Ann Lab Med.  2015 Jan;35(1):111-117. 10.3343/alm.2015.35.1.111.

The Impact of HLA and KIR Ligand Mismatching on Unrelated Allogeneic Hematopoietic Stem Cell Transplantation in Korean Adult Patients

Affiliations
  • 1Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea. eysong1@snu.ac.kr
  • 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
  • 3Department of Laboratory Medicine, Seegene Medical Foundation, Seoul, Korea.

Abstract

BACKGROUND
The impact of HLA and KIR ligand mismatching on the outcome of hematopoietic stem cell transplantation (HSCT) remains unclear. Previous reports have identified considerable ethnic differences in the impact of HLA and KIR ligand mismatches, as well as KIR ligand status, on HSCT; however, to date, no data has been acquired in Korean adult patients.
METHODS
We investigated the association of high-resolution HLA matching on five loci (HLA-A, -B, -C, -DRB1, and -DQB1), KIR ligand mismatching, and KIR ligand status on the outcome of allogeneic HSCT from unrelated donors in 154 Korean adult patients treated at Seoul National University Hospital.
RESULTS
In a multivariate analysis, less than 9/10 allelic matches in five HLA loci was an independent risk factor for acute graft-versus-host disease (GVHD) (grade II to IV) (P=0.019, odds ratio [OR]=2.7). In addition, HLA-A allele mismatching was increasingly prevalent in patients with acute GVHD compared to patients without (61.9% vs. 34.5%, P=0.06). For KIR ligand status, the patient and donor combination of both C1/C1 ligands showed better event-free and overall survival than combinations with C2 ligand patients or donors (P=0.048, P=0.034, respectively) by log-rank test.
CONCLUSIONS
Korean adult transplant patients with less than 9 of 10 HLA allele matches in the HLA-A, -B, -C, -DRB1, and DQB1 loci have a higher likelihood of developing acute GVHD (grade II to IV). Impact of KIR ligand status on clinical outcome should be further studied in a larger patient population.

Keyword

HLA; KIR ligand; Mismatch; Hematopoietic stem cell transplantation

MeSH Terms

Adolescent
Adult
Alleles
Female
Genetic Loci
Graft vs Host Disease/etiology
HLA Antigens/*genetics/metabolism
*Hematopoietic Stem Cell Transplantation/adverse effects/standards
Histocompatibility Testing
Humans
Kaplan-Meier Estimate
Leukemia/mortality/therapy
Male
Middle Aged
Multivariate Analysis
Receptors, KIR/*chemistry/metabolism
Republic of Korea
Risk Factors
Transplantation, Homologous
Young Adult
HLA Antigens
Receptors, KIR

Figure

  • Fig. 1 Kaplan-Meier analysis of event-free and overall survival according to KIR ligand mismatch and ligand status following unrelated hematopoietic stem cell transplantation (HSCT) in Koreans. (A) Event-free survival in recipients with KIR ligand match (n=149) vs. KIR ligand mismatch (n=5), (B) Event-free survival in recipient-donor combination of both with C1/C1 (n=103) vs. recipients with C1/C2 or C2/C2 and donors with C1/C2 or C2/C2 (n=51), (C) Event-free survival in recipient with Bw4/Bw4 (n=28) vs. Bw4/Bw6 or Bw6/Bw6 (n=126), (D) overall survival in recipients with KIR ligand match (n=149) vs. KIR ligand mismatch (n=5), (E) overall survival in recipient-donor combination of both with C1/C1 (n=103) vs. recipients with C1/C2 or C2/C2 and donors with C1/C2 or C2/C2 (n=51), and (F) overall survival in recipient with Bw4/Bw4 (n=28) vs. Bw4/Bw6 or Bw6/Bw6 (n=126).Abbreviation: Rec, recipient.


Reference

1. Perez LE. Outcomes from unrelated donor hematopoietic stem cell transplantation. Cancer Control. 2011; 18:216–221. PMID: 21976240.
Article
2. Shaw BE, Arguello R, Garcia-Sepulveda CA, Madrigal JA. The impact of HLA genotyping on survival following unrelated donor haematopoietic stem cell transplantation. Br J Haematol. 2010; 150:251–258. PMID: 20560963.
Article
3. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002; 295:2097–2100. PMID: 11896281.
Article
4. Malmberg KJ, Schaffer M, Ringdén O, Remberger M, Ljunggren HG. KIR-ligand mismatch in allogeneic hematopoietic stem cell transplantation. MolImmunol. 2005; 42:531–534.
Article
5. Ruggeri L, Mancusi A, Burchielli E, Aversa F, Martelli MF, Velardi A. Natural killer cell alloreactivity in allogeneic hematopoietic transplantation. Curr Opin Oncol. 2007; 19:142–147. PMID: 17272987.
Article
6. Petersdorf EW, Gooley T, Malkki M, Horowitz M. International Histocompatibility Working Group in Hematopoietic Cell Transplantation. Clinical significance of donor-recipient HLA matching on survival after myeloablative hematopoietic cell transplantation from unrelated donors. Tissue Antigens. 2007; 69(S1):25–30. PMID: 17445158.
Article
7. Morishima Y, Kawase T, Malkki M, Petersdorf EW. International Histocompatibility Working Group in Hematopoietic Cell Transplantation Component. Effect of HLA-A2 allele disparity on clinical outcome in hematopoietic cell transplantation from unrelated donors. Tissue Antigens. 2007; 69(S1):31–35. PMID: 17445159.
Article
8. Lee KW, Oh DH, Lee C, Yang SY. Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population. Tissue Antigens. 2005; 65:437–447. PMID: 15853898.
Article
9. Yang JH, Sohn YH, Ko SY, Choi SE, Kim MH, Oh HB. Anthropological analysis of Koreans using HLA class II diversity among East Asians. Tissue Antigens. 2010; 76:282–288. PMID: 20522202.
Article
10. Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood. 2002; 100:1935–1947. PMID: 12200350.
Article
11. 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. PMID: 12689936.
Article
12. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974; 18:295–304. PMID: 4153799.
Article
13. Gratwohl A. The EBMT risk score. Bone Marrow Transplant. 2012; 47:749–756. PMID: 21643021.
Article
14. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K, 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. 2002; 99:4200–4206. PMID: 12010826.
Article
15. Kawase T, Morishima Y, Matsuo K, Kashiwase K, Inoko H, Saji H, et al. High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. Blood. 2007; 110:2235–2241. PMID: 17554059.
Article
16. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007; 110:4576–4583. PMID: 17785583.
Article
17. Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon JD, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006; 12:828–836. PMID: 16864053.
Article
18. Giebel S, Locatelli F, Wojnar J, Velardi A, Mina T, Giorgiani G, et al. Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation. Br J Haematol. 2005; 131:483–486. PMID: 16281939.
Article
19. Fischer JC, Ottinger H, Ferencik S, Sribar M, Punzel M, Beelen DW, et al. Relevance of C1 and C2 epitopes for hemopoietic stem cell transplantation: role for sequential acquisition of HLA-C-specific inhibitory killer Ig-like receptor. J Immunol. 2007; 178:3918–3923. PMID: 17339492.
Article
20. Fischer JC, Kobbe G, Enczmann J, Haas R, Uhrberg M. The impact of HLA-C matching depends on the C1/C2 KIR ligand status in unrelated hematopoietic stem cell transplantation. Immunogenetics. 2012; 64:879–885. PMID: 22923051.
Article
21. Ludajic K, Balavarca Y, Bickeböller H, Rosenmayr A, Fae I, Fischer GF, et al. KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation. Bone Marrow Transplant. 2009; 44:97–103. PMID: 19169284.
Article
22. Gagne K, Busson M, Bignon JD, Balère-Appert ML, Loiseau P, Dormoy A, et al. Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009; 15:1366–1375. PMID: 19822295.
Article
23. Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL, et al. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT. Blood. 2007; 109:5058–5061. PMID: 17317850.
Article
24. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA, 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. Biol Blood Marrow Transplant. 2006; 12:876–884. PMID: 16864058.
Article
25. Willemze R, Ruggeri A, Purtill D, Rodrigues CA, Gluckman E, Rocha V, et al. Is there an impact of killer cell immunoglobulin-like receptors and KIR-ligand incompatibilities on outcomes after unrelated cord blood stem cell transplantation? Best Pract Res Clin Haematol. 2010; 23:283–290. PMID: 20837340.
Article
26. Hollenbach JA, Augusto DG, Alaez C, Bubnova L, Fae I, Fischer G, et al. 16(th) IHIW: population global distribution of killer immunoglobulin-like receptor (KIR) and ligands. Int J Immunogenet. 2013; 40:39–45. PMID: 23280119.
27. Shilling HG, Young N, Guethlein LA, Cheng NW, Gardiner CM, Tyan D, et al. Genetic control of human NK cell repertoire. J Immunol. 2002; 169:239–247. PMID: 12077250.
Article
28. Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N, et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood. 2005; 105:4135–4142. PMID: 15687235.
Article
29. Stern M, de Angelis C, Urbani E, Mancusi A, Aversa F, Velardi A, et al. Natural killer-cell KIR repertoire reconstitution after haploidentical SCT. Bone Marrow Transplant. 2010; 45:1607–1610. PMID: 20173785.
Article
30. Parham P. Immunology.NK cells lose their inhibition. Science. 2004; 305:786–787. PMID: 15297654.
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