Mixed lymphocyte reactions for individuals with phenotypic identity for specific HLA-B, DR determinants: The role of linkage disequilibrium and of specific DR and other class II determinants

Abstract

Although many patients who might benefit from therapeutic bone marrow transplantation lack HLA identical sibling donors, results from many centers now indicate that transplants involving donors other than identical siblings have been successful in a substantial number of cases. Most of these cases were selected because cells from the patient and donor were compatible in mixed lymphocyte culture. We have previously shown that the prediction of mixed lymphocyte culture nonreactivity by HLA-B,DR matching is far more successful if the matched donors shared antigen combinations known to possess significant positive linkage disequilibrium. We now also show that cells from donors with unrelated haplotypes having the specific DR determinants DR1, DR2, and DR3 are more likely than cells from donors with other haplotypes to be mutually compatible in mixed lymphocyte culture. However, even cells from donors with haplotypes with the highest levels of positive linkage disequilibrium frequently show significant mutual stimulation which can, in selected family studies, be attributed to determinants like SB that map between HLA-D/DR and GLO.

Extended family searches for hematopoietic stem cell donors

“…Haplotypes that are common are ones that are resistant to recombination for as yet largely unknown reasons but are very likely, as a result, to contain identical genes in the entire major histocompatibility complex (MHC) region although found in completely unrelated individuals (15). Several examples of this were published in the early 1980s, before any registry of unrelated donors existed and when mixed leukocyte culture (MLC) tests were used to assess MHC compatibility, before most of the class II HLA genes had been identified (15, 16). In one such case, for example (15), an extended family study for an aplastic anemia patient with one very common HLA haplotype, A24, B7, DR2 identified a maternal aunt who shared his mother's relatively rare haplotype A32, B39, DR8 (50% chance, a priori ) and who, by chance, had A11, B7, DR2 (B7, DR2 being known then to have a 5.2% frequency in White people) as her second HLA haplotype; their cells were completely non‐reactive to each other in MLC.…”

Selection of unrelated donors for bone marrow transplantation is improved by HLA class II genotyping with oligonucleotide hybridization.

“…In the case of genetically unrelated donors, however, serological identity might still imply class II allelic differences and result in a positive MLC (24,25). It is generally admitted that T-cell proliferation in primary MLC is induced by incompatibilities at HLA-DR and -DQ.…”

“…It is generally admitted that T-cell proliferation in primary MLC is induced by incompatibilities at HLA-DR and -DQ. Although HLA-DP seems to be of minor importance, DPmediated positive MLC can nevertheless be expected in some cases of HLA identical unrelated donors (25)(26)(27) oligotyping is now systematically performed in our laboratory for the selection of optimally matched donors for BMT. Fig.…”