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Torbenson M, Washington K. Pathology of liver disease: advances in the last 50 years. Hum Pathol 2019; 95:78-98. [PMID: 31493428 DOI: 10.1016/j.humpath.2019.08.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/28/2019] [Indexed: 02/07/2023]
Abstract
Liver disease has been recognized in various forms for centuries. Incredible advances, however, have been made especially in the last 50 years, driven by improvements in histology, the development of immunostains, the development of high resolution imaging methods, improved biopsy and resection methods, and the emergence of the molecular era. With these tools, pathologists and their clinical and basic science colleagues moved from classifying liver disease using an observational, pattern-based approach to a refined classification of disease, one based on etiology for medical disease and tumor classification for neoplastic disease. Examples of liver specific diseases are used to illustrate these exciting advances. These impressive advances of the past provide the foundation for hope in the future, as liver pathology continues to play an important role in improving patient care through disease identification and classification and emerging roles in guiding therapy for cures.
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Affiliation(s)
- Michael Torbenson
- Department of Pathology and Laboratory Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905.
| | - Kay Washington
- C-3321 MCN, Department of Pathology, Vanderbilt University Medical Center, 1161 21(st) Avenue S, Nashville, TN 37232.
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Xie HY, Huang DS, Jia CK, Zheng SS. Infusion of nonmyeloablative bone marrow alleviates acute rejection reaction in liver allotransplantation. J Zhejiang Univ Sci B 2006; 6:1188-94. [PMID: 16358377 PMCID: PMC1390642 DOI: 10.1631/jzus.2005.b1188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To study the effect and implication of nonmyeloablative donor specific bone marrow (DSBM) infusion on the immunoreaction of liver allotransplantation. METHODS Orthotopic liver transplantation model was used in this study. Groups were set as follows: Group I, syngeneic control (Wistar-to-Wistar); Group II, acute rejection (SD-to-Wistar); Group III, acute rejection treated with cyclosporine A (CsA) by intramuscular injection (SD-to-Wistar+CsA); Group IV, bone marrow infusion at 7 d pretransplantation followed by short-term CsA treatment (SD-to-Wistar+DSBM); Another group of short-term CsA treatment preoperatively without bone marrow infusion was also set as control. General characteristics and survival time were observed. Histological grades of rejection were determined by pathological examination. IL-2 and IFN-gamma level in peripheral blood and donor liver were detected respectively by Enzyme-Linked Immuno-Sorbent Assay (ELISA) and Western blot. Chimerism of donor cells was measured by PCR for a male-specific marker (Y-chromosome-specific sequence, Sry). RESULTS No signs of rejection were found in Group I. Acute rejection occurred in both Group II and the short-term CsA treated group. All the recipients died at (9-15) d posttransplantation with a median survival time of (10.7+/-0.5) d and (11.2+/-2.4) d, respectively. Only mild rejection could be seen in Group III. In Group IV, 4 out of 6 recipients had long-term survival (>100 d), the histological grade of rejection was significantly lower than that of Group II, so did the expression level of IL-2 and IFN-gamma in both peripheral blood and grafted liver. Y-chromosome-specific sequence (Sry) of male SD rats could be detected in the bone marrow, spleen and thymus of female recipients at 15 d after bone marrow infusion. CONCLUSION Mild preconditioning nonmyeloablative donor specific bone marrow infusion can enhance chimerism formation in recipients, alleviate the rejection of liver allotransplantation and prolong survival of liver allotransplantation.
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Jiang GP, Hu ZH, Zheng SS, Jia CK, Zhang AB, Wang WL. Adenovirus-mediated CTLA4Ig gene inhibits infiltration of immune cells and cell apoptosis in rats after liver transplantation. World J Gastroenterol 2005; 11:1065-9. [PMID: 15742417 PMCID: PMC4250774 DOI: 10.3748/wjg.v11.i7.1065] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of adenovirus-mediated CTLA4Ig gene therapy in inhibiting the infiltration of macrophages and CD8+T cells and cell apoptosis after liver transplantation.
METHODS: The rat orthotopic liver transplantation model was applied. The rats were divided into three groups: group I: rejection control (SD-to-Wistar); group II: acute rejection treated with intramuscular injection of CsA 3.0 mg/(kg·d) for 12 d (SD-to-Wistar+CsA); groupIII: injection of 1×109 PFU adenovirus-mediated CTLA4Ig gene liquor in dorsal vein of penis 7 d before liver transplantation (SD-to-Wistar+CTLA4Ig). Immunohistochemistry and transferase-mediated dUTP nick-end labeling (TUNEL) were used to analyze the expression of CTLA4Ig gene in liver, infiltration of macrophages and CD8+T cells, cell apoptosis in grafts at different time-points after liver transplantation. Histopathological examination was done.
RESULTS: CTLA4Ig gene expression was positive in liver on d 7 after administering adenovirus-mediated CTLA4Ig gene via vein, and remained positive until day 60 after liver transplantation. Infiltration of macrophages and CD8+T cells in CTLA4Ig-treated group was less than in rejection control group and CsA-treated group. The apoptotic index of rejection group on d 3, 5, and 7 were significantly higher than that of CTLA4Ig-treated group. A good correlation was found between severity of rejection reaction and infiltration of immune activator cells or cell apoptotic index in grafts.
CONCLUSION: CTLA4Ig gene is constantly expressed in liver and plays an important role in inducing immune tolerance.
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Affiliation(s)
- Guo-Ping Jiang
- Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
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Jia CK, Zheng SS, Zhang AB. Intrathymic inoculation of donor liver specific antigen alleviates rejection of liver allotransplantation. JOURNAL OF ZHEJIANG UNIVERSITY. SCIENCE 2003; 4:485-490. [PMID: 12861628 DOI: 10.1631/jzus.2003.0485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
UNLABELLED Use and effects of liver specific antigen in orthotopic liver transplantations were researched in this study. Group I: syngeneic control (Wistar-to-Wistar); Group II: acute rejection (SD-to-Wistar); Group III: Thymic inoculation of SD rat LSA day 7 before transplantation. The observation of common situation and survival time, rejection grades, NF-KappaB activity of splenocytes and IL-2mRNA expression of grafted liver were used to analyze acute rejection severity and immune state of animals in different groups. The common situation of group I was very well after transplantation and no signs of rejection were found. Recipients of group II lost body weight progressively. All dead within day 9 to day 13 posttransplantation; median survival time was 10.7+/-0.51 days. It was an optimal acute rejection control. As for group III, 5 out of 6 recipients survived for a long time and common situation was remarkably better than that of group II. Its rejection grades were significantly lower than that of group II(P < 0.05). NF-KappaB activity was only detected in group I at day 5 and day 7 after transplantation, whereas high activity of NF-KappaB was detected at all time points in group II and the low NF-KappaB activity detected in group III was significantly lower than that of group II(P < 0.05). No IL-2mRNA expression was detected at any time point in group I, whereas high level expression was detected at all time points in group II and the low level expression only detected at day 3 in group III was significantly lower than that of group II(P < 0.05). CONCLUSION LSA is an important transplantation antigen which is involved directly in the immunorejection of liver transplantation. We report here for the first time that intrathymic inoculation of LSA can alleviate the rejection of liver allotransplantation; and that grafts can survive for a long time thereby, thus leading to a novel way to achieve liver transplantation immunotolerance.
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Affiliation(s)
- Chang-Ku Jia
- Department of Hepatobiliary Pancreatic Surgery, Key Lab of combined Multi Organ Transplantation of Ministry of Public Health, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
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Jia CK, Zheng SS, Li QY, Zhang AB. Immunotolerance of liver allotransplantation induced by intrathymic inoculation of donor soluble liver specific antigen. World J Gastroenterol 2003; 9:759-64. [PMID: 12679927 PMCID: PMC4611445 DOI: 10.3748/wjg.v9.i4.759] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of liver specific antigen (LSA) on the immunoreaction of liver allotransplantation and its significance.
METHODS: Orthotopic liver transplantation was used in this study. Group I: syngeneic control (Wistar-to-Wistar); Group II: acute rejection (SD-to-Wistar). Group III: acute rejection treated by intramuscular injection of cyclosporine A (CsA) (SD-to-Wistar + CsA). Group IV: Intrathymic inoculation of SD rat LSA one week before transplantation (LSA + SD-to-Wistar). The common situation and survival time, rejection grades, NF-κB activity of splenocytes and intragraft cytokine gene expression were observed to analyze the acute rejection severity and immune state of animals.
RESULTS: The common situation of Wistar-to-Wistar group was very good after the transplantation and no signs of rejection were found. Recipients of SD-to-Wistar group lost body weight progressively. All died within 9 to 13 d after transplantation with the median survival time of 10.7 ± 0.51 d. It was an optimal control for acute rejection. The common situation of SD-to-Wistar + CsA group was bad during CsA medication but only with mild rejection. As for LSA + SD-to-Wistar group, 5 of 6 recipients survived for a long time and common situation was remarkably better than that of SD-to-Wistar group and SD-to-Wistar + CsA group. Its rejection grades were significantly lower than that of SD-to-Wistar group (P = 0.026). Furthermore, no significant discrepancies of rejection were found between SD-to-Wistar group and LSA + SD-to-Wistar group at day 7 and day 12 (P = 0.067). NF-κB activity, IFN-γ and IL-2mRNA expression were significantly inhibited in LSA + SD-to-Wistar group compared with that of SD-to-Wistar group (P < 0.05).
CONCLUSION: LSA is an important transplantation antigen which involves in the immunorejection of liver transplantation directly. We reported for the first time that intrathymic inoculation of LSA can induce immnotolerance of liver allotransplantation and grafts can survive for a long time thereby, thus leading to a novel way to liver transplantation immunotolerance.
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Affiliation(s)
- Chang-Ku Jia
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou 310003, China.
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Demetris AJ, Ruppert K, Dvorchik I, Jain A, Minervini M, Nalesnik MA, Randhawa P, Wu T, Zeevi A, Abu-Elmagd K, Eghtesad B, Fontes P, Cacciarelli T, Marsh W, Geller D, Fung JJ. Real-time monitoring of acute liver-allograft rejection using the Banff schema. Transplantation 2002; 74:1290-6. [PMID: 12451268 DOI: 10.1097/00007890-200211150-00016] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND The Banff schema is the internationally accepted standard for grading acute liver-allograft rejection, but it has not been prospectively tested. METHODS Complete Banff grading was prospectively applied to 2,038 liver-allograft biopsies from 901 adult tacrolimus-treated primary hepatic allograft recipients between August 1995 and September 2001. Histopathologic data was melded with demographic, clinical, and laboratory data into a database on an ongoing basis using locally developed software. RESULTS Acute rejection developed in 575 of 901 (64%) patients and the worst grade was mild in 422 of 575 (73%). At least one episode of moderate or severe acute rejection developed in 153 of 901 (17%) patients and most episodes, irrespective of severity, occurred within the first year after transplantation. Patients with moderate or severe acute rejection showed higher alanine aminotransferase (P =0.007) and aspartate aminotransferase ( P=0.07) levels and were more likely to develop perivenular fibrosis on follow-up biopsies (P =0.001) and graft failure from acute or chronic rejection ( P=0.004) than those with mild rejection. Regardless of severity, 80% of patients with acute rejection did not develop significant fibrosis in follow-up biopsies, and graft failure from acute or chronic rejection occurred in only 11 of 901 (1%) allografts. CONCLUSIONS Most acute-rejection episodes are mild and do not lead to clinically significant architectural sequelae. When tested prospectively under real-life and -time conditions, the Banff schema can be used to identify those few patients who are potentially at risk for more significant problems. Creation, capture, and integration of non-free text, or "digital," pathology data can be used to prospectively conduct outcomes-based research in transplantation.
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Affiliation(s)
- A J Demetris
- Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Jain A, Demetris AJ, Kashyap R, Blakomer K, Ruppert K, Khan A, Rohal S, Starzl TE, Fung JJ. Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years. Liver Transpl 2001; 7:623-30. [PMID: 11460230 PMCID: PMC2965463 DOI: 10.1053/jlts.2001.25364] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tacrolimus has proven to be a potent immunosuppressive agent in liver transplantation (LT). Its introduction has led to significantly less frequent and severe acute rejection. Little is known about the rate of chronic rejection (CR) in primary LT using tacrolimus therapy. The aim of the present study is to examine the long-term incidence of CR, risk factors, prognostic factors, and outcome after CR. The present study evaluated the development of CR in 1,048 consecutive adult primary liver allograft recipients initiated and mostly maintained on tacrolimus-based immunosuppressive therapy. They were evaluated with a mean follow-up of 77.3 +/- 14.7 months (range, 50.7 to 100.1 months). To assess the impact of primary diagnosis on the rate and outcome of CR, the population was divided into 3 groups. Group I included patients with hepatitis C virus (HCV)- or hepatitis B virus (HBV)-induced cirrhosis (n = 312); group II included patients diagnosed with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH; n = 217); and group III included patients with all other diagnoses (n = 519). Overall, 32 of 1,048 patients (3.1%) developed CR. This represented 13 (4.1%), 12 (5.5%), and 7 patients (1.3%) in groups I, II, and III, respectively. The relative risk for developing CR was 3.2 times greater for group I and 4.3 times greater for group II compared with group III. This difference was statistically significant (P =.004). The incidence of acute rejection and total number of acute rejection episodes were significantly greater in patients who developed CR compared with those who did not (P <.0001). Similarly, the mean donor age for CR was significantly older than for patients without CR (43.0 v 36.2 years; P =.02). Thirteen of the 32 patients (40.6%) who developed CR retained their original grafts for a mean period of 54 +/- 25 months after diagnosis. Seven patients (21.9%) underwent re-LT, and 12 patients (38.3%) died. Serum bilirubin levels and the presence of arteriopathy, arterial loss, and duct loss on liver biopsy at the time of diagnosis of CR were significantly greater among the 3 groups of patients. In addition, patient and graft survival for group I were significantly worse compared with groups II and III. We conclude that CR occurred rarely among patients maintained long term on tacrolimus-based immunosuppressive therapy. When steroid use is controlled, the incidence of acute rejection, mean donor age, HBV- and/or HCV-induced cirrhosis, or a diagnosis of PBC, PSC, or AIH were found to be predictors of CR. Greater values for serum bilirubin level, duct loss, arteriopathy, arteriolar loss, and presence of HCV or HBV were found to be poor prognostic factors for the 3 groups; greater total serum bilirubin value (P =.05) was the only factor found to be significant between patients who had graft loss versus those who recovered.
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Affiliation(s)
- Ashok Jain
- Department of Surgery, Thomas E. Starzl Transplantation Institute
- School of Pharmaceutical Sciences, University of Pittsburgh Medical Center, Pittsburgh, PA
| | | | - Randeep Kashyap
- Department of Surgery, Thomas E. Starzl Transplantation Institute
| | - Karen Blakomer
- Department of Pathology, Thomas E. Starzl Transplantation Institute
| | - Kris Ruppert
- Graduate School of Public Health, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Akhtar Khan
- Department of Surgery, Thomas E. Starzl Transplantation Institute
| | - Susan Rohal
- Department of Surgery, Thomas E. Starzl Transplantation Institute
| | - Thomas E. Starzl
- Department of Surgery, Thomas E. Starzl Transplantation Institute
| | - John J. Fung
- Department of Surgery, Thomas E. Starzl Transplantation Institute
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Neil DA, Hubscher SG. Are parenchymal changes in early post-transplant biopsies related to preservation-reperfusion injury or rejection? Transplantation 2001; 71:1566-72. [PMID: 11435966 DOI: 10.1097/00007890-200106150-00014] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND The progression of parenchymal changes in liver allograft biopsies due to preservation-reperfusion injury (PRI) and their differentiation from rejection related changes is poorly understood. The aim of this study was to determine which changes in a 1-week posttransplant biopsy could be attributed to PRI and which to acute rejection. METHODS One week protocol liver transplant biopsies from patients with mild PRI (day 1 AST<400 IU/L) were compared with those from patients with severe PRI (day 1 AST>2000 IU/L). Parenchymal changes (cholestasis, ballooning, steatosis, necrosis) and rejection-related inflammatory features (portal tract inflammation, bile duct inflammation, portal vein endothelial inflammation, hepatic vein endothelial inflammation, and centrilobular inflammation) were blindly assessed semiquantitatively. RESULTS Fat, cholestasis, and hepatocyte ballooning were significantly worse in the severe PRI group, and these features showed no correlation with histological features related to acute rejection. Centrilobular hepatocyte necrosis correlated with hepatic venular endothelial inflammation and centrilobular inflammation but not with rejection related features in portal tracts or with PRI. These findings suggest that centrilobular necrosis is a manifestation of a rejection-related parenchymal injury and may involve different pathogenetic mechanisms to rejection-related features in portal tracts. CONCLUSIONS This study indicates that in early posttransplant biopsies, fat, cholestasis, and ballooning can largely be attributed to PRI. By contrast, centrilobular hepatocyte loss should be suspected as a rejection related phenomenon, even if typical portal tract changes are not prominent, and augmentation of immunosuppression should be considered.
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Affiliation(s)
- D A Neil
- Department of Pathology, Medical School, University of Birmingham, Edgbaston, Birmingham, UK.
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Demetris A, Adams D, Bellamy C, Blakolmer K, Clouston A, Dhillon AP, Fung J, Gouw A, Gustafsson B, Haga H, Harrison D, Hart J, Hubscher S, Jaffe R, Khettry U, Lassman C, Lewin K, Martinez O, Nakazawa Y, Neil D, Pappo O, Parizhskaya M, Randhawa P, Rasoul-Rockenschaub S, Reinholt F, Reynes M, Robert M, Tsamandas A, Wanless I, Wiesner R, Wernerson A, Wrba F, Wyatt J, Yamabe H. Update of the International Banff Schema for Liver Allograft Rejection: working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000; 31:792-9. [PMID: 10706577 DOI: 10.1002/hep.510310337] [Citation(s) in RCA: 358] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- A Demetris
- University of Pittsburgh Medical Center, PA 15213, USA.
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Gapany C, Zhao M, Zimmermann A. The apoptosis protector, bcl-2 protein, is downregulated in bile duct epithelial cells of human liver allografts. J Hepatol 1997; 26:535-42. [PMID: 9075660 DOI: 10.1016/s0168-8278(97)80418-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Apoptosis of bile duct cells occurs in hepatic allografts and is correlated with acute rejection. bcl-2 protein counteracts apoptosis and prolongs cell survival. We therefore tested the expression of bcl-2 protein in bile ducts of liver grafts in comparison with those of liver cirrhosis. METHODS 115 biopsies from 17 liver allografts and 47 biopsies of liver cirrhosis were analyzed and compared with 22 normal controls and with biopsies from patients with primary sclerosing cholangitis or primary biliary cirrhosis. bcl-2 protein and PCNA (proliferating cell nuclear antigen) expression was assessed using immunohistochemistry, and apoptosis was analyzed employing in situ DNA end-labeling. RESULTS A high apoptotic rate was detected in bile duct cells of allograft biopsies. In contrast to controls, bile duct cells of allografts and liver cirrhosis had high proliferative activity (mean PCNA labeling index: 1.0% vs. 40.7% and 18.6%, respectively). In liver grafts, bcl-2 protein positivity of bile duct and ductular cells was found in 3.6% and 4.4% of sections, respectively, and in cirrhosis in 44% and 79%, respectively (allografts vs. cirrhosis p<0.01). In controls, only one biopsy was bcl-2 positive. CONCLUSIONS Whereas increased proliferative activity of small bile ducts and ductules in cirrhosis is associated with a high degree of bcl-2 expression, bile duct and ductular cells in liver grafts have a very low bcl-2 protein reactivity, even though their proliferative activity is high. These findings suggest that downregulation of bcl-2 expression in allograft bile duct cells might play a role in the increased apoptosis of these cells in acute rejection.
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Affiliation(s)
- C Gapany
- Institute of Pathology of the University of Berne, Switzerland
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Li J, Helm K, Howell CD. Contributions of donor CD4 and CD8 cells to liver injury during murine graft-versus-host disease. Transplantation 1996; 62:1621-8. [PMID: 8970618 DOI: 10.1097/00007890-199612150-00016] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We have determined the capacity of donor CD4 and CD8 T cells to mediate liver injury in the B10.D2 (donor) into BALB/c (host) chronic graft-versus-host disease (GVHD) model. First, we compared the effects of treating GVHD mice with anti-CD4 or anti-CD8 versus no treatment on the liver histology scores and elevated serum IgE levels in this model. We also examined the abilities of purified donor total T, CD4, and CD8 cells to mediate hepatic GVHD lesions. Anti-CD4 and anti-CD8 treatments caused profound depletion of peripheral CD4+ and CD8+ cells, respectively, and produced a relative enrichment of the CD8+ and CD4+ cells in the liver. Hepatic GVHD lesions and elevated serum IgE concentrations were both suppressed by anti-CD4 treatment. Anti-CD8 treatment had no effect on the severity of hepatic lesions and caused a significant increase in serum IgE levels. Attempts to induce hepatic GVHD with purified donor CD4 and CD8 cells were inconclusive because the onset of liver lesions was delayed and the lesions in both groups were contaminated by the opposite subset. Altogether, our results indicate that both hepatic lesions and elevated serum IgE concentrations in this GVHD model are dependent on donor CD4 cells. Donor CD4 cells mediated hepatic GVHD in the absence of CD8 cells. Donor CD8 cells did not produce hepatic GVHD in the absence of CD4 cells and appeared to be dependent on CD4 cells.
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Affiliation(s)
- J Li
- University of Maryland, Baltimore School of Medicine 21201, USA
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13
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Pappo O, Ramos H, Starzl TE, Fung JJ, Demetris AJ. Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation. Am J Surg Pathol 1995; 19:192-206. [PMID: 7832279 PMCID: PMC3095883 DOI: 10.1097/00000478-199502000-00008] [Citation(s) in RCA: 97] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The clinicopathologic features of liver allograft dysfunction occurring in 51 symptomatic recipients after more than 5 years' survival (mean 7.1 years) with the same hepatic allograft were compared with those of a similar group of 14 asymptomatic patients (mean survival, 9.9 years) who underwent a nonclinically indicated protocol liver biopsy evaluation. Predictably, patients who had clinically indicated biopsies more frequently showed histopathologic alterations (76% versus 36%, p < 0.002). After detailed clinicopathologic correlation, the changes in the symptomatic patients were attributed primarily to definite or presumed viral hepatitis in 17 of 51 (33%) patients, 11 of whom had recurrent viral disease; seven of 51 (14%) had nonviral recurrent original disease, three (6%) had obstructive cholangiopathy, and 11 (22%) had acute and/or chronic rejection. In 13 of 51 (25%) of the symptomatic patients, the clinical and pathologic abnormalities were minimal. Long-term liver allograft survival in nine of 14 (64%) of the asymptomatic patients was associated with minimally abnormal histologic alterations. Two of the asymptomatic patients had obstructive cholangiopathy; two others has recurrence of the original disease and one has possible viral hepatitis. Viral hepatitis types B and C, alcoholic liver disease, autoimmune hepatitis, granulomatous hepatitis (not otherwise specified), and probably primary biliary cirrhosis and primary sclerosing cholangitis were shown to recur after hepatic transplantation. The histopathologic changes associated with acute and chronic rejection frequently overlapped with other syndromes causing late dysfunction, such as chronic viral or autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis; more than one insult could be identified in 15 cases, which made the differential diagnosis of causes of late liver allograft dysfunction much more difficult than early after hepatic transplantation. It is important to correlate the biopsy findings with the liver injury tests, the results of viral and autoimmune antibody serologic studies, and review of previous biopsies and to be aware of the original disease, recent changes in immunosuppression, and results of therapeutic intervention(s) to identify correctly the causes of liver allograft dysfunction in this patient population.
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Affiliation(s)
- O Pappo
- Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania 15213
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Affiliation(s)
- S G Hubscher
- Department of Pathology, Medical School, University of Birmingham, UK
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15
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Abstract
Orthotopic liver transplantation (OLT) has been used with increasing frequency as a definitive treatment for end-stage liver disease. Whereas the spectrum of pathology in the early posttransplant period is well documented, the clinicopathologic features of patients with late hepatic dysfunction are less clearly defined. In a series of 100 OLTs we identified 12 patients with progressive liver dysfunction 4 months after transplantation. Four patients succumbed rapidly to fulminant hepatitis 4 to 6 months following transplantation, three of whom had recurrent hepatitis B infection. One patient lost two successive grafts owing to hepatitis C. Liver biopsies were diagnostic for hepatitis in all cases. The outcome of the remaining eight patients with late hepatic dysfunction was grim. Their clinical courses were notable for intractable and progressive cholestasis. Five patients died and two others required retransplantation. Only one patient responded to increased immunosuppression with FK506. Ductopenia was a common feature of liver biopsies in these cases, but severe ductopenia (vanishing bile duct syndrome) was seen in the liver biopsies of only four patients. In contrast, occlusive arteriopathy and secondary ischemic changes were ubiquitous. In summary, the liver biopsy is a useful adjunct in the diagnosis of late OLT dysfunction, particularly in distinguishing recurrent viral hepatitis from chronic graft rejection. Centrilobular ischemic changes occur frequently in chronic rejection, whereas ductopenia may be difficult to document consistently.
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Affiliation(s)
- R Rubin
- Department of Pathology, Jefferson Medical College, Philadelphia, PA 19107
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Demetris AJ, Belle SH, Hart J, Lewin K, Ludwig J, Snover DC, Tillery GW, Detre K. Intraobserver and interobserver variation in the histopathological assessment of liver allograft rejection. The Liver Transplantation Database (LTD) Investigators. Hepatology 1991; 14:751-5. [PMID: 1937381 DOI: 10.1002/hep.1840140502] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A study to determine the reproducibility of histopathological findings and diagnoses of rejection was carried out on a series of 42 liver allograft needle biopsy specimens by five pathologists practicing at four liver transplant centers. Pathologists from each of the four centers read each slide independently on two different occasions and were asked to assess 12 histopathological features and render a diagnosis. For all histological variables, the intrarater agreement was higher than the interrater agreement. Moderate to excellent agreement occurred among the pathologists about all histological variables thought to be important in establishing the diagnosis of acute rejection (i.e., portal tract inflammation, subendothelial inflammation and bile duct damage). Other variables such as lobular disarray, bile duct proliferation and particularly arteritis, however, were only fairly or poorly reproducible. Surprisingly, the diagnosis of acute rejection was more reproducible than the individual histopathological findings that were thought to be the basis for the diagnosis. The agreement for the diagnosis of chronic rejection, however, varied according to observer. We noted that relatively inexperienced observers within this group had some difficulties agreeing with more experienced observers in establishing a diagnosis of chronic rejection. These findings demonstrate that the histopathological diagnosis of acute cellular liver allograft rejection is highly reproducible within a group of experienced pathologists and that this diagnosis can be pooled in a common data base with confidence.
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Affiliation(s)
- A J Demetris
- Presbyterian University Hospital, Department of Pathology, Pittsburgh 15213
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Wiesner RH, Ludwig J, van Hoek B, Krom RA. Current concepts in cell-mediated hepatic allograft rejection leading to ductopenia and liver failure. Hepatology 1991. [PMID: 1916676 DOI: 10.1002/hep.1840140424] [Citation(s) in RCA: 104] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hepatic allograft rejection is presently classified into acute and chronic rejection based on histological features, timing and reversibility. However, because features of both types of rejection can occur at any time, and in many combinations, the terms "acute" and "chronic" seem inappropriate in some instances. Thus the term "cellular rejection" better defines the histological features of portal hepatitis, nonsuppurative destructive cholangitis and endotheliitis, which are independent of time and response to therapy. Similarly, because progressive bile duct destruction leading to a decrease in the number of interlobular and septal bile ducts is the major histological feature of "chronic rejection," the term "ductopenic rejection," defined as the loss of bile ducts in 50% or more of portal tracts independent of time and reversibility, seems more appropriate. The pathogenesis of cell-mediated rejection has not been completely explained; however, direct immunocytic attack on small bile ducts and small arteries appear to be the major feature. The process may lead to bile duct loss ("ductopenia"). The pathogenetic role of foam-cell arteritis resulting in ischemic bile duct injury and the role of humoral mechanisms in causing ductopenic rejection awaits further clarification. In the past, irreversible ductopenic rejection occurred in approximately 10% of all patients who underwent their first liver transplantation; this figure, however, appears to be decreasing. The clinical features of irreversible rejection include persistent and progressive cholestasis; rising serum levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase; and a decrease in hepatic synthetic function. Ductopenic rejection can occur early (2 to 5 wk after liver transplantation) but most often develops between 6 wk and 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- R H Wiesner
- Division of Hepatology and Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905
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Otto G, Thies J, Kraus T, Manner M, Herfarth C, Hofmann WJ, Schlag H, Meuer S. Monoclonal anti-CD25 for acute rejection after liver transplantation. Lancet 1991; 338:195. [PMID: 1677101 DOI: 10.1016/0140-6736(91)90192-r] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Nonomura A, Mizukami Y, Matsubara F, Kobayashi K. Clinicopathological study of lymphocyte attachment to endothelial cells (endothelialitis) in various liver diseases. LIVER 1991; 11:78-88. [PMID: 2051905 DOI: 10.1111/j.1600-0676.1991.tb00496.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
An attachment of lymphocytes to the vascular wall, a feature called "endothelialitis" (ETL) or "endotheliitis", was investigated in various liver biopsies, including acute hepatitis (AH), hepatic infectious mononucleosis (IM), drug-induced hepatitis, alcoholic hepatitis and fibrosis, chronic persistent hepatitis (CPH), chronic active hepatitis (CAH), liver cirrhosis (LC), primary biliary cirrhosis (PBC), nonspecific reactive hepatitis (NSRH), and cases with a variety of diseases having almost normal liver histology as control material. Although ETL has been considered to be nearly pathognomic of graft-versus-host disease (GVHD) and acute transplant rejection, ETL was found in both portal and central veins with a variable incidence, not only in all categories of liver diseases, but also in the control group. The incidence of central vein ETL was significantly higher in AH, CAH, PBC, IM, alcoholic fibrosis, and NSRH than that of the control group, and that of portal vein ETL was significantly higher in AH, CPH, CAH, LC, PBC, IM, and alcoholic fibrosis. Even under the light microscope, lymphocytes attached to the endothelial cells had irregular cytoplasmic processes making contact with endothelial cells. Also lymphocytes located beneath the endothelial lining were frequently found. When ETL-positive and -negative cases in the same category were compared, the levels of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were usually higher in the ETL-positive group, and statistically significant differences were observed in CPH, CAH, LC, PBC and NSRH. In chronic hepatitis, the occurrence of portal vein ETL paralleled the histologic activity of portal inflammation, whereas central vein endothelialitis was associated with active parenchymal inflammation such as sinusoidal lymphocyte infiltration and spotty hepatocyte necrosis, indicating that ETL may be a phenomenon more frequently associated with active hepatic inflammation. Immunohistochemical observations revealed that about 70% of lymphocytes attached to the endothelial cells were T cells, while about 10% were B cells. These data indicate that ETL in the liver is not specifically pathognomonic for GVHD and rejection of liver transplants, and is universally found in a variety of liver diseases with a varying incidence and activity, related to the activity of hepatic inflammation, portal vein ETL occurring in relation to active portal inflammation and central vein ETL to parenchymal inflammation. Thus ETL is considered to be an intimate T lymphocyte-endothelial cell interaction universally associated with active hepatic inflammation; it may be an important phenomenon leading to accumulation of cellular exudates and their reaction at the site of antigen in the tissue.
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Affiliation(s)
- A Nonomura
- Pathology Section, Kanazawa University Hospital, School of Medicine, Japan
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Hubscher SG. Histological findings in liver allograft rejection--new insights into the pathogenesis of hepatocellular damage in liver allografts. Histopathology 1991; 18:377-83. [PMID: 2071098 DOI: 10.1111/j.1365-2559.1991.tb00865.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- S G Hubscher
- Department of Pathology, University of Birmingham Medical School, UK
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Goldstein NS, Hart J, Lewin KJ. Diffuse hepatocyte ballooning in liver biopsies from orthotopic liver transplant patients. Histopathology 1991; 18:331-8. [PMID: 2071091 DOI: 10.1111/j.1365-2559.1991.tb00854.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Mild to moderate liver injury to the orthotopically transplanted liver may result from acute rejection, mild ischaemia, or viral hepatitis. Because these conditions are often clinically indistinguishable, liver biopsy is frequently helpful. We previously characterized and reported the morphological spectrum of mild-to-moderate ischaemic injury from 170 liver biopsies (51 liver transplant patients). During this review, we found eight patients with a diffuse hepatocyte ballooning pattern. This pattern had some similarity to 'preservation injury' described by others, and in fact seven of the eight patients had these changes within the first 2 weeks post-transplant. However, two of the seven patients also displayed these changes up to 6 months post-transplant and the eighth patient developed these histological patterns only after the early post-transplant period. Follow-up data on patients with diffuse hepatocyte ballooning showed that some reverted to normal histology, some transformed to well-delineated perivenular ballooning, and some progressed to perivenular necrosis and/or infarction. Only when superimposed perivenular necrosis became apparent did the injury become irreversible, necessitating allograft removal or resulting in death. The pathogenesis of diffuse hepatocyte ballooning is unclear. However, the association of some of the cases with 'preservation injury' pattern in the early post-transplant period and the progression of others to necrosis and infarction, suggest an ischaemic basis for this lesion.
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Affiliation(s)
- T E Starzl
- Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania
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Ray R, Lewin K. Reply. Hum Pathol 1989. [DOI: 10.1016/0046-8177(89)90281-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Gubernatis G, Kemnitz J, Tusch G, Pichlmayr R. HLA compatibility and different features of liver allograft rejection. Transpl Int 1988; 1:155-60. [PMID: 3075475 DOI: 10.1007/bf00348839] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The influence of human leukocyte antigen (HLA) on acute liver allograft rejection was investigated in 48 adult patients. The diagnosis of rejection was always based on the full triad of histological findings, clinical signs, and the required antirejection treatment. Sixty-two percent of the patients closely observed for 6 months postoperatively revealed acute rejection within the first 3 weeks, mostly on days 7-11. HLA compatibility was not observed to have any significant influence on the incidence of acute rejection. However, different histological and clinical features were revealed in conjunction with DR compatibility. Patients without DR compatibility showed a type of rejection with fever and increase of bilirubin, frequently associated with cholestasis and cholangitis, which sometimes persisted for weeks. Patients with 1 DR compatibility showed a predominant increase of transaminases, which was never associated with cholangitis. The conjunction of different DR compatibilities and various clinical signs may indicate possible pathways from immunological assault to the clinical appearance of acute rejection. A knowledge of a patient's individual compatibility and an expectation of certain rejection patterns may lead to earlier and more reliable diagnosis and treatment.
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Affiliation(s)
- G Gubernatis
- Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschuls, Hannover, Federal Republic of Germany
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