Abstract
A fully major histocompatilbility complex (MHC) matched donor is not available for the majority of patients in need of a haematopoietic stem cell transplantation (SCT), which illustrates the need for a tool to define acceptable MHC disparities. Previously, we noticed that a variety of single MHC class I mismatched allogeneic donor–recipient pairs did not elicit an allogeneic cytotoxic-lymphocyte (CTL) response in vitro if the MHC amino-acid sequences had five or more differences in the α-helices plus five or more differences in the β-sheet (⩾5α5β) (7). To address the clinical relevance of this observation, we analysed CTL precursor (CTLp) assay outcome and SCT outcome in 53 Dutch recipients of a single MHC class I mismatched graft from an unrelated donor. Overall patient survival was 44% after 4 years. In multivariate analysis, recipients of a ⩾5α5β mismatched graft with negative CTLp frequencies in vitro before transplantation demonstrated superior survival: survival at 4 years was 80% as compared to 47% in recipients of other mismatched grafts with negative CTLp frequencies (hazard ratio=0.131; 95% CI=(0.03–0.61); P=0.009). This option of acceptable mismatches may enlarge the pool of potentially acceptable stem cell donors.
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References
Dini G, Lanino E, Lamparelli T, Barbanti M, Sacchi N, Carcassi C et al. Unrelated donor marrow transplantation: initial experience of the Italian bone marrow transplant group (GITMO). Bone Marrow Transplant 1996; 17: 55–62.
O'Shea J, Cleaver S, Little AM, Madrigal A . Searching for an unrelated haemopoietic stem cell donor – a United Kingdom perspective. Clin Transplant 1999, 129–137.
Barker JN, Krepski TP, DeFor TE, Davies SM, Wagner JE, Weisdorf DJ . Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant 2002; 8: 257–260.
Heemskerk MB, van Walraven SM, Cornelissen JJ, Barge RM, Bredius RG, Egeler RM et al. How to improve the search for an unrelated haematopoietic stem cell donor. Faster is better than more! Bone Marrow Transplant 2005; 35: 645–652.
Petersdorf EW . HLA matching in allogeneic stem cell transplantation. Curr Opin Hematol 2004; 11: 386–391.
Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M 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 2004; 104: 1923–1930.
Heemskerk MB, Roelen DL, Dankers MK, van Rood JJ, Claas FH, Doxiadis II et al. Allogeneic MHC class I molecules with numerous sequence differences do not elicit a CTL response. Hum Immunol 2005; 66: 969–976.
Sharrock CE, Kaminski E, Man S . Limiting dilution analysis of human T cells: a useful clinical tool. Immunol Today 1990; 11: 281–286.
Spencer A, Brookes PA, Kaminski E, Hows JM, Szydlo RM, van Rhee F et al. Cytotoxic T lymphocyte precursor frequency analyses in bone marrow transplantation with volunteer unrelated donors. Value in donor selection. Transplantation 1995; 59: 1302–1308.
Speiser DE, Loliger CC, Siren MK, Jeannet M . Pretransplant cytotoxic donor T-cell activity specific to patient HLA class I antigens correlating with mortality after unrelated BMT. Br J Haematol 1996; 93: 935–939.
Keever-Taylor CA, Passweg J, Kawanishi Y, Casper J, Flomenberg N, Baxter-Lowe LA . Association of donor-derived host-reactive cytolytic and helper T cells with outcome following alternative donor T cell-depleted bone marrow transplantation. Bone Marrow Transplant 1997; 19: 1001–1009.
van der MA, Joosten I, Schattenberg AV, de Witte TJ, Allebes WA . Cytotoxic T-lymphocyte precursor frequency (CTLp-f) as a tool for distinguishing permissible from non-permissible class I mismatches in T-cell-depleted allogeneic bone marrow transplantation. Br J Haematol 2000; 111: 685–694.
Dolezalova L, Vrana M, Dobrovolna M, Loudova M, Cukrova V, Vitek A et al. Cytotoxic T lymphocyte precursor frequency analysis in the selection of HLA matched unrelated donors for hematopoietic stem cell transplantation: the correlation of CTLp frequency with HLA class I genotyping and aGVHD development. Neoplasma 2002; 49: 26–32.
Davis MM, Bjorkman PJ . T-cell antigen receptor genes and T-cell recognition. Nature 1988; 334: 395–402.
Alam SM, Travers PJ, Wung JL, Nasholds W, Redpath S, Jameson SC et al. T-cell-receptor affinity and thymocyte positive selection. Nature 1996; 381: 616–620.
Zerrahn J, Held W, Raulet DH . The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 1997; 88: 627–636.
Goldrath AW, Bevan MJ . Selecting and maintaining a diverse T-cell repertoire. Nature 1999; 402: 255–262.
Sherman LA, Morgan DJ, Nugent CT, Hernandez FJ, Kreuwel HT, Murtaza A et al. Self-tolerance and the composition of T cell repertoire. Immunol Res 2000; 21: 305–313.
de Bueger M, Bakker A, van Rood JJ, Van der WF, Goulmy E . Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J Immunol 1992; 149: 1788–1794.
Oudshoorn M, Doxiadis II, van den Berg-Loonen PM, Voorter CE, Verduyn W, Claas FH . Functional versus structural matching: can the CTLp test be replaced by HLA allele typing? Hum Immunol 2002; 63: 176–184.
Zhang L, Li SG, Vandekerckhove B, Termijtelen A, van Rood JJ, Claas FH . Analysis of cytotoxic T cell precursor frequencies directed against individual HLA-A and -B alloantigens. J Immunol Methods 1989; 121: 39–45.
Taswell C . Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol 1981; 126: 1614–1619.
Taswell C . Limiting dilution assays for the determination of immunocompetent cell frequencies. III. Validity tests for the single-hit Poisson model. J Immunol Methods 1984; 72: 29–40.
Strijbosch LW, Buurman WA, Does RJ, Zinken PH, Groenewegen G . Limiting dilution assays. Experimental design and statistical analysis. J Immunol Methods 1987; 97: 133–140.
Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.
Sullivan M . Graft-versus-host-disease. In: Thomas ED, Blume KG, Forman SJ (eds). Bone Marrow Transplantation. Blackwell Scientific Publications: Cambridge, USA, 1994, pp 339–362.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.
Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med 2001; 345: 1794–1800.
Ferrara GB, Bacigalupo A, Lamparelli T, Lanino E, Delfino L, Morabito A 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 2001; 98: 3150–3155.
Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R et al. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med 1993; 178: 597–604.
van der Meer A, Allebes WA, Paardekooper J, Ruiter J, Joosten I . HLA-C mismatches induce strong cytotoxic T-cell reactivity in the presence of an additional DRB/DQB mismatch and affect NK cell-mediated alloreactivity. Transplantation 2001; 72: 923–929.
Colonna M, Borsellino G, Falco M, Ferrara GB, Strominger JL . HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proc Natl Acad Sci USA 1993; 90: 12000–12004.
Mandelboim O, Reyburn HT, Vales-Gomez M, Pazmany L, Colonna M, Borsellino G et al. Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules. J Exp Med 1996; 184: 913–922.
Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood 2002; 100: 3825–3827.
Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003; 102: 814–819.
Lowe EJ, Turner V, Handgretinger R, Horwitz EM, Benaim E, Hale GA et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol 2003; 123: 323–326.
Bornhauser M, Schwerdtfeger R, Martin H, Frank KH, Theuser C, Ehninger G . Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood 2004; 103: 2860–2861.
de Santis D, Bishara A, Witt CS, Nagler A, Brautbar C, Slavin S et al. Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants. Tissue Antigens 2005; 65: 519–528.
Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 2005; 105: 2594–2600.
Ruggeri L, Capanni M, Mancusi A, Martelli MF, Velardi A . The impact of donor natural killer cell alloreactivity on allogeneic hematopoietic transplantation. Transplant Immunol 2005; 14: 203–206.
Davies SM, Kollman C, Anasetti C, Antin JH, Gajewski J, Casper JT et al. Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the National Marrow Donor Program. Blood 2000; 96: 4096–4102.
Castro-Malaspina H, Harris RE, Gajewski J, Ramsay N, Collins R, Dharan B et al. Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 2002; 99: 1943–1951.
Boeckh M, Nichols WG . The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 2004; 103: 2003–2008.
Randolph SS, Gooley TA, Warren EH, Appelbaum FR, Riddell SR . Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004; 103: 347–352.
Gordon RD, Simpson E, Samelson LE . In vitro cell-mediated immune responses to the male specific(H-Y) antigen in mice. J Exp Med 1975; 142: 1108–1120.
den Haan JM, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995; 268: 1476–1480.
Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–285.
Dickinson AM, Wang XN, Sviland L, Vyth-Dreese FA, Jackson GH, Schumacher TN et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nat Med 2002; 8: 410–414.
Acknowledgements
We thank the technologists of the HLA typing laboratory and the laboratory for cellular histocompatibility testing of the Leiden University Medical Center.
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Heemskerk, M., Cornelissen, J., Roelen, D. et al. Highly diverged MHC class I mismatches are acceptable for haematopoietic stem cell transplantation. Bone Marrow Transplant 40, 193–200 (2007). https://doi.org/10.1038/sj.bmt.1705721
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DOI: https://doi.org/10.1038/sj.bmt.1705721
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