High resolution HLA matching associated with decreased mortality after unrelated bone marrow transplantation

Abstract

As compared with related HLA-identical sibling donors, bone marrow transplantation (BMT) with phenotypically HLA ABDR-compatible unrelated donors is associated with increased mortality. This may be due to hidden HLA incompatibilities not detected by conventional typing. We have analyzed 44 unrelated patient-donor pairs who were matched for HLA- A, -B, and -DR by routine tissue typing. Our comprehensive HLA typing approach consisted of serology, cytotoxic T-cell precursor (CTLp) tests, T-cell cloning, oligotyping, and DNA sequencing. Using these techniques, we identified numerous HLA allele mismatches not detected by the previously applied routine typing. Twenty-four patient-donor pairs were highly matched and had a low CTLp frequency, whereas the remaining 20 pairs were allele-mismatched for HLA-A, -B, -C, -DR, -DQ antigens and/or had a positive result of the CTLp test. Patient and donor age, diagnosis, and treatment did not differ significantly between the matched and mismatched transplants. The probability for severe acute graft-versus-host disease grades III-IV was 21% in the matched and 47% in the mismatched patients (P = .0464). Transplant- related mortality was 21% and 57% (P = .0072) and actuarial patient survival rates at 3 years were 61% and 13% (P = .0005). We conclude that both HLA class I and class II allele mismatches between unrelated phenotypically ABDR-compatible patient-donor pairs are frequent and associated with increased incidence of posttransplant complications.

Pretransplant cytotoxic donor T‐cell activity specific to patient HLA class I antigens correlating with mortality after unrelated BMT

“…All the remaining HLA-A, -B, -C, -DRB1/ B3/B5 and -DQB1 antigens (not shown) were matched between patient and donor. The complete list of patient and donor HLA antigens is published elsewhere (Speiser et al, 1996). association with oligotyping for HLA class II antigens.…”

“…Their diagnoses were CML, MDS and histiocytosis. The table of all the histocompatibility antigens of the 44 patients is published elsewhere in a report analysing the association between comprehensive HLA matching and clinical results (Speiser et al, 1996).…”

Hematopoietic stem cell transplants from unrelated donors

“…Other explanations could also accotmt for discrepancies between the results of in vitro assays and clinical outcome. Antigens which generate a CTL response might not evoke GVHD because of inappropriate tissue distribution in vivo, low T-cell receptor afRnity which might be sufficient to generate a response in vitro but not in vivo (56), or an inadequate helper T-cell response in vivo (57). Likewise, antigens which generate HTL responses might not evoke GVHD in the absence of a CTL response (58).…”

Clinical outcomes of HLA‐DPB1 mismatches in 10/10 HLA‐matched unrelated donor‐recipient pairs undergoing allogeneic stem cell transplant

“…1 Currently, matching at HLA-A, HLA-B, HLA-C, HLA-DRB1, and DQB1 (10/10) is considered optimal, with a single mismatch at any non-DQB1 allele associated with 5%-10% increase in mortality and/or significant GVHD, whereas DQB1 mismatches are thought to be better tolerated. [2][3][4][5][6][7][8][9][10] Recent literature has suggested that matching at the HLA-DPB1 locus, in addition to the standard loci, may impact outcomes in ASCT. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] The β-chain of the HLA-DP antigen is known to be highly polymorphic, with 716 alleles encoding 591 proteins and 19 null variants, while the α-chain has 44 alleles encoding 22 proteins.…”