The selection of hematopoietic stem cell transplantation (HSCT) donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA) match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR) genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection. 1. Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) has been established as a mode of curative therapy for hematologic malignancies and other hematologic or immune disorders. Hematopoietic stem cell donor selection has been almost exclusively based on selecting an human leukocyte antigen (HLA) identical donor or near-identical donor; however, not all patients are able to find a suitable donor. Advances in HLA testing and matching and understanding donor selection factors are therefore important to improve outcomes of unrelated donor (UD) HSCT. HLAs can elicit an immune response either by presentation of variable peptides or by recognition of polymorphic fragments of foreign HLA molecules. HLA disparity has been associated with graft failure, delayed immune reconstitution, graft-versus-host disease (GVHD), and mortality. Since many patients lack HLA-matched donors, current research is focused on the identifying permissible HLA mismatches. Recently, extensive research has accumulated evidence on the role of each HLA locus mismatch on clinical outcome for UD HSCT, making it easy to search for and select a partially matched donor [1, 2]. In this paper, we will focus on the current understanding of HLA typing and its clinical implications on UD HSCT. 2. HLA Typing HLA class I and II loci are the most polymorphic genes in the human genome, with a highly clustered and patchwork pattern of sequence motifs [3]. Each individual carries 10 to 12 genes that encode the HLA-A, -B, -C, -DR, -DQ, and -DP. Most of these genes are highly polymorphic, ranging from 13 (HLA-DRB4) to 699 (HLA-B) alleles per locus [4]. Extensive allelic diversity has made, and continues to make, high-resolution HLA-DNA typing very challenging. Over the past three decades, the
References
[1]
T. Kawase, Y. Morishima, K. Matsuo et al., “High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism,” Blood, vol. 110, no. 7, pp. 2235–2241, 2007.
[2]
S. J. Lee, J. Klein, M. Haagenson et al., “High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation,” Blood, vol. 110, no. 13, pp. 4576–4583, 2007.
[3]
H. Erlich, “HLA DNA typing: past, present, and future,” Tissue Antigens, vol. 80, no. 1, pp. 1–11, 2012.
[4]
S. G. E. Marsh, E. D. Albert, W. F. Bodmer et al., “Nomenclature for factors of the HLA system, 2004,” Tissue Antigens, vol. 65, no. 4, pp. 301–369, 2005.
[5]
P. Parham, “Histocompatibility typing—Mac is back in town,” Immunology Today, vol. 9, no. 5, pp. 127–130, 1988.
[6]
J. R. Argüello and J. A. Madrigal, “HLA typing by Reference Strand Mediated Conformation Analysis (RSCA),” Reviews in immunogenetics, vol. 1, no. 2, pp. 209–219, 1999.
[7]
J. R. Argüellol, A. M. Little, A. L. Pay et al., “Mutation detection and typing of polymorphic loci through double-strand conformation analysis,” Nature Genetics, vol. 18, no. 2, pp. 192–194, 1998.
[8]
B. E. Shaw, R. Arguello, C. A. Garcia-Sepulveda, and J. A. Madrigal, “The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation,” British Journal of Haematology, vol. 150, no. 3, pp. 251–258, 2010.
[9]
I. Yakoub-Agha, F. Mesnil, M. Kuentz et al., “Allogeneic marrow stem-cell transplantation from human leukocyte antigen-identical siblings versus human leukocyte antigen-allelic-matched unrelated donors (10/10) in patients with standard-risk hematologic malignancy: a prospective study from the French society of bone marrow transplantation and cell therapy,” Journal of Clinical Oncology, vol. 24, no. 36, pp. 5695–5702, 2006.
[10]
Y. Morishima, T. Sasazuki, H. Inoko et al., “The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors,” Blood, vol. 99, no. 11, pp. 4200–4206, 2002.
[11]
M. Park, K. N. Koh, B. E. Kim et al., “The impact of HLA matching on unrelated donor hematopoietic stem cell transplantation in Korean children,” Korean Journal of Hematology, vol. 46, no. 1, pp. 11–17, 2011.
[12]
E. W. Petersdorf, J. A. Hansen, P. J. Martin et al., “Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation,” New England Journal of Medicine, vol. 345, no. 25, pp. 1794–1800, 2001.
[13]
E. W. Petersdorf, T. A. Gooley, C. Anasetti et al., “Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient,” Blood, vol. 92, no. 10, pp. 3515–3520, 1998.
[14]
N. Flomenberg, L. A. Baxter-Lowe, D. Confer et al., “Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome,” Blood, vol. 104, no. 7, pp. 1923–1930, 2004.
[15]
T. Sasazuki, T. Juji, Y. Morishima et al., “Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor,” New England Journal of Medicine, vol. 339, no. 17, pp. 1177–1185, 1998.
[16]
E. W. Petersdorf, C. Kollman, C. K. Hurley et al., “Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program experience,” Blood, vol. 98, no. 10, pp. 2922–2929, 2001.
[17]
E. W. Petersdorf, T. Gooley, M. Malkki, and M. Horowitz, “Clinical significance of donor-recipient HLA matching on survival after myeloablative hematopoietic cell transplantation from unrelated donors,” Tissue Antigens, vol. 69, supplement 1, pp. 25–30, 2007.
[18]
Y. Morishima, T. Kawase, M. Malkki, and E. W. Petersdorf, “Effect of HLA-A2 allele disparity on clinical outcome in hematopoietic cell transplantation from unrelated donors,” Tissue Antigens, vol. 69, supplement 1, pp. 31–35, 2007.
[19]
K. Fleischhauer, E. Zino, B. Mazzi et al., “Peripheral blood stem cell allograft rejection mediated by CD4+ T lymphocytes recognizing a single mismatch at HLA-DPβ1*0901,” Blood, vol. 98, no. 4, pp. 1122–1126, 2001.
[20]
E. Zino, G. Frumento, S. Marktel et al., “A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation,” Blood, vol. 103, no. 4, pp. 1417–1424, 2004.
[21]
R. Crocchiolo, E. Zino, L. Vago et al., “Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation,” Blood, vol. 114, no. 7, pp. 1437–1444, 2009.
[22]
E. W. Petersdorf, T. Gooley, M. Malkki et al., “The biological significance of HLA-DP gene variation in haematopoietic cell transplantation,” British Journal of Haematology, vol. 112, no. 4, pp. 988–994, 2001.
[23]
D. Gallardo, S. Brunet, A. Torres et al., “HLA-DPB1 mismatch in HLA-A-B-DRB1 identical sibling donor stem cell transplantation and acute graft-versus-host disease,” Transplantation, vol. 77, no. 7, pp. 1107–1110, 2004.
[24]
M. Schaffer, A. Aldener-Cannavá, M. Remberger, O. Ringdén, and O. Olerup, “Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation,” Tissue Antigens, vol. 62, no. 3, pp. 243–250, 2003.
[25]
E. W. Petersdorf, C. Anasetti, P. J. Martin et al., “Limits of HLA mismatching in unrelated hematopoietic cell transplantation,” Blood, vol. 104, no. 9, pp. 2976–2980, 2004.
[26]
H. T. Greinix, I. Faé, B. Schneider et al., “Impact of HLA class I high-resolution mismatches on chronic graft-versus-host disease and survival of patients given hematopoietic stem cell grafts from unrelated donors,” Bone Marrow Transplantation, vol. 35, no. 1, pp. 57–62, 2005.
[27]
C. Liao, J. Y. Wu, Z. P. Xu et al., “Indiscernible benefit of high-resolution HLA typing in improving long-term clinical outcome of unrelated umbilical cord blood transplant,” Bone Marrow Transplantation, vol. 40, no. 3, pp. 201–208, 2007.
[28]
M. B. A. Heemskerk, J. J. Cornelissen, D. L. Roelen et al., “Highly diverged MHC class I mismatches are acceptable for haematopoietic stem cell transplantation,” Bone Marrow Transplantation, vol. 40, no. 3, pp. 193–200, 2007.
[29]
G. B. Ferrara, A. Bacigalupo, T. Lamparelli et al., “Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain,” Blood, vol. 98, no. 10, pp. 3150–3155, 2001.
[30]
T. Teshima, K. Matsuo, K. Matsue et al., “Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors,” British Journal of Haematology, vol. 130, no. 4, pp. 575–587, 2005.
[31]
B. E. Shaw, N. H. Russell, S. Devereux et al., “The impact of donor factors on primary non-engraftment in recipients of reduced intensity conditioned transplants from unrelated donors,” Haematologica, vol. 90, no. 11, pp. 1562–1569, 2005.
[32]
A. J. Mead, K. J. Thomson, E. C. Morris et al., “HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning,” Blood, vol. 115, no. 25, pp. 5147–5153, 2010.
[33]
R. Crocchiolo, F. Ciceri, K. Fleischhauer et al., “HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: a study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry,” Bone Marrow Transplantation, vol. 44, no. 9, pp. 571–577, 2009.
[34]
F. H. Claas, “Clinical relevance of circulating donor-specific HLA antibodies,” Current Opinion in Organ Transplantation, vol. 15, no. 4, pp. 462–466, 2010.
[35]
C. Lefaucheur, C. Suberbielle-Boissel, G. S. Hill et al., “Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation,” Contributions to Nephrology, vol. 162, pp. 1–12, 2009.
[36]
E. M. Van Den Berg-Loonen, E. V. A. Billen, C. E. M. Voorter et al., “Clinical relevance of pretransplant donor-directed antibodies detected by single antigen beads in highly sensitized renal transplant patients,” Transplantation, vol. 85, no. 8, pp. 1086–1090, 2008.
[37]
R. Storb, “B cells versus T cells as primary barrier to hematopoietic engraftment in allosensitized recipients,” Blood, vol. 113, no. 5, p. 1205, 2009.
[38]
M. Gabbianelli, G. Boccoli, S. Petti et al., “Expression and in-vitro modulation of HLA antigens in ontogenic development of human hemopoietic system,” Annals of the New York Academy of Sciences, vol. 511, pp. 138–147, 1987.
[39]
P. I. Terasaki, M. R. Mickey, D. P. Singal, K. K. Mittal, and R. Patel, “Serotyping for homotransplantation. XX. Selection of recipients for cadaver donor transplants,” New England Journal of Medicine, vol. 279, no. 20, pp. 1101–1103, 1968.
[40]
S. Spellman, R. Bray, S. Rosen-Bronson et al., “The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure,” Blood, vol. 115, no. 13, pp. 2704–2708, 2010.
[41]
S. O. Ciurea, M. De Lima, P. Cano et al., “High risk of graft failure in patients with anti-hla antibodies undergoing haploidentical stem-cell transplantation,” Transplantation, vol. 88, no. 8, pp. 1019–1024, 2009.
[42]
D. Focosi, A. Zucca, and F. Scatena, “The role of anti-HLA antibodies in hematopoietic stem cell transplantation,” Biology of Blood and Marrow Transplantation, vol. 17, no. 11, pp. 1585–1588, 2011.
[43]
L. Moretta and A. Moretta, “Killer immunoglobulin-like receptors,” Current Opinion in Immunology, vol. 16, no. 5, pp. 626–633, 2004.
[44]
P. Parham, “MHC class I molecules and KIRS in human history, health and survival,” Nature Reviews Immunology, vol. 5, no. 3, pp. 201–214, 2005.
[45]
M. A. Cook, D. W. Milligan, C. D. Fegan et al., “The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia,” Blood, vol. 103, no. 4, pp. 1521–1526, 2004.
[46]
E. J. Lowe, V. Turner, R. Handgretinger et al., “T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation,” British Journal of Haematology, vol. 123, no. 2, pp. 323–326, 2003.
[47]
S. S. Farag, A. Bacigalupo, M. Eapen et al., “The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry,” Biology of Blood and Marrow Transplantation, vol. 12, no. 8, pp. 876–884, 2006.
[48]
S. Giebel, F. Locatelli, T. Lamparelli et al., “Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors,” Blood, vol. 102, no. 3, pp. 814–819, 2003.
[49]
S. Cooley, E. Trachtenberg, T. L. Bergemann et al., “Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia,” Blood, vol. 113, no. 3, pp. 726–732, 2009.
[50]
S. Cooley, D. J. Weisdorf, L. A. Guethlein et al., “Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia,” Blood, vol. 116, no. 14, pp. 2411–2419, 2010.
[51]
L. Ruggeri, M. Capanni, E. Urbani et al., “Effectiveness of donor natural killer cell aloreactivity in mismatched hematopoietic transplants,” Science, vol. 295, no. 5562, pp. 2097–2100, 2002.
[52]
J. Clausen, D. Wolf, A. L. Petzer et al., “Impact of natural killer cell dose and donor killer-cell immunoglobulin-like receptor (KIR) genotype on outcome following human leucocyte antigen-identical haematopoietic stem cell transplantation,” Clinical and Experimental Immunology, vol. 148, no. 3, pp. 520–528, 2007.
[53]
R. Willemze, C. A. Rodrigues, M. Labopin et al., “KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia,” Leukemia, vol. 23, no. 3, pp. 492–500, 2009.
[54]
H. J. Pegram, D. S. Ritchie, M. J. Smyth et al., “Alloreactive natural killer cells in hematopoietic stem cell transplantation,” Leukemia Research, vol. 35, no. 1, pp. 14–21, 2011.
