非人類白血球抗原(non-HLA)基因多型性對於
HLA相容之造血幹細胞移植的影響

造血幹細胞移植(hematopoietic stem cell transplantation, HSCT)用以治療多種良性及惡性血液疾病與先天性免疫缺乏疾病。然而在HLA相容的異體移植中，仍有20-40%病人會發生移植體抗宿主疾病(graft-versus-host disease, GVHD)，顯示非HLA基因(non-HLA)的多型性對於移植後的臨床結果有所影響。本論文從兩方面探討non-HLA基因多型性對HSCT的影響：(1)捐贈者和病人次要組織相容性抗原(minor histocompatibility antigen, mHag) HA-1及HA-2的不相容；(2)T細胞調控基因CTLA-4及ICOS的基因多型性。為排除HLA的影響，總計收集123對帶有HLA-A2及/或HLA-B60之HLA-matched sibling HSCT病人及捐贈者的DNA檢體，利用DNA定序法做HLA-A2基因型鑑定，及聚合酶連鎖反應加上限制酶片段長度多型性(polymerase chain reaction- restriction fragment length polymorphism) 方法鑑定HA-1、HA-2、CTLA-4 -318C/T、CTLA-4 +49A/G、ICOS c.602及ICOS c.1624的基因型。並將病人和捐贈者的基因型與移植後的臨床結果，包括：急性GVHD、慢性GVHD、疾病復發、無疾病存活(disease-free survival)和總存活(overall survival)，進行單變項及多變項統計分析。結果發現：HA-1不相容對於移植後急性和慢性GVHD、復發、disease-free survival和overall survival的臨床結果皆無顯著影響。另外，在HLA-A*0201+的病人與捐贈者間未發現HA-2不相容，同時在306例對照組中亦未發現非免疫性(non-immunogenic)的HA-2M/M基因型者，顯示HA-2不相容在臺灣對於評估HSCT臨床結果可能不重要。另一方面，在多變項分析中顯示：捐贈者的CTLA-4 -318T allele，會使病人發生急性GVHD的可能性增加(P=0.0133; OR=3.25; 95% CI, 1.28-8.26)，尤其捐贈者為CTLA-4 -318T/T基因型時，其病人復發率會增加(P =0.0313; HR=5.91; 95% CI, 1.17-29.79)。再者，捐贈者為ICOS c.602C/C基因型時，對於病人disease-free survival (P=0.0115; HR=5.97; 95% CI, 1.49-23.87)有顯著的不良影響。此外，病人為ICOS c.1624T/T基因型對於overall survival(P=0.0019; HR=12.98; 95% CI, 2.58-65.35)亦有顯著的不良影響。總結本論文研究結果，mHag HA-1/HA-2 不相容在臺灣對於移植後的臨床結果可能沒有影響，另一方面，帶有CTLA-4 -318T/T與ICOS c.602C/C基因型的捐贈者及帶有ICOS c.1624T/T 基因型的病人，在移植後的臨床結果較差，這顯示病人和捐贈者之T細胞調控基因的多型性會影響移植後病人的臨床結果。

關鍵字

造血幹細胞移植；次要組織相容性抗原； T細胞調控基因；基因多型性；移植體抗宿主疾病

並列摘要

Hematopoietic stem cell transplantation (HSCT) has evolved into an effective therapy for non-malignant and malignant hematological diseases as well as congenital immunodeficiencies. Graft-versus-host disease (GVHD) occurs in 20-40% of patients even with HLA-matched allogeneic HSCT. It indicates that non-HLA genetic polymorphisms may influence HSCT outcome. In this study, we investigated the impacts of non-HLA genetic polymorphisms on the outcome of HLA-matched sibling HSCT including: (1) minor histocompatibility antigens HA-1 and HA-2 mismatch; (2) polymorphisms of T cell regulatory genes, CTLA-4 and ICOS, in patients and donors. In order to exclude the effect of HLA, 123 pairs of DNA samples of HLA-A2- and/or HLA-B60-positive HLA-matched sibling HSCT were recruited. HLA-A2 alleles were identified by sequencing-based typing. Genotypes of single nucleotide polymorphisms at HA-1, HA-2, CTLA-4 -318C/T, CTLA-4 +49A/G, ICOS c.602A/C and ICOS c.1624C/T were analyzed by polymerase chain reaction and restriction fragment length polymorphism. The non-HLA genetic polymorphisms were examined for the association with HSCT outcome, including acute GVHD, chronic GVHD, disease relapse, disease-free survival and overall survival, by univariable and multivariable analyses. The results showed there was no significant correlation between HA-1 mismatch and the outcome of HSCT. Besides, no HA-2 mismatch was found in the cases studied and no non-immunogenic HA-2M/M genotype in control population, either. It suggestes that HA-2 mismatch may not be essential to evaluate HSCT outcome in Taiwan. In multivariable analyses, donor CTLA-4 -318T/T genotype, donor ICOS c.602C/C genotype and recipient ICOS c.1624T/T genotype had influence on HSCT outcome. Donor CTLA-4 -318T allele increased the risk of acute GVHD (P=0.0133; OR=3.25; 95% CI, 1.28-8.26). Additionally donor CTLA-4 -318T/T genotype increased the risk of disease relapse (P=0.0313; HR=5.91; 95% CI, 1.17-29.79). Patients receiving hematopoietic stem cells from a donor with ICOS c.602C/C genotype had worse disease-free survival (P=0.0115; HR=5.97; 95% CI, 1.49-23.87). On the other hand, patients with ICOS c.1624T/T genotype had worse overall survival (P=0.0019; HR=12.98; 95% CI, 2.58-65.35). According to the present study, neither HA-1 nor HA-2 mismatch was associated with the outcome of HLA-matched sibling HSCT. However, donor CTLA-4 -318T/T genotype, donor ICOS c.602C/C genotype and recipient ICOS c.1624T/T genotype were risk factors for HLA-matched sibling HSCT. These results suggest that genetic polymorphisms at T cell regulatory genes, CTLA-4 and ICOS, are associated with the HSCT outcome.

並列關鍵字

hematopoietic stem cell transplantation ； minor histocompatibility antigen ； T cell regulatory gene ； genetic polymorphisms ； graft-versus-host disease

參考文獻

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3. Thomas, E.D., H.L. Lochte, Jr., J.H. Cannon, O.D. Sahler, and J.W. Ferrebee, Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest, 1959. 38: p. 1709-16.

4. van Bekkum, D.W., M.J. de Vries, and D. van der Waay, Lesions characteristic of secondary disease in germfree heterologous radiation chimeras. J Natl Cancer Inst, 1967. 38(2): p. 223-31.

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非人類白血球抗原(non-HLA)基因多型性對於 HLA相容之造血幹細胞移植的影響

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