HLA-C–Dependent Prevention of Leukemia Relapse
by Donor Activating KIR2DS1
KIR2DS1が活性化しているドナーによるHLA-C依存的な白血病再発予防
J. M. Venstorm et al. N Engl J Med 2012; 367:805-816 August 30, 2012
非常に興味深いお話です。ですが、どうやら、私には論文を悠長に読んで補足解説を加えている暇はないようです。よって、原文を丸ごと掲載いたします。いつか加筆するかもしれませんし、加筆しないかもしれません。私としては、研究仲間の悪友に日本語訳とreferenceも付けた解説を書いていただきたいのですが。←よろしく。
造血幹細胞移植(HSCT)は、造血器腫瘍・固形腫瘍(神経芽腫など)・再生不良性貧血・原発性免疫不全症の治療法として確立されています。悪性腫瘍を駆逐するには、どうしたらよいか。GVHDが起こった症例ではGVL効果も認めやすいということは…。この論文のキーとなる発想は、『NK細胞の特性を活かす』、これだと思います。
Background Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)–cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT.
Methods We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes.
Results Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01).
Conclusions Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C–dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.)