Mismatches at the HLA-DR and HLA-B Loci Are Risk Factors for Acute Rejection after Lung Transplantation

Abstract

Early high-grade acute rejections (pathologic grade A2 or A3) in recipients of lung allografts are a major risk factor for the subsequent development of obliterative bronchiolitis (OB). We analyzed the risk factors for high-grade acute rejections in 152 recipients of single (100) or bilateral (52) lung allografts transplanted at our institution between 1990 and 1996. Using Kaplan-Meier product limit estimate analysis, there was a 50% probability of grade A2 or A3 rejection by 1 yr after transplant. By univariate analysis, the only significant predictor of early high-grade rejections was the presence of one or more mismatches at the HLA-DR locus (p = 0.038). This association was confirmed using the Cox proportional hazards model for multivariable analysis, with HLA-DR locus mismatch being the only risk factor identified for high-grade rejection (p = 0.036). Using repeated rejection analysis, recipients with one or more matches at the HLA-DR locus had a lower cumulative rate of grade A2 or A3 rejections during the first year compared with recipients with no matches at the HLA-DR locus (0.73 versus 1.32). In addition, recipients with one or more HLA-B locus matches had a lower cumulative rate of grade A2 or A3 rejections in the first year than did recipients with no matches at the HLA-B locus (0.59 versus 1.30). These results indicate that mismatches between donors and recipients at the HLA-DR and HLA-B loci are important risk factors for early high-grade rejections after lung transplantation. Immunosuppressive protocols that are more effective in preventing recipient T-cell activation by donor alloantigens are likely to reduce the rate of high-grade acute rejections in recipients of lung transplants, and may directly impact on the time to onset of OB.

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

“…It is the leading cause of death for recipients who survive beyond 1 year post-transplant [2,3], and it is widely perceived as the physiological surrogate of immunologically-mediated phenomena due to many observations that include its association with acute cellular rejection [11], the tendency of recipients who develop BOS to have greater degrees of human leukocyte antigen (HLA) mismatch [12], and accumulating evidence of the involvement of autoimmune pathways [13]. Furthermore, there are striking similarities to OB that can occur in allogeneic bone marrow or stem cell transplant recipients as well as in patients with connective tissue diseases, which are also perceived as alloimmune or autoimmune disorders, respectively.…”

Influence of HLA Mismatching on Survival in Lung Transplantation

“…Prior research on HLA mismatching in LTx has shown inconsistent results on the role of the various loci mismatches on clinical outcomes [3][4][5][6][7][8][9][10][11][12][13]. Poor survival has been reported in association with HLA mismatches at the A locus [3], B locus [4], and DR locus [5,6] as well as separate combinations of these loci [7,8] or all three loci [9,10]. Recent studies using large registry databases are reporting more consistently that all loci or both HLA classes are contributing to poor survival [9,10].…”

“…The long-term outcomes after LTx remain a challenge and continue to lag behind outcomes in other solid organ transplants [2]. Although still limited, data in LTx demonstrate that human leukocyte antigen (HLA) compatibility is important and impacts clinical outcomes [3][4][5][6][7][8][9][10][11][12][13].…”

International practical guidelines on diagnosis, prevention and treatment of bronchiolitis obliterans syndrome

“…СОБ является также ведущей причи ной смерти реципиентов, проживших > 1 года после трансплантации [2,3], и на основании многочислен ных наблюдений повсеместно воспринимается как физиологический суррогатный маркер разнообраз ных иммуноопосредованных феноменов: СОБ не редко сопровождается ОКО [11], более выраженной несовместимостью по системе HLA (человеческого лейкоцитарного антигена) [12]); накапливается объ ем информации об активации аутоиммунных меха низмов при СОБ [13]. Состояния, аналогичные СОБ, встречаются после аллогенной транспланта ции костного мозга и стволовых клеток, а также у больных с системными заболеваниями соедини тельной ткани, в основе которых также лежат алло иммунные или аутоиммунные нарушения соответ ственно.…”