本帖最後由 lsc0019 於 2009-4-22 00:45 編輯
作者：Fran Lowry
出處：WebMD醫學新聞
April 8, 2009 — 根據發表於4月版肝臟移植期刊的一篇研究結果，器官捐贈者與接受者之間不相同的人類白血球組織抗原(HLA)C型同種抗原免疫球蛋白，會增加C型肝炎(HCV)感染病患在肝臟移植之後肝炎復發以及惡化成肝硬化的風險。
肝臟移植是HCV感染導致的肝硬化以及肝癌現有的最佳治療。不幸的是，多數案例發生HCV再度感染，導致在移植後5年內，移植的器官也發生肝硬化。
義大利米蘭Ospedale Maggiore Polliclinico器官與組織移植免疫、再生醫學部門的Alejandro Espadas de Arias醫師等人，試圖研究肝臟移植病患的先天免疫系統及其對HCV復發和疾病預後(惡化成肝硬化)之基因敏感性的影響。
Espadas de Arias醫師等人寫道，對HCV感染的免疫反應包括自然殺手細胞[NK]以及殺手細胞免疫球蛋白樣受體(KIRs)，可特定辨識目標細胞上的[HLA]第1類抗原。NK細胞的效應子功能受到抑制KIR與自己的HLA第1類配位體之交互作用影響，而HLA-C是最主要的。
研究目標是檢視KIR基因型與其HLA配位體，對於肝臟移植之後、HCV疾病復發和預後的影響。
研究者回溯分析北義大利移植計畫的151對捐贈者與接受者，這些病患在1991至2001年間移植；全都是高加索-義大利後代。從周邊血液分離基因體DNA，在移植後第1、 3、5、7、10年採取肝臟切片，以確認有無肝炎復發、纖維化程度、以及在這10年間有無發生肝硬化。
他們發現，捐贈者與接受者之KIR與HLA-C配位體不符與肝炎復發有關(P = .008)，接受者的KIR基因2DL3 (KIR2DL3)與惡化成肝纖維化有關(P = .04)，只有在出現KIR2DL3時，HLA-KIR配位體不符的復發肝炎會惡化成纖維化(P = .04)。
作者寫道，我們的初步資料指出，KIR2DL3陽性接受者，若指派HLA-KIR相符的捐贈者會比較好，以減少肝臟移植之後發生嚴重纖維化的風險；如果在移植前測定KIR基因型，對HCV陽性病患會有潛在利益。
他們指出，他們正進行一個前溯研究，包括了功能性細胞分析，以進一步確認這些發現。
科羅拉多大學健康科學中心的Lucy Golden-Mason醫師在編輯評論中，形容本研究為「有重大臨床意義且描述良好、執行良好」；儘管只是初步資料，該研究已經對後續研究提供有價值的觀點。
根據Golden-Mason醫師表示，肝臟移植者之NK細胞活性的基因組成與慢性HCV感染之間的證據，將有助於描繪出適當使用捐贈者器官的後續策略，特別是器官捐贈短缺的情況下。
Golden-Mason醫師結論表示，該研究支持對此類病患活化NK細胞的一種模式，對於HCV感染之肝臟移植接受者的HCV復發有利也有弊，也就是保護與同種異體移植的傷害；需要以更大型的自然史研究來確認這些結果。
Ricerce Corrente 2007 (義大利米蘭Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Istituto di Ricovero e Cura a Carattere Scientifico)支持本研究。作者宣告沒有相關財務關係。
Genetically Mismatched Liver Transplants Predict HCV Recurrence, Progression
By Fran Lowry
Medscape Medical News
April 8, 2009 — A disparity in human leukocyte antigen (HLA)-C allotypes between recipient and donor appears to increase the risk for recurrence of hepatic inflammation and progression to cirrhosis after liver transplantation in patients with hepatitis C virus (HCV) infection, according to the results of a study published in the April issue of Liver Transplantation.
Liver transplantation is the best treatment available for the cirrhosis and hepatocellular carcinoma that result from HCV infection. Unfortunately, reinfection with HCV occurs in most cases, leading to cirrhosis of the graft within 5 years of transplant.
Researchers led by Alejandro Espadas de Arias, MD, from the Department of Regenerative Medicine, Organ and Tissue Transplantation Immunology, Ospedale Maggiore Polliclinico, Milan, Italy, sought to investigate the influence of the innate immunological system and its elements on genetic susceptibility to both HCV recurrence and disease progression to cirrhosis in liver transplant patients.
"The immunological response to HCV infection involves natural killer [NK] cells and killer cell immunoglobulin-like receptors (KIRs), which specifically recognize [HLA] class I antigens present on target cells," Dr. Espadas de Arias and colleagues write. "The effector functions of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant."
The goal of this study was to examine the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and progression after liver transplant.
The investigators retrospectively studied 151 consecutive donor/recipient pairs from the North Italy Transplant Program. Patients were transplanted between 1991 and 2001; all were of Caucasian-Italian descent.
Genomic DNA was isolated from peripheral blood, and liver biopsies were taken at 1, 3, 5, 7, and 10 years posttransplant to define the absence or presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis during the 10-year period.
They found that mismatching of KIR-HLA-C ligands between donor-recipient pairs was associated with the recurrence of hepatitis (P = .008), that the presence of the KIR gene 2DL3 (KIR2DL3) in the recipient was linked to progression to liver fibrosis (P = .04), and that the mismatching of HLA-KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = .04).
"Our preliminary data indicate that KIR2DL3-positive recipients would be better assigned a matched donor for the HLA-KIRs in order to reduce the risk of developing severe fibrosis after liver transplantation," the authors write. "It would be potentially beneficial to the HCV-positive patients if the KIR genotype was determined pre-transplantation."
They add that they are currently undertaking a prospective study including functional cellular assays to further confirm the findings.
In an accompanying editorial, Lucy Golden-Mason, MD, from the University of Colorado Health Sciences Center, Aurora, called the study "clinically relevant and well described," as well as well-conducted. In spite of the preliminary data set, the study has revealed interesting associations "that provide valuable insight for the design of future studies," she writes.
According to Dr. Golden-Mason, the evidence that a genetic component contributes to NK cell activity in the setting of liver transplant for chronic HCV infection will be useful in delineating future strategies for the optimal use of donor organs, which are in short supply.
"This study supports a model in which activation of NK cells in this setting has both beneficial and detrimental influences on HCV recurrence in HCV-infected [liver transplant] recipients, that is, protection versus injury of the allograft. Confirmation of these results in larger natural history studies is warranted," Dr. Golden-Mason concludes.
This work was supported by Ricerce Corrente 2007 (Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy). The authors have disclosed no relevant financial relationships.
Liver Transplantation. 2009;15:357–359, 390–399. |
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