Korean J Hematol.  2006 Sep;41(3):139-148. 10.5045/kjh.2006.41.3.139.

Killer Cell Immunoglobulin-like Receptor (KIR) Analysis in Adult Korean Patients with Acute Myeloid Leukemia

• Kim HJ
• Choi Y
• Jeong HY
• Min WS
• Kim CC
• Kim TG

• KMID: 2252294
• DOI: http://doi.org/10.5045/kjh.2006.41.3.139

Abstract

BACKGROUND: The prevalent natural killer (NK) cells induce alloreaction against leukemic cells during post-transplant. NK cell alloreactivity depends on the compatibility of killer cell immunoglobulin-like receptors (KIR) epitopes for graft-versus-host disease. Genotypic expressions of inhibitory or activating KIR in patients with acute myelogenous leukemia (AML) and their HLA-matched sibling donors, as a model for Korean KIR haplotype diversity and NK alloreactivity, were investigated.
METHODS
Ninety-two patients in complete remission and their 76 HLA-matched sibling donors were enrolled in this study. All the patients were scheduled to receive allogeneic hematopoietic stem cell transplantations (HSCT). KIR PCR-SSP typing was performed for 19 different kinds of KIR genes and pseudogenes. The PCR data representing the KIR genotypes from both the patients and donors were compared.
RESULTS
We found 43 Korean KIR haplotypes. Thirty-three variable haplotypes for the AML patients, in addition to 25 haplotypes for the normal HSCT donors, were demonstrated. Of note, the expressions of specific genes such as 2DL2 (P=0.026), 2DS2 (P=0.042), and 2DS4 (P=0.037) revealed remarkable differences between the patients and the normal donors. Korean HLA-identical sibling pairs showed 38% KIR matches in terms of the gene content and allelic polymorphism. Although the KIR gene content was the same between the patients and the donors, 40% of those matched pairs of patients and donors showed allelic polymorphism, specifically in the context of 2DL5 and 2DS4 genes.
CONCLUSION
These results indicate that the expressions of donor inhibitory and activating repertoire of KIR genotypes, even in the HLA-matched sibling setting, are unique parameters to be considered when we perform allogeneic sibling HSCT.

Keyword

NK cells alloreactivity; KIR; HSCT; Korean AML; Haplotype

MeSH Terms

Adult*
Epitopes
Genotype
Graft vs Host Disease
Haplotypes
Hematopoietic Stem Cells
Humans
Killer Cells, Natural
Leukemia, Myeloid, Acute*
Polymerase Chain Reaction
Pseudogenes
Receptors, KIR*
Siblings
Tissue Donors
Epitopes
Receptors, KIR

Figure

• 

  Fig. 1 KIR genotyping by PCR-SSP in a specific AML patient. Details are described in ‘Materials and Methods’. 1, 2DL1; 2, 2DL2; 3, 2DL3; 4, 2DL4; 5, 2DL5A; 6, 2DL5B∗002/004; 7, 2DL5B∗003; 8, 2DS1; 9, 2DS2; 10, 2DS3; 11, 2DS4∗ 00101/00102/002; 12, 2 DS4∗003; 13, 2DS5; 14, 3DL1; 15, 3DL2; 16, 3DL3; 17, 3DS1; 18, 2DP1; 19, 3DP1∗001/001; 20, 3DP1∗00301/00302; 21, negative control; M, marker.

Reference

1). Ruggeri L., Capanni M., Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002. 295:2097–100.

2). Parham P., McQeen KL. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nat Rev Immunol. 2003. 3:108–22.

3). Godfrey DI., MacDonald HR., Kronenberg M., Smyth MJ., Van Kaer L. NKT cells: what's in a name? Nat Rev Immunol. 2004. 4:231–7.

4). Degli-Esposti MA., Smyth MJ. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol. 2005. 5:112–24.

5). 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. 100:1935–47.

6). Ljunggren HG., Karre K. In search of the ‘missing self': MHC molecules and NK cell recognition. Immunol Today. 1990. 11:237–44.

7). Gagne K., Brizard G., Gueglio B, et al. Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol. 2002. 63:271–80.

8). Aversa F., Tabilio A., Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998. 339:1186–93.

9). Hsu KC., Chida S., Geraghty DE., Dupont B. The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism. Immunol Rev. 2002. 190:40–52.

10). Kim HJ., Min WS., Kim YJ., Kim DW., Lee JW., Kim CC. Haplotype mismatched transplantation using high doses of peripheral blood CD34+ cells together with stratified conditioning regimens for high-risk adult acute myeloid leukemia patients: a pilot study in a single Korean institution. Bone Marrow Transplant. 2005. 35:959–64.

11). Verheyden S., Schots R., Duquet W., Demanet C. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation. Leukemia. 2005. 19:1446–51.

12). Cook MA., Milligan DW., Fegan CD, 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. 2004. 103:1521–6.