are the most ideal donors. As 10/10 (HLA-A, -B, -C,-DRB1, -DQB1) matched donors, are not available for all patients, the identification of permissive/non-immunogenic mismatches is important to inmprove the outcome of HLA mismatched transplants. Alleles that share the amino acid sequence of the antigen recognition site (ARS)(exon 2 and 3 for HLA class I or exon 2 for HLA-DRB1) or differences outside the peptide binding groove or α -helices (as the HLA-C*03:03 vs C*03:04 mismatch) are good candidates for permissive mismatches as these differences are not likely to induce T cell alloreactivity. An inventory of the functional impact of such mismatches was performed by in vitro cellular assays including the Cytotoxic T Lymphocyte precursor test (CTLp) for HLA-class I allele differences and the MLC, IFN- γ elispot and Primed Lymphocyte Test (PLT) for HLA-DRB1 differences. CTLp assays were performed for: HLA-A*23:17 vs 23:01 (differ at pos 283, exon 5), HLA-C*07:06 vs *07:01 (pos 307 & 324 exon 5 & 6), HLA-C*04:30 vs 04:01 (pos 327, exon 7), HLA-C*03:62 vs 03:03:01 (pos 197, exon 4), HLA-C*03:03 vs 03:04 (pos 91, exon 3) and HLA-B*35:02 vs 35:04 (pos 109, exon 3). The only positive CTLp test was for HLA-C*07:06 vs *07:01. DRB1*14:01 vs DRB1*14:54 differ at pos 112 and a 2nd mismatch of DRB3*02:01 vs DRB3*02:02, respectively, yielded complicated results. Five of 6 combinations tested did not respond in the MLC and 3 of 6 in the Elispot against the combined DRB1/DRB3 mismatch and only in one direction; DRB1*14:01/DRB3*02:01 against DRB1*14:54/DRB3*02:02. PLT results suggested that the DRB1* mismatch was responsible for the response. In conclusion, mismatches involving positions outside the ARS are not very immunogenic. However, some mismatches can lead to T cell reactivity in vitro. The impact of these mismatches on clinical outcome of HSCT remains to be established.