2012年09月01日 訊 /生物谷BIOON/ --根據(jù)一項刊登在2012年8月30日那期New England Journal of Medicine期刊上的研究,，患有急性髓系白血病(acute myeloid leukemia, AML)的病人接受來自攜帶有活性的殺傷性細胞免疫球蛋白樣受體(killer-cell immunoglobulin-like receptor, KIR)基因型KIR2DS1的供者體內(nèi)的干細胞移植物之后，他們有較低的疾病復發(fā)率,，其中基因型KIR2DS1對人白細胞抗原-C2(human leukocyte antigen-C2, HLA-C2)擁有配體特異性。
來自美國紐約斯隆凱特靈紀念癌癥中心Memorial Sloan-Kettering Cancer Center的Jeffrey M. Venstrom博士和同事們回顧了1277名患有AML的病人在接受來自非親緣供者的異體造血干細胞移植物(allogeneic hematopoietic stem-cell transplant)之后的數(shù)據(jù),。他們進行KIR基因型分析和評估供者KIR基因型的臨床影響,。
研究人員發(fā)現(xiàn)對于接受來自攜帶基因型KIR2DS1的供者的干細胞移植的病人而言，他們的疾病復發(fā)率顯著性降低(危險比為0.76),。這種影響似乎是通過HLA-C來調(diào)節(jié)的,，對于來自攜帶純合性或雜合性HLA-C1抗原的供者的干細胞移植而言，它的保護性影響是顯著性(復發(fā)率為24.9%),，但是對于來自攜帶純合性HLA-C2抗原的供者的干細胞移植而言,，它的影響并不顯著(復發(fā)率為37.3%，危險比為0.46),。如果供者攜帶基因型KIR2DS1，那么對與單個HLA-C位點存在錯配的那些病人而言,，疾病復發(fā)率更加顯著性地下降(危險比為0.40),。與基因型KIR2DS1存在遺傳連鎖不平衡的基因型KIR3DS1與更加低的死亡率相關(guān)聯(lián)(危險比為0.83),。Venstrom和同事們作出結(jié)論,，“激活供者KIR基因與異體造血干細胞移植治療AML的不同治療結(jié)果相關(guān)聯(lián),。”(生物谷Bioon.com)
doi: 10.1056/NEJMoa1200503
PMC:
PMID:
HLA-C–Dependent Prevention of Leukemia Relapse by Donor Activating KIR2DS1
Jeffrey M. Venstrom, M.D., Gianfranco Pittari, M.D., Ted A. Gooley, Ph.D., Joseph H. Chewning, M.D., Stephen Spellman, M.S., Michael Haagenson, M.S., Meighan M. Gallagher, B.A., Mari Malkki, Ph.D., Effie Petersdorf, M.D., Bo Dupont, M.D., D.Sc., and Katharine C. Hsu, M.D., Ph.D.
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.) The views expressed in this article do not reflect the official policy or position of the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the U.S. government.
Supported in part by grants from the National Institutes of Health (U01 AI69197, KL2 RR024997, R01 HL088134, and P01 CA23766). The CIBMTR is supported by a Public Health Service grant/cooperative agreement from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (U24-CA76518); a grant/cooperative agreement from the NHLBI and NCI (5U01HL069294); a contract with the Health Resources and Services Administration (HHSH234200637015C); grants from the Office of Naval Research (N00014-10-1-0204 and N00014-1-1-0339); and funding from Allos Therapeutics, Amgen, Angioblast Systems, Ariad, Be the Match Foundation, Blue Cross and Blue Shield Association, Buchanan Family Foundation, CaridianBCT, Celgene, CellGenix, Children's Leukemia Research Association, Fresenius Biotech North America, Gamida Cell–Teva Joint Venture, Genentech, Genzyme, GlaxoSmithKline, Kiadis Pharma, the Leukemia and Lymphoma Society, the Medical College of Wisconsin, Millennium Pharmaceuticals, Milliman USA, Miltenyi Biotec, National Marrow Donor Program, OptumHealth Care Solutions, Otsuka America Pharmaceutical, Seattle Genetics, Sigma-Tau Pharmaceuticals, Soligenix, Swedish Orphan Biovitrum, Therakos, WellPoint, and an anonymous donation to the Medical College of Wisconsin.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Dr. Mary Horowitz for assistance in study design; Dr. Stephanie Lee for comments; and Ms. Clara Pinto, Ms. Reenat Hassan, Ms. Alice Yeh, and Ms. Zoe Harris for technical assistance.
