Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Baumann, Anna; Schlué, Jérôme; Noyan, Fatih; Hardtke‐Wolenski, Matthias; Lehner, Frank; Barg‐Hock, Hannelore; Klempnauer, J.; Manns, Michael P.; Taubert, Richard; Jaeckel, Elmar

doi:10.1002/lt.24427

Cited by 27 publications

(37 citation statements)

References 36 publications

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“…However, liver enzyme elevations above this threshold were independent risk factors for a reduced patient and graft survival in the setting of early subTCMR 29 . SubTCMR defined by liver enzymes below two times ULN had no progression to cTCMR or subsequent progressive fibrosis when left untreated later after transplantation 19,30 . The same thresholds were also used for the description of subclinical graft injury in other studies in adults 3 .…”

Section: Discussionmentioning

confidence: 99%

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Höfer

Jonigk

Hartleben

et al. 2020

Sci Rep

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The majority of liver grafts exhibit abnormal histological findings late after transplantation, even when liver enzymes are normal. Such subclinical graft injuries were associated with rejection and fibrosis progression in recent studies. The identification of non-invasive biomarkers for subclinical graft injury might help to individualize immunosuppression. Therefore, graft injury was assessed in 133 liver biopsies with normal/near normal liver enzymes from a prospective liver biopsy program. Cytokeratin-18 cell death marker (M65) and donor specific anti-HLA antibodies (DSA) were measured as non-invasive markers in paired plasma samples in addition to routine parameters. M65 was associated with subclinical graft injury but this association was too weak for reasonable clinical application. DSA positivity was associated with more graft inflammation (OR = 5.4) and more fibrosis (OR = 4.2). Absence of DSA excluded fibrosis in 87-89%, while presence of DSA excluded histological criteria for immunosuppression minimization attempts in 92-97%. While CK18 cell death marker had no diagnostic value for the detection of subclinical liver graft injury, DSA testing can help to preselect patients for immunosuppression reduction in case of DSA negativity, while DSA positivity should prompt elastography or liver biopsy for the assessment of subclinical graft injury. Abbreviations ALP Alkaline phosphatase ALT Alanine transaminase AMR Antibody-mediated rejection AST Aspartate transaminase cAMR Possible chronic antibody-mediated rejection CK18 Cytokeratin-18 CI 95% Confidence interval CNI Calcineurin inhibitor CsA Cyclosporine A cTCMR Clinical T cell-mediated rejection DSA Donor-specific anti-human leukocyte antigen antibodies gGT Gamma-glutamyltransferase GH Graft hepatitis HCMini Histological criteria for minimization of immunosuppression HLA Anti-human leukocyte antigens IND Indeterminate histological findings LAF Liver allograft fibrosis

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Section: Discussionmentioning

confidence: 99%

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Höfer

Jonigk

Hartleben

et al. 2020

Sci Rep

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“…Because preferential accumulation of Tregs in liver allografts during acute cellular rejection (ACR) is reportedly associated with reduced severity of rejection, suggesting a role of Tregs in preventing excessive progress of ACR, the present study investigated the impact of FOXP3 single nucleotide polymorphisms (SNPs) on the severity of ACR in liver transplant (LT) recipients.…”

Section: Introductionmentioning

confidence: 99%

“…Consistent with this, a possible association between the genotype at the FOXP3 rs3761548 locus and rejectionfree allograft survival in renal transplantation has been demonstrated, although the impact of FOXP3 polymorphisms on the severity of the rejection reaction toward kidney allografts remains to be elucidated. (12) Because preferential accumulation of Tregs in liver allografts during acute cellular rejection (ACR) is reportedly associated with reduced severity of rejection, (13,14) suggesting a role of Tregs in preventing excessive progress of ACR, the present study investigated the impact of FOXP3 single nucleotide polymorphisms (SNPs) on the severity of ACR in liver transplant (LT) recipients.…”

Section: Introductionmentioning

confidence: 99%

Significant association between FOXP3 gene polymorphism and steroid‐resistant acute rejection in living donor liver transplantation

Verma

Tanaka

Shimizu

et al. 2017

Hepatology Communications

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Previous studies have found that preferential accumulation of regulatory T (Treg) cells in liver allografts during acute cellular rejection (ACR) is associated with less severe rejection, suggesting a role of Treg cells in preventing excessive progress of ACR. We investigated the impact of single nucleotide polymorphisms (SNPs) in the Forkhead box P3 (FOXP3) gene, a master regulator gene of Treg cells, on ACR severity in liver transplant (LT) recipients. In total, 102 living donor LT patients were enrolled in this study and categorized into no rejection (n = 86), steroid‐sensitive acute rejection (SSAR; n = 11), and steroid‐resistant acute rejection (SRAR; n = 5). FOXP3 SNPs –3499 A/G (rs3761547), –3279 A/C (rs3761548), and –924 A/G (rs2232365) were genotyped using the polymerase chain reaction restriction fragment length polymorphism technique. T‐cell responses to allostimulation were evaluated by the mixed lymphocyte reaction assay. We found no statistical association between the FOXP3 SNP genotype frequencies and ACR incidence. However, significantly higher incidence of SRAR was observed in LT patients with the FOXP3 rs3761548 A/C+A/A genotype than in those with the C/C genotype (A/C+A/A versus C/C; no rejection, SSAR, SRAR, 85.71%, 0%, 14.29% versus 83.58%, 16.42%, 0%, respectively; P = 0.0005). The mixed lymphocyte reaction assay performed at the time of ACR diagnosis showed higher anti‐donor CD4+ T‐cell responses in patients carrying rs3761548 A/C+A/A than in those with the C/C genotype (P = 0.019). No significant association was observed between the incidence of SRAR and either rs3761547A/G or rs2232365 A/G. Infectious complications and overall survival were not related to FOXP3 SNPs. Conclusion: Our findings indicate that FOXP3 SNP rs3761548 A/C might be a predisposing factor for SRAR after liver transplantation. (Hepatology Communications 2017;1:406–420)

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“…CD4 ve CD8 değerleri özellikle T lenfositlerin hakimiyetinin olduğu pek çok hastalıkta önem taşımaktadır (13)(14)(15). Mevcut çalışmamızda yeterli hasta sayısında BAL'ın yapılmamış, CD4 ve CD8 düzeylerinin incelenmemiş olması nedeniyle diğer parametrelerimizle birlikte değerlendirmeye alamadık.…”

Section: Discussionunclassified

Value of Mean Platelet Volume for Disease Activity in Patients with Pulmonary Sarcoidosis

Özçelik¹,

Bayram²,

Kılıç³

et al. 2016

Bezmialem Science

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ÖZAmaç: Bu çalışmada pulmoner sarkoidozlu hastalarda inflamasyon belirteci olarak ortalama trombosit hacminin (mean platelet volume: MPV) hastalık aktivasyonu ve şiddetinin tahmininde değeri olup olmadığını araştırdık. Yöntemler: 2011-2014 yılları arasında Bezmialem Vakıf Üni-versitesi Göğüs Hastalıkları Anabilim Dalı'nda sarkoidoz tanısı konulan ya da daha önce tanı almış ve göğüs hastalıkları polikliniğimizde takipli olan 84 hasta retrospektif olarak değerlendi-rildi. Hastalar aktif veya remisyonda, akut veya kronik olmaları, akciğer grafilerine göre evreleri ve ektrapulmoner tutulumlarının varlığına göre gruplandırılarak; ilk başvuru esnasındaki MPV ve anjiotensin konverting enzim (ACE) seviyeleri değerlendirildi ve aralarında ilişki olup olmadığına bakıldı. Bulgular: Hastaların 63'ü (%75) kadındı. Yaş ortalaması 44 (38-52)'dü. 52 hasta (%62) evre 1, 32 hasta (%38) evre 2'ydi. Medyan ACE düzeyi 59,6 (42,6-92), MPV düzeyi 10,1 (9,7-10,7)'di. Bronkoalveoler lavaj (BAL) 24 hastaya yapılabilmişti, tüm hastalarda lenfosit hakimiyeti vardı ve medyan CD4/CD8 oranı 4,8 (3,2-12,5)'di. Gruplardan bağımsız olarak ACE ile MPV arasında negatif korelasyon tespit edildi ve istatistiksel olarak anlamlıydı (p<0,038). Hastalar aktif veya remisyonda, akut veya kronik, evre 1 ve 2, ekstrapulmoner tutulumlarının varlığına göre gruplandırılarak MPV düzeylerine bakıldığında anlamlı farklılık elde edilemedi (p>0.05). Sonuç: Bulgularımıza göre; MPV'nin sarkoidoz hastalığında inflamasyon veya aktivasyon belirteci olarak anlamlı olmadığı söy-lenebilir ve pulmoner sarkoidozda tanı ve takip indikatörü olarak kullanıma uygun görünmemektedir. Anahtar Kelimeler: Sarkoidoz, MPV, trombosit ABSTRACT Objective: We aimed to investigate the importance of mean platelet volume (MPV) as a marker for the activation and severity of disease in patients with pulmonary sarcoidosis. Methods: The data of 84 patients diagnosed with pulmonary sarcoidosis in our clinic between 2011 and 2014 were evaluated retrospectively. Patients were divided into groups according to the activation status (active or in remission), acute or chronic disease, stage according to chest X-ray, and extrapulmonary involvement. The correlation of the initial MPV and ACE levels was evaluated. Results: Sixty-three of the patients were female, with an average age of 44 (38-52) years. Fifty-two of the patients (62%) were in stage 1, and 32 (38%) were in stage 2. The median ACE level was 59.6 (42.6-92), and the MPV level was 10.1 (9.7-10.7). Bronchoalveolar lavage was applied to 24 patients; all of these had predominant lymphocytes, and the median CD4/CD8 rate of the patients was 4.8 (3.2-12.5). A significant negative correlation was detected between ACE and MPV independently of the groups (p<0.038). There were no significant differences in MPV levels between patients whose activation status was active or in remission, between acute or chronic patients, between patients in stage 1 or stage 2, or between patients with or without extrapulmonary involvement (p>0.05 for all). Conclusion: Acco...

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Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts

Cited by 27 publications

References 36 publications

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies

Significant association between FOXP3 gene polymorphism and steroid‐resistant acute rejection in living donor liver transplantation

Value of Mean Platelet Volume for Disease Activity in Patients with Pulmonary Sarcoidosis

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