Table 1.

Major milestone publications impacting practice in the clinical consideration of HLA-DPB1

ReferenceNo.Patient and HCT characteristicsEraHLA matching* and clinical outcomesMajor findings/impact
461 CML200111/12 in GVH direction; case report, acute rejectionFirst evidence that mismatched HLA-DPB1 can be the target of CD4+ T-cell–mediated allograft rejection
 Case report
47143 Various diseases1996-200110/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapseFirst evidence of a GVL effect targeted to HLA-DPB1 allele mismatches after UD-HCT
 Myeloablative conditioning
 T-cell depletion
62118 Various diseases1995-200210/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRMFirst description of a T-cell epitope matching score for HLA-DPB1
 Myeloablative conditioning
 T-cell depletion
50423 Various diseases1996-200310/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse, better OS in ALLConfirmation of Shaw et al47 and possibly improved survival of ALL patients after HLA-DPB1 mismatched HCT
 Myeloablative conditioning
 T-cell depletion
5572 Thalassemia1992-200410/10; HLA-DPB1 nonpermissive HVG mismatches; increased graft rejectionFirst association of nonpermissive TCE mismatches with outcome of HCT for nonmalignant disease
79N/A N/AN/AN/AFirst protocol of targeted epitope-specific HLA-DPB1 typing for UD-HCT
385929 Various diseases1984-20055-8/8; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapseFirst definitive confirmation of GVL targeted to HLA-DPB1 allele mismatches after UD-HCT in a T-cell–replete cohort
 Registry study (14th IHIW)
531 Lymphoblastic lymphoma200610/10; 1 permissive and 1 nonpermissive HlA-DPB1 TCE mismatchFirst isolation of CD4+ T cells alloreactive to mismatched HLA-DPB1 from a patient clearing residual malignant disease after donor lymphocyte infusion from an UD
 Case report
63621 Various diseases1999-200610/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OSFirst demonstration of a negative impact of nonpermissive HLA-DPB1 mismatches in a large multicenter registry cohort
 Myeloablative and reduced-intensity conditioning
 Registry study (IBMDR)
51488 AML, ALL, CML1996-200610/10 and <10/10; HLA-DPB1 allele mismatches; decreased relapse, increased NRM, worse OS in early disease in 10/10; improved OS in late disease in <10/10Differential impact of HLA-DPB1 allele mismatches in 10/10 or <10/10 according to disease status
 Myeloablative and reduced-intensity conditioning
 T-cell depletion
494 Healthy donorsN/AIn vitro generation of 16 T-cell clones alloreactive to a variety of HLA-DP specificities by stimulation with transfected HELA cellsConfirmation that CD4+ T-cell alloreactivity to HLA-DPB1 can be elicited by both permissive and nonpermissive mismatch combinations
6524 Healthy donorsN/AIn vitro mixed lymphocyte reactions between 10/10 matched, HLA-DPB1 permissive or nonpermissive UDFirst experimental evidence for more potent T-cell alloreactivity to nonpermissive than to permissive HLA-DPB1 TCE mismatches
56115 AML, ALL, CML, MDS, UD-HCT1990-20026/12 to 12/12; retrospective matched control study graft failure vs engraftmentGraft failure is associated with donor-specific HLA antibodies, over half of them against HLA-DP
57592 AML, ALL, MDS and others, UD-HCT2005-20099/12 to 12/12; prospective HLA antibody testingDonor-specific antibodies in 1.4% of patients, all against mismatched HLA-DP; significantly associated with graft failure
398539 AML, ALL, CML, MDS1993-200710/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OSFirst definitive demonstration of a negative impact of nonpermissive HLA-DPB1 mismatches on OS in 10/10 and 9/10 UD-HCT
 Registry study (15th IHIW)
5424 Various diseases2000-200810/10; CD4+ DLI for mixed chimerism or relapse; ex vivo analysis of T cells alloreactive to HLA-DPB1 in responding or nonresponding patientsFirst demonstration of reliable emergence of CD4+ T cells alloreactive to HLA-DP in patients responding to DLI after UD-HCT
 T-cell–depleted UD-HCT
68N/A N/AN/AN/ALaunch of the first free online tool for HLA-DPB1 nonpermissive/permissive TCE match assignment
362 AMLN/A10/10; HLA-DPB1 nonpermissive GVH mismatch in both patients; severe aGVHD of the gut after CMV reactivationHost-derived CMV-specific T cells can trigger CD4+ T-cell alloreactivity against mismatched HLA-DPB1 after UD-HCT, leading to severe GVHD
 2 case reports
661281 AML, ALL, CML, MDS1988-200310/10; HLA-DPB1 nonpermissive GVH mismatches significantly lower relapse than permissive mismatches; no impact of concomitant mismatching for DPA1GVL effect by nonpermissive GVH mismatches; no impact of DPA1 on nonpermissive TCE mismatches
 Registry study (CIBMTR)
48003 AML, ALL, CML, MDS1999-201110/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased NRM, worse OS in 10/10 but not in 9/10First confirmation of a negative impact of nonpermissive HLA-DPB1 mismatches in 10/10 on OS in an independent validation cohort from a registry
 Registry study (CIBMTR)
714 Healthy donorsN/AGeneration of 12 site-directed mutants of HLA-DPB1*09:01 at 10 key amino acid positions; investigation of their allorecognition by 17 T-cell effectors alloreactive to wild-type HLA-DPB1*09:01; determination of the median impact of each substitution on T-cell alloreactivity (FD)Development of a FD score system for individual amino acid polymorphism in HLA-DPB1, and for HLA-DPB1 alleles. The FD score of any current or future HLA-DPB1 allele can be used to predict its assignment to TCE groups
527898 Various diseases1993-201010/10; role of HLA-locus mismatches including HLA-DPB1 allelic disparity; increased aGVHD, decreased relapseConfirmation of lower relapse risk associated with HLA-DPB1 allele mismatches; no such association was observed with HLA-DRB1 allele mismatches
 Registry study (JMDP)
642029 AML, ALL, CML, MDS1988-200810/10; truly unidirectional GVH HLA-DPB1 expression mismatches; increased aGVHD when patient carries high-expression mismatchFirst demonstration that expression levels determine nonpermissive GVH HLA-DPB1 mismatches; conclusive association between 3′ UTR expression SNPs and exon HLA-DPB1 types
 Registry Study (CIBMTR)
801342 Various diseases2000-200810/10; increased grade III-IV aGVHD with 2 allelic HLA-DPB1 mismatches, increased relapse with TCE nonpermissive HVG disparitiesHLA-DPB1 impacts aGVHD and relapse by number of allelic mismatches and TCE HVG disparities, respectively
 Registry study (RFGM)
69N/A N/A2013N/ADescription of the Optimatch UD search tool from the German registry (ZKRD) including the possibility to select for HLA-DPB1 permissive donors
70N/A N/A2016N/ADescription of the HapLogic UD search tool from the US registry (NMDP) including the possibility to select for HLA-DPB1 permissive donors
71416 AL, MDS2005-201410/10; HLA-DPB1 nonpermissive TCE or ΔFD between patient and donor; ΔFD > 2.665: worse OS and EFS due to less relapse and less NRM; better predictive than nonpermissive TCE in this cohortRefinement of nonpermissive HLA-DPB1 TCE mismatches by ΔFD scores might further improve the predictive value of the algorithm
 Myeloablative conditioning
 T-cell depletion and T-cell replete UD-HCT
75N/A AMLN/ADevelopment of an in vitro protocol to generate CD4+ T cells alloreactive to mismatched HLA-DPB1 on AML blasts or from RNA-transfected dendritic cells; preclinical humanized mouse model of GVL targeted to HLA-DPB1First protocol for the isolation and expansion of CD4+ T cells from the naive repertoire using primary AML blasts or transfected autologous dendritic cells for cellular immunotherapy; first demonstration of the in vivo efficacy of CD4+ T cells alloreactive to HLA-DPB1 in mediating GVL against AML
67595 Patients searching for an UDN/A10/10; probability to find an HLA-DPB1 allele-matched or permissive UD70% of patients have a 10/10, young, HLA-DPB1 TCE permissive UD
  • aGVHD, acute GVHD; AL, acute leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CIBMTR, Center for International Blood and Marrow Transplant Research; CML, chronic myeloid leukemia; CMV, cytomegalovirus; DLI, donor lymphocyte infusion; EFS, event-free survival; IBMDR, Italian Bone Marrow Donor Registry; IHIW, International Histocompatibility Workshop; JMDP, Japanese Marrow Donor Program; MDS, myelodysplastic syndrome; N/A, not applicable; NMDP, National Marrow Donor Program; NRM, nonrelapse mortality; OS, overall survival; RFGM, Registre France Greffe de Moelle; UTR, untranslated region; ZKRD, Zentrales Knochenmarkregister Deutschland.

  • * HLA matching is reported as the number of matched HLA-A, -B, -C, -DRB1, -DQB1 alleles (10 of 10 or other), followed by the algorithm used to consider HLA-DPB1 mismatches (alleles, nonpermissive TCE, or other).