ISHLT 2009:可以從灌洗液體得知長期肺移植物排斥的早期徵兆


  April 24, 2009(法國巴黎) — 密西根大學的研究者在國際心肺移植協會第29屆年會與科學會議中表示,肺臟移植病患的支氣管肺泡灌洗(bronchoalveolar lavage,BAL)液體中出現肺中的間葉系幹細胞,可以作為長期移植物排斥的早期標記與及早介入的訊號。
  
  密西根大學肺病與重症照護小組的Vibha N. Lama醫師報告指出,肺移植接受者的BAL樣本中,出現肺中的間葉細胞超過10菌落形成單位(CFUs)者,在移植後一年發生阻塞性細支氣管炎症候群(bronchiolitis obliterans syndrome,BOS)的風險高出將近9倍。
  
  Lama醫師發表報告時表示,出現的殘留間葉系幹細胞是來自捐贈者的器官,這些細胞移動到肺空隙中而引起免疫傷害;肺殘留的幹細胞數量越多,則更可預期BOS發生,BAL中的幹細胞可以作為免疫損傷與發生BOS的預測標記。
  
  在Medscape Transplantation的訪問中,Lama醫師表示,她們在研究規範中有部份常規使用BAL來評估病患,她們正探討針對捐贈者間葉系幹細胞的BOS治療試驗,但是還未確認何種治療劑適合使用。
  
  她表示,移植物排斥的病因還未被充分瞭解,但已經知道這與捐贈者器官殘留的細胞有關,會造成接受者衍生可溶性調解子產生的效應細胞。
  
  她表示,肺殘留細胞有重要影響,特別是慢性移植器官排斥,不過,此一過程迄今少有詳細探討。
  
  在之前的研究中,Lama醫師等人指出,BAL含有符合國際細胞治療協會,包括以塑膠附著法分離、特定表面抗原表現、多效分化潛力等的間葉系幹細胞規範。他們也確認,肺移植接受者之BAL分離出的此類細胞來自捐贈者,肺移植者分離出他們的能力顯著超過控制組,移植後初期出現的濃度最高。
  
  至於目前的研究,研究者希望確認間葉系幹細胞在移植之後累積在肺空氣中的動力學,以確認會影響此一過程的臨床變項。
  
  他們蒐集了92名肺移植病患的177件BAL樣本,測量它們的纖維母細胞之CFU。他們發現,這些樣本在CFU計算上有顯著差異,範圍從0-60 (平均9.59 CFUs;SD, 12.92)。
  
  分析顯示,肺臟移植後超過90天(與數量較少有關)、切片出現急性排斥、出現BOS的移植肺的BAL的CFU數量是最有力的預測因子。
  
  他們接著分析其中接受捐贈肺部至少6個月、且灌洗時沒有BOS之62個病患的76件樣本,作者們使用Cox正比例風險模式評估與發生BOS時間有關的樣本。
  
  研究者發現,CFU數量高、每BAL樣本中10單位以上,是發生BOS的強力預測因子(風險比8.65;95%信心區間3.30 - 22.6;P< .0001)。
  
  間葉系幹細胞10 CFUs以上之BAL樣本中,發生BOS的平均時間為75天。在一年時,BAL樣本中細胞數量10 CFUs以上之病患中,63%發生BOS,小於10 CFUs者中,12%發生BOS (P< .001)。
  
  多變項正比例風險分析中,校正其他因素,如兩側移植、出現急性排斥、移植前診斷、移植後時間、男性之後,只有CFU 數量達10以上仍是發生BOS的顯著預測因子(風險比,11.76;95% CI、3.93 - 35.18;P< .0001)。
  
  主持會議但未參與該研究的英國Newcastle-Upon-Tyne大學胸腔內科教授Paul Corris醫師向Medscape Transplantation表示,樂見可信賴的BOS 早期生物標記,但是迄今還沒有足夠證據認為BAL中的間葉系幹細胞可以作為標記。
  
  他認為還不足以讓每個中心都如此進行,他希望看到更多證據解釋此一狀況。
  
  Corris醫師指出,BAL中的嗜中性白血球增加也是發生BOS的有力生物標記,只是這不是個單純的標記,因為發炎時,嗜中性白血球也會增加。
  
  他表示,我們顯然需要更敏感與專一的標記,特別是對BOS的專一性。
  
  Lama醫師宣告沒有相關財務關係;Corris醫師是Novartis的科學顧問。
  
  國際心肺移植協會(ISHLT)第29屆年會與科學會議:摘要 143。發表於2009年4月23日。
  

ISHLT 2009: Lavage Fluid May Yield Signs of Earlier Chronic Lung-Graft Rejection

By Neil Osterweil
Medscape Medical News

April 24, 2009 (Paris, France) — The presence of lung-resident mesenchymal stem cells in bronchoalveolar lavage (BAL) fluid from lung-transplant recipients might be an early marker for chronic allograft rejection and a signal for early intervention, suggest University of Michigan researchers here at the International Society for Heart and Lung Transplantation 29th Annual Meeting and Scientific Sessions.

Lung-transplant recipients with more than 10 colony-forming units (CFUs) or clusters of lung-resident mesenchymal cells in BAL samples had a nearly 9-fold greater risk of developing bronchiolitis obliterans syndrome (BOS) at 1 year posttransplant than did patients with 10 or fewer CFUs, reported Vibha N. Lama, MD, MS, from the Division of Pulmonary and Critical Care Medicine at the University of Michigan, in Ann Arbor.

"There is a resident population of mesenchymal stem cells, which is a donor-derived graft population, and [the cells] are mobilized to air space in response to immune injury. Increased numbers of lung-resident stem cells precede and predict BOS onset, and their presence in BAL can be potential markers of immune injury and BOS onset," said Dr. Lama during her presentation.

In an interview with Medscape Transplantation, Dr. Lama said that BAL is routinely used to evaluate patients at her center as part of a research protocol, and her team is investigating a treatment trial for BOS targeted at donor-derived mesenchymal stem cells, but have not determined which therapeutic agents are most suited to the task.

The pathogenesis of allograft rejection is not fully understood, she said, but it is known to involve cells resident in the donor graft, the presence of which causes recruitment of recipient-derived effector cells by soluble mediators.

"Lung-resident cells play an important role, especially in cases of chronic allograft rejection," she said. "However, this process has received little scrutiny to date."

In previous studies, Dr. Lama and colleagues demonstrated that BAL contains cells that meet all the criteria for mesenchymal stem cells, as outlined by the International Society for Cellular Therapy, including isolation by plastic adherence, specific surface antigen expression, and multipotent differentiation potential. They also determined that such cells isolated in BAL from lung-graft recipients came from the donor, that the ability to isolate them was significantly greater in lung-transplant recipients than in control subjects, and that the highest concentrations appeared to occur early posttransplant.

For the current study, the researchers hoped to define the kinetics of lung-resident mesenchymal stem cell accumulation in air spaces after transplantation, and to determine the clinical variables that might influence the process.

They collected 177 BAL samples from 92 lung-transplant recipients and counted them by measuring fibroblast CFUs. They found that in the samples there was significant variability in CFU counts, ranging from 0 in some samples to as many as 60 in others (mean, 9.59 CFUs; SD, 12.92).

Analysis showed that the only significant predictors of the number of CFUs in BAL samples from lung-transplant recipients were a posttransplant time of more than 90 days (associated with fewer counts), the presence of acute rejection on biopsy, and the presence of BOS.

They then looked at a subset of 76 samples from 62 patients who had received donor lungs at least 6 months earlier and were free of BOS at the time of lavage. The authors used Cox proportional hazard models to assess variables related to time to BOS.

The investigators found that a high CFU count, defined as 10 or more per BAL sample, was a highly significant predictor of BOS development (hazard ratio, 8.65; 95% confidence interval, 3.30 - 22.6; P?< .0001).

The median time to development of BOS from a BOS sample with 10 or more CFUs of mesenchymal stem cells was 75 days. At 1 year, 63% of patients who had BAL samples with 10 or more CFUs had developed BOS compared with 12% of patients who had samples with fewer than 10 CFUs (P?< .001).

On multivariate proportional hazards analysis, adjusted for other factors such as bilateral transplant, the presence of acute rejection, pretransplant diagnosis, time posttransplant, or male sex, only CFU counts of 10 or more remained a significant predictor of BOS onset (hazard ratio, 11.76; 95% CI, 3.93 - 35.18; P?< .0001).

Paul Corris, MD, professor of thoracic medicine at the University of Newcastle-Upon-Tyne, in the United Kingdom, who moderated the session but was not involved in the study, told Medscape Transplantation that a reliable early biomarker of BOS would be welcome, but that there is not enough evidence as yet to suggest that mesenchymal stem cells in BAL is that marker.

"I think it's a bit premature to say that every center should be doing this. I'd like to see more evidence to suggest that it's the answer to what's going on," he said.

Dr. Corris noted that the increase in neutrophils in BAL is also a potential biomarker for the onset of BOS, but that it is a "dirty" marker, because an increase in neutrophils can be associated with infection,

"What we clearly need is a more sensitive and specific marker — emphasis on the specificity — for BOS," he said.

Dr. Lama has disclosed no relevant financial relationships. Dr. Corris is a consultant and scientific advisor to Novartis.

International Society for Heart and Lung Transplantation (ISHLT) 29th Annual Meeting and Scientific Sessions: Abstract 143. Presented April 23, 2009.

    
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