Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: A retrospective study

Unit of Molecular and Functional Immunogenetics, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico H San Raffaele, Milan, Italy.
The Lancet Oncology (Impact Factor: 24.69). 02/2012; 13(4):366-74. DOI: 10.1016/S1470-2045(12)70004-9
Source: PubMed


The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation.

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    • "Nonpermissive mismatches, defined by the TCE model, are highly correlated to alloreactivity as reflected by GvHD, graft rejection, and transplant-related mortality after HLA-DPB1-mismatched HSCT [4, 90–92]. Counterintuitively, in these situations, the direction of the nonpermissiveness appears not to be important: both HvG and GvH nonpermissive mismatches lead to alloreactivity in the GvH direction (i.e., GvHD) [4, 91]. Therefore, both HvG and GvH nonpermissive mismatches are considered overall nonpermissive [4, 91]. "
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    ABSTRACT: Human leukocyte Antigen (HLA) mismatching leads to severe complications after solid-organ transplantation and hematopoietic stem-cell transplantation. The alloreactive responses underlying the posttransplantation complications include both direct recognition of allogeneic HLA by HLA-specific alloantibodies and T cells and indirect T-cell recognition. However, the immunogenicity of HLA mismatches is highly variable; some HLA mismatches lead to severe clinical B-cell- and T-cell-mediated alloreactivity, whereas others are well tolerated. Definition of the permissibility of HLA mismatches prior to transplantation allows selection of donor-recipient combinations that will have a reduced chance to develop deleterious host-versus-graft responses after solid-organ transplantation and graft-versus-host responses after hematopoietic stem-cell transplantation. Therefore, several methods have been developed to predict permissible HLA-mismatch combinations. In this review we aim to give a comprehensive overview about the current knowledge regarding HLA-directed alloreactivity and several developed in vitro and in silico tools that aim to predict direct and indirect alloreactivity.
    Research Journal of Immunology 04/2014; 2014(11):159479. DOI:10.1155/2014/159479
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    • "Recently published data from comprehensive studies reviewed by Shaw B. E. and colleagues [5] demonstrated a significant survival advantage in HSCT when using donors matched for HLA-A, -B, -C and -DRB1 at allelic resolution. The loci HLA-DQB1 and -DPB1 are still under discussion [6]. "
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    ABSTRACT: Background Human leukocyte antigen matching at allelic resolution is proven clinically significant in hematopoietic stem cell transplantation, lowering the risk of graft-versus-host disease and mortality. However, due to the ever growing HLA allele database, tissue typing laboratories face substantial challenges. In light of the complexity and the high degree of allelic diversity, it has become increasingly difficult to define the classical transplantation antigens at high-resolution by using well-tried methods. Thus, next-generation sequencing is entering into diagnostic laboratories at the perfect time and serving as a promising tool to overcome intrinsic HLA typing problems. Therefore, we have developed and validated a scalable automated HLA class I and class II typing approach suitable for diagnostic use. Results A validation panel of 173 clinical and proficiency testing samples was analysed, demonstrating 100% concordance to the reference method. From a total of 1,273 loci we were able to generate 1,241 (97.3%) initial successful typings. The mean ambiguity reduction for the analysed loci was 93.5%. Allele assignment including intronic sequences showed an improved resolution (99.2%) of non-expressed HLA alleles. Conclusion We provide a powerful HLA typing protocol offering a short turnaround time of only two days, a fully integrated workflow and most importantly a high degree of typing reliability. The presented automated assay is flexible and can be scaled by specific primer compilations and the use of different 454 sequencing systems. The workflow was successfully validated according to the policies of the European Federation for Immunogenetics. Next-generation sequencing seems to become one of the new methods in the field of Histocompatibility.
    BMC Genomics 04/2013; 14(1):221. DOI:10.1186/1471-2164-14-221 · 3.99 Impact Factor
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    • "Although calculated on a limited number of searches that include essentially patients of European ancestry, this is the first evaluation of the success rate of prospective DPB1 typing aiming at the identification of a 12/12 matched donor. If no DPB1-matched donor can be identified, donors can be selected according the T-cell epitope (TCE)3 matching algorithm [4]. "
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    ABSTRACT: In transplantation of hematopoietic stem cells (HSCs) from unrelated donors a high HLA compatibility level decreases the risk of acute graft-versus-host disease and mortality. The diversity of the HLA system at the allelic and haplotypic level and the heterogeneity of HLA typing data of the registered donors render the search process a complex task. This paper summarizes our experience with a search algorithm that includes at the start of the search a probability estimate (high/intermediate/low) to identify a HLA-A, B, C, DRB1, DQB1-compatible donor (a 10/10 match). Based on 2002-2011 searches about 30% of patients have a high, 30% an intermediate, and 40% a low probability search. Search success rate and duration are presented and discussed in light of the experience of other centers. Overall a 9-10/10 matched HSC donor can now be identified for 60-80% of patients of European descent. For high probability searches donors can be selected on the basis of DPB1-matching with an estimated success rate of >40%. For low probability searches there is no consensus on which HLA incompatibilities are more permissive, although HLA-DQB1 mismatches are generally considered as acceptable. Models for the discrimination of more detrimental mismatches based on specific amino acid residues rather than specific HLA alleles are presented.
    11/2012; 2012:695018. DOI:10.1155/2012/695018
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