Major milestone publications impacting practice in the clinical consideration of HLA-DPB1
| Reference . | No. . | Patient and HCT characteristics . | Era . | HLA matching* and clinical outcomes . | Major findings/impact . |
|---|---|---|---|---|---|
| 46 | 1 | CML | 2001 | 11/12 in GVH direction; case report, acute rejection | First evidence that mismatched HLA-DPB1 can be the target of CD4+ T-cell–mediated allograft rejection |
| Case report | |||||
| 47 | 143 | Various diseases | 1996-2001 | 10/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse | First evidence of a GVL effect targeted to HLA-DPB1 allele mismatches after UD-HCT |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 62 | 118 | Various diseases | 1995-2002 | 10/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM | First description of a T-cell epitope matching score for HLA-DPB1 |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 50 | 423 | Various diseases | 1996-2003 | 10/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse, better OS in ALL | Confirmation of Shaw et al47 and possibly improved survival of ALL patients after HLA-DPB1 mismatched HCT |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 55 | 72 | Thalassemia | 1992-2004 | 10/10; HLA-DPB1 nonpermissive HVG mismatches; increased graft rejection | First association of nonpermissive TCE mismatches with outcome of HCT for nonmalignant disease |
| 79 | N/A | N/A | N/A | N/A | First protocol of targeted epitope-specific HLA-DPB1 typing for UD-HCT |
| 38 | 5929 | Various diseases | 1984-2005 | 5-8/8; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse | First definitive confirmation of GVL targeted to HLA-DPB1 allele mismatches after UD-HCT in a T-cell–replete cohort |
| Registry study (14th IHIW) | |||||
| 53 | 1 | Lymphoblastic lymphoma | 2006 | 10/10; 1 permissive and 1 nonpermissive HlA-DPB1 TCE mismatch | First 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 | |||||
| 63 | 621 | Various diseases | 1999-2006 | 10/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OS | First demonstration of a negative impact of nonpermissive HLA-DPB1 mismatches in a large multicenter registry cohort |
| Myeloablative and reduced-intensity conditioning | |||||
| Registry study (IBMDR) | |||||
| 51 | 488 | AML, ALL, CML | 1996-2006 | 10/10 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 <10/10 | Differential impact of HLA-DPB1 allele mismatches in 10/10 or <10/10 according to disease status |
| Myeloablative and reduced-intensity conditioning | |||||
| T-cell depletion | |||||
| 49 | 4 | Healthy donors | N/A | In vitro generation of 16 T-cell clones alloreactive to a variety of HLA-DP specificities by stimulation with transfected HELA cells | Confirmation that CD4+ T-cell alloreactivity to HLA-DPB1 can be elicited by both permissive and nonpermissive mismatch combinations |
| 65 | 24 | Healthy donors | N/A | In vitro mixed lymphocyte reactions between 10/10 matched, HLA-DPB1 permissive or nonpermissive UD | First experimental evidence for more potent T-cell alloreactivity to nonpermissive than to permissive HLA-DPB1 TCE mismatches |
| 56 | 115 | AML, ALL, CML, MDS, UD-HCT | 1990-2002 | 6/12 to 12/12; retrospective matched control study graft failure vs engraftment | Graft failure is associated with donor-specific HLA antibodies, over half of them against HLA-DP |
| 57 | 592 | AML, ALL, MDS and others, UD-HCT | 2005-2009 | 9/12 to 12/12; prospective HLA antibody testing | Donor-specific antibodies in 1.4% of patients, all against mismatched HLA-DP; significantly associated with graft failure |
| 39 | 8539 | AML, ALL, CML, MDS | 1993-2007 | 10/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OS | First 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) | |||||
| 54 | 24 | Various diseases | 2000-2008 | 10/10; CD4+ DLI for mixed chimerism or relapse; ex vivo analysis of T cells alloreactive to HLA-DPB1 in responding or nonresponding patients | First 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 | |||||
| 68 | N/A | N/A | N/A | N/A | Launch of the first free online tool for HLA-DPB1 nonpermissive/permissive TCE match assignment |
| 36 | 2 | AML | N/A | 10/10; HLA-DPB1 nonpermissive GVH mismatch in both patients; severe aGVHD of the gut after CMV reactivation | Host-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 | |||||
| 66 | 1281 | AML, ALL, CML, MDS | 1988-2003 | 10/10; HLA-DPB1 nonpermissive GVH mismatches significantly lower relapse than permissive mismatches; no impact of concomitant mismatching for DPA1 | GVL effect by nonpermissive GVH mismatches; no impact of DPA1 on nonpermissive TCE mismatches |
| Registry study (CIBMTR) | |||||
| 4 | 8003 | AML, ALL, CML, MDS | 1999-2011 | 10/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased NRM, worse OS in 10/10 but not in 9/10 | First 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) | |||||
| 71 | 4 | Healthy donors | N/A | Generation 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 |
| 52 | 7898 | Various diseases | 1993-2010 | 10/10; role of HLA-locus mismatches including HLA-DPB1 allelic disparity; increased aGVHD, decreased relapse | Confirmation of lower relapse risk associated with HLA-DPB1 allele mismatches; no such association was observed with HLA-DRB1 allele mismatches |
| Registry study (JMDP) | |||||
| 64 | 2029 | AML, ALL, CML, MDS | 1988-2008 | 10/10; truly unidirectional GVH HLA-DPB1 expression mismatches; increased aGVHD when patient carries high-expression mismatch | First 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) | |||||
| 80 | 1342 | Various diseases | 2000-2008 | 10/10; increased grade III-IV aGVHD with 2 allelic HLA-DPB1 mismatches, increased relapse with TCE nonpermissive HVG disparities | HLA-DPB1 impacts aGVHD and relapse by number of allelic mismatches and TCE HVG disparities, respectively |
| Registry study (RFGM) | |||||
| 69 | N/A | N/A | 2013 | N/A | Description of the Optimatch UD search tool from the German registry (ZKRD) including the possibility to select for HLA-DPB1 permissive donors |
| 70 | N/A | N/A | 2016 | N/A | Description of the HapLogic UD search tool from the US registry (NMDP) including the possibility to select for HLA-DPB1 permissive donors |
| 71 | 416 | AL, MDS | 2005-2014 | 10/10; 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 cohort | Refinement 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 | |||||
| 75 | N/A | AML | N/A | Development 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-DPB1 | First 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 |
| 67 | 595 | Patients searching for an UD | N/A | 10/10; probability to find an HLA-DPB1 allele-matched or permissive UD | 70% of patients have a 10/10, young, HLA-DPB1 TCE permissive UD |
| Reference . | No. . | Patient and HCT characteristics . | Era . | HLA matching* and clinical outcomes . | Major findings/impact . |
|---|---|---|---|---|---|
| 46 | 1 | CML | 2001 | 11/12 in GVH direction; case report, acute rejection | First evidence that mismatched HLA-DPB1 can be the target of CD4+ T-cell–mediated allograft rejection |
| Case report | |||||
| 47 | 143 | Various diseases | 1996-2001 | 10/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse | First evidence of a GVL effect targeted to HLA-DPB1 allele mismatches after UD-HCT |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 62 | 118 | Various diseases | 1995-2002 | 10/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM | First description of a T-cell epitope matching score for HLA-DPB1 |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 50 | 423 | Various diseases | 1996-2003 | 10/10; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse, better OS in ALL | Confirmation of Shaw et al47 and possibly improved survival of ALL patients after HLA-DPB1 mismatched HCT |
| Myeloablative conditioning | |||||
| T-cell depletion | |||||
| 55 | 72 | Thalassemia | 1992-2004 | 10/10; HLA-DPB1 nonpermissive HVG mismatches; increased graft rejection | First association of nonpermissive TCE mismatches with outcome of HCT for nonmalignant disease |
| 79 | N/A | N/A | N/A | N/A | First protocol of targeted epitope-specific HLA-DPB1 typing for UD-HCT |
| 38 | 5929 | Various diseases | 1984-2005 | 5-8/8; HLA-DPB1 allele mismatches; increased aGVHD, decreased relapse | First definitive confirmation of GVL targeted to HLA-DPB1 allele mismatches after UD-HCT in a T-cell–replete cohort |
| Registry study (14th IHIW) | |||||
| 53 | 1 | Lymphoblastic lymphoma | 2006 | 10/10; 1 permissive and 1 nonpermissive HlA-DPB1 TCE mismatch | First 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 | |||||
| 63 | 621 | Various diseases | 1999-2006 | 10/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OS | First demonstration of a negative impact of nonpermissive HLA-DPB1 mismatches in a large multicenter registry cohort |
| Myeloablative and reduced-intensity conditioning | |||||
| Registry study (IBMDR) | |||||
| 51 | 488 | AML, ALL, CML | 1996-2006 | 10/10 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 <10/10 | Differential impact of HLA-DPB1 allele mismatches in 10/10 or <10/10 according to disease status |
| Myeloablative and reduced-intensity conditioning | |||||
| T-cell depletion | |||||
| 49 | 4 | Healthy donors | N/A | In vitro generation of 16 T-cell clones alloreactive to a variety of HLA-DP specificities by stimulation with transfected HELA cells | Confirmation that CD4+ T-cell alloreactivity to HLA-DPB1 can be elicited by both permissive and nonpermissive mismatch combinations |
| 65 | 24 | Healthy donors | N/A | In vitro mixed lymphocyte reactions between 10/10 matched, HLA-DPB1 permissive or nonpermissive UD | First experimental evidence for more potent T-cell alloreactivity to nonpermissive than to permissive HLA-DPB1 TCE mismatches |
| 56 | 115 | AML, ALL, CML, MDS, UD-HCT | 1990-2002 | 6/12 to 12/12; retrospective matched control study graft failure vs engraftment | Graft failure is associated with donor-specific HLA antibodies, over half of them against HLA-DP |
| 57 | 592 | AML, ALL, MDS and others, UD-HCT | 2005-2009 | 9/12 to 12/12; prospective HLA antibody testing | Donor-specific antibodies in 1.4% of patients, all against mismatched HLA-DP; significantly associated with graft failure |
| 39 | 8539 | AML, ALL, CML, MDS | 1993-2007 | 10/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased aGVHD and NRM, worse OS | First 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) | |||||
| 54 | 24 | Various diseases | 2000-2008 | 10/10; CD4+ DLI for mixed chimerism or relapse; ex vivo analysis of T cells alloreactive to HLA-DPB1 in responding or nonresponding patients | First 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 | |||||
| 68 | N/A | N/A | N/A | N/A | Launch of the first free online tool for HLA-DPB1 nonpermissive/permissive TCE match assignment |
| 36 | 2 | AML | N/A | 10/10; HLA-DPB1 nonpermissive GVH mismatch in both patients; severe aGVHD of the gut after CMV reactivation | Host-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 | |||||
| 66 | 1281 | AML, ALL, CML, MDS | 1988-2003 | 10/10; HLA-DPB1 nonpermissive GVH mismatches significantly lower relapse than permissive mismatches; no impact of concomitant mismatching for DPA1 | GVL effect by nonpermissive GVH mismatches; no impact of DPA1 on nonpermissive TCE mismatches |
| Registry study (CIBMTR) | |||||
| 4 | 8003 | AML, ALL, CML, MDS | 1999-2011 | 10/10 and 9/10; HLA-DPB1 nonpermissive TCE mismatches; increased NRM, worse OS in 10/10 but not in 9/10 | First 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) | |||||
| 71 | 4 | Healthy donors | N/A | Generation 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 |
| 52 | 7898 | Various diseases | 1993-2010 | 10/10; role of HLA-locus mismatches including HLA-DPB1 allelic disparity; increased aGVHD, decreased relapse | Confirmation of lower relapse risk associated with HLA-DPB1 allele mismatches; no such association was observed with HLA-DRB1 allele mismatches |
| Registry study (JMDP) | |||||
| 64 | 2029 | AML, ALL, CML, MDS | 1988-2008 | 10/10; truly unidirectional GVH HLA-DPB1 expression mismatches; increased aGVHD when patient carries high-expression mismatch | First 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) | |||||
| 80 | 1342 | Various diseases | 2000-2008 | 10/10; increased grade III-IV aGVHD with 2 allelic HLA-DPB1 mismatches, increased relapse with TCE nonpermissive HVG disparities | HLA-DPB1 impacts aGVHD and relapse by number of allelic mismatches and TCE HVG disparities, respectively |
| Registry study (RFGM) | |||||
| 69 | N/A | N/A | 2013 | N/A | Description of the Optimatch UD search tool from the German registry (ZKRD) including the possibility to select for HLA-DPB1 permissive donors |
| 70 | N/A | N/A | 2016 | N/A | Description of the HapLogic UD search tool from the US registry (NMDP) including the possibility to select for HLA-DPB1 permissive donors |
| 71 | 416 | AL, MDS | 2005-2014 | 10/10; 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 cohort | Refinement 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 | |||||
| 75 | N/A | AML | N/A | Development 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-DPB1 | First 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 |
| 67 | 595 | Patients searching for an UD | N/A | 10/10; probability to find an HLA-DPB1 allele-matched or permissive UD | 70% 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).