Early Chronic Rejection Research Articles

Long-term CMV monitoring and chronic rejection in renal transplant recipients.

Cytomegalovirus (CMV) is well established to be an independent risk factor for graft loss after kidney transplantation (KTx). Monitoring for CMV in the chronic phase is not defined in the current guideline. The effects of CMV infection, including asymptomatic CMV viremia, in the chronic phase are unclear. We performed a single-center retrospective study to investigate incidence of CMV infection in the chronic phase, defined as more than 1 year after KTx. We included 205 patients who received KTx between April 2004 and December 2017. The CMV pp65 antigenemia assays to detect CMV viremia were continuously performed every 1-3 months. The median duration of the follow-up was 80.6 (13.1-172.1) months. Asymptomatic CMV infection and CMV disease were observed in 30.7% and 2.9% in the chronic phase, respectively. We found that 10-20% of patients had CMV infections in each year after KTx which did not change over 10 years. The history of CMV infection in the early phase (within 1 year after KTx) and chronic rejection were significantly associated with CMV viremia in the chronic phase. CMV viremia in the chronic phase was significantly associated with graft loss. This is the first study to examine the incidence of CMV viremia for 10 years post KTx. Preventing latent CMV infection may decrease chronic rejection and graft loss after KTx.

Regular protocol liver biopsy is useful to adjust immunosuppressant dose after adult liver transplantation.

Adjusting immunosuppression to minimal levels post-adult liver transplantation (LT) is critical; however, graft rejection has been reported in LT recipients with normal liver function evaluated by liver biopsy (LBx). Continual protocol liver biopsy (PLB) is performed regularly in LT recipients with normal liver function in some centers; however, its usefulness remains inadequately evaluated. This study aimed to assess retrospectively the usefulness of late PLB after adult LT. LBx evaluations of LT recipients with normal liver function and hepatitis B and C virus seronegativity were defined as PLB. The cases requiring immunosuppressive therapy for rejection findings based on Banff criteria were extracted from the PLBs, and pathological data collected before and after immunosuppressive dosage adjustment (based on modified histological activity index [HAI] score) were compared. Among 548 LBx cases, 213 LBx in 110 recipients fulfilled the inclusion criteria for PLB. Immunosuppressive therapy after PLB was intensified in 14 LBx (6.6%) recipients (12.7%); of these, nine had late-onset acute rejection, three had isolated perivenular inflammation, one had plasma cell-rich rejection, and one had early chronic rejection. Follow-up LBx after immunosuppressive dose adjustment showed improvement in the modified HAI score grading in 10 of 14 cases (71.4%). No clinical background and blood examination data, including those from the post-LT period, immunosuppressant trough level, or examination for de novo DSA, predicted rejection in PLB. Complications of PLB were found in only three cases. PLB is useful in the management of seemingly stable LT recipients, to discover subclinical rejection and allow for appropriate immunosuppressant dose adjustment.

Modulation of tissue resident memory T cells by glucocorticoids after acute cellular rejection in lung transplantation.

Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single-cell RNA and TCR sequencing on recipient-derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with rejection and compare them with T cells obtained from the same patients after treatment of rejection with high-dose systemic glucocorticoids. At the time of rejection, we found an oligoclonal expansion of cytotoxic CD8+ T cells that all persisted as tissue resident memory T cells after successful treatment. Persisting CD8+ allograft-resident T cells have reduced gene expression for cytotoxic mediators after therapy with glucocorticoids but accumulate around airways. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in situ expansion. We thus highlight the accumulation of cytotoxic, recipient-derived tissue resident memory T cells within the lung allograft that persist despite the administration of high-dose systemic glucocorticoids. The long-term clinical consequences of this persistence have yet to be characterized.

ABOi - A2 to O Liver Transplantation in a High MELD ESLD Patient: A Case Report

Introduction: Many ESLD patients die while on the waitlist due to limited donor pool. The inclusion of ABO incompatible donors to the pool has increased the number of transplants and expanded the donor pool. Case History: 43 year old male with ESLD secondary to PSC was listed for transplant with MELD of 40. He got A2 primary liver offer and underwent OLT in a bi-caval fashion. He required a hepaticojejunostomy due to PSC. On POD 5 he underwent a trans-jugular liver biopsy for rise in bilirubin and it was suggestive of AMR. His Anti A titers peaked at 1:1024 and Anti A2 at 1:256. He was treated with methylprednisolone and for rising antibody titers he required 6 sessions of PLEX/IVIG. His Anti A and Anti A2 titers were down to 1:256 and 1:32 respectively. Patient’s bilirubin and liver enzymes normalized and patient was discharged home. Discussion: ABOi liver transplant has been debatable due to higher incidence of early graft loss, acute and chronic rejection, vascular and biliary complications. With the advent of pre and post-transplant treatment modalities, the success rate of ABOi transplants match those of ABOc transplants. It becomes really important to break the barriers and transplant the incompatible livers as it needs to be increasingly utilized in the national liver allocation system so that better organ utilization and lower waitlist mortalities can be achieved. Hence, a non-identical liver transplant can be life-saving for a high MELD patient who would otherwise die awaiting an identical blood type offer.

Biliary and duodenal complications after «en bloc» liver-small bowel transplantation in children. A single center cohort study.

The technique of « en bloc» liver and small bowel transplantation (L-BT) spares a biliary anastomosis, but does not protect against biliary complications. We analyze biliary and duodenal complications (BDC) in our pediatric series. Between 1994 and 2020, 54 L-BT were performed in 53 children. The procurement technique included in situ vascular dissection and pancreatic reduction to the head until 2009 (group A). Thereafter, the whole pancreas was recovered (group B). Nine BDCs occurred in 8/53 (15%) patients (7 in group A and 1 in group B): leak of the donor's duodenal stump (2), stenosis of the extra-pancreatic bile duct (5), and intra-pancreatic bile duct stenosis (2). Median delay for diagnosis of stricture was 8months (4-168). Interventional radiology was successful in one child only, the others required reoperations. Two patients died, of biliary cirrhosis or cholangitis, 15-month and 12-year post-L-BT. One was listed and liver re-transplanted 13years post-L-BT. At last follow-up, two patients only had normal liver tests and ultrasound. BDC after L-BT can cause severe morbidities. Pancreatic reduction might increase this risk. Early surgical complications or chronic pancreatic rejection might be co-factors. Early diagnosis and treatment are key to the long-term prognosis.

Chronic lung allograft pathology lesions in two rat strain combinations.

BackgroundChronic lung allograft dysfunction remains an obstacle to long-term survival after lung transplantation. Two phenotypes have been described: obliterative bronchiolitis and restrictive allograft syndrome. Preclinical models are essential to analyze chronic lung allograft dysfunction pathophysiology.MethodsOrthotopic lung transplants from 38 Lewis into Fischer 344 (Lew→F344) and 67 Brown-Norway into Lewis (BN→Lew) rats were performed in our center in the last decade. We carefully reviewed and quantified all grafts with chronic rejection (40 cases) (18 Lew→F344, 22 BN→Lew) with the aim to investigate if histological changes of chronic lung allograft dysfunction could be also detected in rat grafts.ResultsAll animals showed human reminiscent histological lesions. Early chronic rejection lesions were detected in BN→Lew. End-stage chronic rejection with features of obliterative bronchiolitis was observed in 33% of Lew→F344; end-stage with restrictive allograft syndrome chronic rejection in 67% and 80% of Lew→F344 and BN→Lew, respectively. BN→Lew showed higher grades of endotheliitis, vascular fibrosis, and lower grades of lymphoid aggregates than Lew→F344 (P=0.007, P=0.043, P=0.004, respectively).ConclusionsChronic rejection lesions in rat lung allografts mimic those in humans. The frequent occurrence of restrictive allograft syndrome-like lesions in BN→Lew may be related to a higher degree of mismatch in this strain combination. These animal models could allow future mechanistic studies to better understand chronic lung allograft dysfunction pathogenesis.

Severe Unresolved Cholestasis Due to Unknown Etiology Leading to Early Allograft Failure Within the First 3 Months of Liver Transplantation.

Causes of severe cholestasis after liver transplantation (LT) are multi-factorial. Although the etiology is predictable in some, others culminate in graft/patient loss without a definitive cause identified. Severe cholestasis is usually associated with overlapped histological findings of rejection and biliary features, and diagnostic interpretation may pose a challenge. This is 10-year retrospective analysis of patients with unexplained severe cholestasis resulting in death/graft loss within 90 days of LT. Of 1 583 LT during the study period, 90-day graft failure occurred in 129 (8%) cases; a total of 45 (3%) patients had unresolving severe cholestasis (bilirubin, >100 μmol/L; alkaline phosphatase, >400 UI/L after 15 days from LT), excluding those due to primary nonfunction/sepsis/vascular causes (n = 84). Demographics, allograft biopsies, radiological investigations, and clinical outcome were analyzed. All patients had persistent abnormal liver biochemistry. Doppler ultrasound scan was normal in all cases. Thirty-five (78%) recipients had at least 1 allograft biopsy (2 [1-9]). On the first biopsy, 22 (63%) patients had acute rejection, 4 (18%) early-chronic rejection, 12 (34%) antibody-mediated rejection. In subsequent biopsies chronic rejection was evident in 5 (14%) cases. Donor-specific antibodies were detected in all patients tested. Biliary anatomy was studied in detail in 9 (20%) patients, all presenting biliary strictures. The majority (n = 39; 87%) died within 32 (10-91) days, only survivors were from retransplantation (n = 3;6.5%) and biliary intervention (n = 3;6.5%). Unresolving severe cholestasis after LT is a key parameter predicting patient/allograft outcome. Histologically, rejection seems to overlap with biliary strictures; hence, allograft biopsy with signs of rejection should not be a reason to overlook biliary problems, in particular when biliary features are present. Only extensive radiological investigation/intervention or retransplantation prevents patient/allograft loss.

Intimal Arteritis Associated with Microvascular Inflammation even in the Absence of Donor-Specific Antibodies might result into early Chronic Rejection

Intimal Arteritis Associated with Microvascular Inflammation even in the Absence of Donor-Specific Antibodies might result into early Chronic Rejection

Avascular Osteonecrosis of the Knee in a Post Liver Transplant Patient with Recurrent Cholangitis and Early Chronic Rejection

Avascular Osteonecrosis of the Knee in a Post Liver Transplant Patient with Recurrent Cholangitis and Early Chronic Rejection

How Do Dendritic Cells Play the Role in Ischemia/Reperfusion Triggered Kidney Allograft Rejection.

In deceased donors, Ischemia/Reperfusion Injury (IRI) is an important cause of allograft dysfunction. Prolonged cold and warm ischemia time leads to a high risk of early post-transplant complications, including acute and chronic rejection. Ischemia not only up-regulates inflammatory cytokines and chemokines, but also enhances the expression of MHC-class II and adhesion molecules on epithelial and dendritic cells. Moreover, the Danger Associated Molecular Patterns (DAMPs) released from stressed or dying cells, not only cause or amplify tissue inflammation and trigger tissue repair in response to IRI, but also act as adjuvants that enhance DC maturation and potentiate the adaptive immune response. In this review, we will also discuss about whether donor or recipient DCs are more important in the process of ischemia enhanced acute rejection.

Proton Pump Inhibitors Independently Protect Against Early Allograft Injury or Chronic Rejection After Lung Transplantation.

Acid reflux has been associated with poor outcomes following lung transplantation. Unlike surgical fundoplication, the role of noninvasive, pharmacologic acid suppression remains uncertain. To assess the relationship between post-transplant acid suppression with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) and onset of early allograft injury or chronic rejection following lung transplantation. This was a retrospective cohort study of lung transplant recipients at a tertiary center in 2007-2014. Patients with pre-transplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess acid suppression therapy and onset of acute or chronic rejection, defined histologically and clinically. Subgroup analyses were performed to assess PPI versus H2RA use. A total of 188 subjects (60% men, mean age 54, follow-up 554 person-years) met inclusion criteria. During follow-up, 115 subjects (61.5%) developed rejection, with all-cause mortality of 27.6%. On univariate analyses, acid suppression and BMI, but not other patient demographics, were associated with rejection. The Kaplan-Meier curve demonstrated decreased rejection with use of acid suppression therapy (log-rank p=0.03). On multivariate analyses, acid suppression (HR 0.39, p=0.04) and lower BMI (HR 0.67, p=0.04) were independently predicted against rejection. Subgroup analyses demonstrated that persistent PPI use was more protective than H2RA or no antireflux medications. Post-lung transplant exposure to persistent PPI therapy results in the greatest protection against rejection in lung transplant recipients, independent of other clinical predictors including BMI, suggesting that PPI may have antireflux or anti-inflammatory effects in enhancing allograft protection.

(65) - Matrix Metalloproteinase-7 May Be a Biomarker of Early Chronic Lung Rejection

(65) - Matrix Metalloproteinase-7 May Be a Biomarker of Early Chronic Lung Rejection

Peritubular capillary basement membrane multilayering in early and advanced transplant glomerulopathy: quantitative parameters and diagnostic aspects.

The ultrastructural quantitative aspects of peritubular capillary basement membrane multilayering (PTCBML) were examined in 57 kidney transplant biopsies with transplant glomerulopathy (TG). The measurements included three cutoffs [permissive: 1 PTC with 5 basement membrane (BM) layers, intermediate: 3 PTCs with 5 layers or 1 PTC with 7 layers, strict: 1 PTC with 7 layers and 2 PTCs with 5 layers] and the mean number of BM layers (PTCcirc). Two groups were assigned, namely patients with mild TG (Banff cg1a and cg1b) and those with moderate-to-severe TG (cg2 and cg3). Their respective clinical, serological, and morphological characteristics were then compared. The clinical data revealed that mild TG corresponded to early chronic antibody-mediated rejection (cABMR), while moderate-to-severe TG corresponded to the advanced stage of the disease. The permissive threshold displayed the lowest specificity (73%) and the highest sensitivity (83%) for moderate-to-severe TG, and its corresponding PTCcirc value was 3 layers. In contrast, the strict threshold-adopted by the Banff 2013 classification-displayed a specificity and sensitivity of 93 and 52%, respectively, and the corresponding PTCcirc was 4 layers. In mild TG, 26% of the cases met the permissive cutoff and 6% the strict cutoff. Mild TG was associated with a lower PTCcirc (2.6 layers vs 4.5 layers in moderate-to-severe TG; p<0.0001). Amongst the various criteria, the permissive criterion was associated most frequently with mild TG, and had prognostic relevance. Because of this, we propose its usage as a marker of early cABMR-induced PTCBML if non-alloimmune causes of PTCBML can be ruled out.

A proteomic analysis of transplanted liver in a rat model of chronic rejection

Chronic rejection (CR) is an important cause of liver allograft failure. In the latter condition, re-transplantation of the liver (ReLT) is the only option for survival. Unfortunately, with the current state of knowledge, it is difficult to diagnose and treat early CR. To explore the biomarkers of the chronic rejection in orthotopic liver transplantation (OLT). A rat model of chronic liver allograft rejection was established, and the differential protein expression in chronic allograft rejection (CR) was analyzed by iTRAQ-MALDI-TOF/TOF. Expression of sixty-two proteins was found to be significantly changed in CR rats. In the present study, CLU, Lcn2 and Krt19 were identified and quantified as early and reliable biomarkers for chronic rejection. Analysis of differential protein expression by iTRAQ-MALDI-TOF/TOF is a potentially effective method to help understand the mechanism of CR in orthotopic liver transplantation. The proteins CLU, Lcn2 and Krt19 might be potential prognostic markers for predicting chronic rejection after liver transplantation.

OR38: CARFIZOMIB FOR REFRACTORY ANTIBODY MEDIATED REJECTION IN LUNG TRANSPLANTATION THE IMPACT ON DSA

Aim Antibody mediated rejection (AMR) after lung transplantation (LTx) is associated with early and severe chronic rejection and death. Conventional therapies consisting of plasma exchange and IVIG with and without Rituximab are partially effective. Newer therapies with proteasome inhibitors (Carfizomib (CFZ) and Bortezomib (BTZ)) that target both B and plasma cells may be more effective in removing the donor specific antibodies (DSA). CFZ, unlike BTZ, irreversibly inhibits the activity of 20S proteasome and results in less neuropathic side effects. Method We evaluated the impact of CFZ therapy in 7 LTx on DSA level and function and correlated with clinical outcome as measured by pulmonary function test. All 7 patients had DSA IgG specificity and titer measured by single antigen bead Luminex assay and DSA function of complement binding by C1q-screen at baseline and at 1 month and 3 months post-treatment. Results The specificity, strengths and C1q reactivity pre- and post-therapy is summarized in Table below. All 7 patients had class II DSA and 6/7 were DQ specific with C1q reactivity. 5/7 LTx responded to initial treatment with a drop in IgG DSA level, with negative C1q DSA reactivity ( 15,000 MFI the IgG DSA was inhibited (“prozone effect”), however IgG DSA significantly increased in the presence of EDTA (LTx 3, 5, 6, 7). Conclusion In this small cohort of LTx who mostly failed conventional therapies and have persistent DSA, CFZ based approach appears to be useful, initially. However, 5/7 LTx recovered their C1q DSA reactivity upon longer follow-up suggesting that one cycle of CFZ it may not be effective to impact the rebound of circulating DSA.

68: Predictive markers for the detection of antibody-mediated rejection in kidney transplantation : Procalcitonin and CH50

Aims Antibody-mediated rejection (AMR) is the leading cause of early allograft loss, chronic rejection and graft failure. The aim of this research is to clarify useful predictive serum marker for occurrence of AMR in patients after kidney transplantation (KT). Methods Forty-two KT patients were studied; 32 with AMR and 10 without AMR. The AMR is confirmed by presence of donor-specific antibodies and positive C4d staining on renal biopsy. Plasma levels of IL-6, procalcitonin (PCT) and CH50 were measured in KT patients and 40 healthy subjects. Statistical analyses were performed by Kruskal–Wallis test. Results Median levels of CH50 were 18.20, 46.40 and 28.15 U/mL in KT patients with AMR, KT patients without AMR, and healthy subjects, respectively. And, PCT levels were 0.045, 0.033 and less than 0.020 ng/mL; and IL-6 were 1.93, 3.48, and less than 1.50 pg/mL, respectively. IL-6 and PCT showed no statistically significant differences, but CH50 was significantly decreased in the group with AMR than without AMR after KT ( p p = 0.0020) and without AMR (0.0335 ng/mL, p = 0.0010). Conclusions The significant decline of CH50 in KT patients with AMR may implicate that the complement system participates in renal antibody-mediated rejection and CH50 would be useful predictive marker for the detection of AMR in KT patients. Also, further evaluation on the usefulness of PCT is needed as a predictive marker of early AMR in KT.

Early Chronic Rejection in Lung Transplant Recipients Is Significantly Increased in Patients With a HLA-DR15+ Donor.

Background: Previous studies have shown that lung transplant patients who develop Th17 autoimmunity to collagen type V (colV) are significantly more likely to develop bronchiolitis obliterans syndrome (BOS) than those who remain colV-unresponsive. HLA-DR15 is associated with a high immune response to colV and binds several peptides of colV α1 with very high affinity. Furthermore, a DR1+, colV-reactive patient who was negative for DR15, but received a lung transplant from a DR15-expressing donor, was able to respond strongly to both DR1- and DR15-binding peptides. Purpose: The purpose of this study was to determine if there are donor HLA-DR types that are significantly more frequent in lung transplant patients that develop severe BOS, and if so, whether DR15 is one. Methods: Demographic data from lung transplant donors and recipients transplanted at a single center was retrospectively collected using an institutionally approved IRB protocol. Severe BOS2 was diagnosed when the recipient's forced expiratory volume (FEV1) dropped below 65% of their maximum post-transplant value. Comparisons were made between recipients who did or did not develop BOS2 and significant differences were determined using a two-tailed Fisher's Exact Test. Results: Data was analyzed from 279 subjects receiving a single or bilateral lung transplant between 1988 and December 2008. Patients were followed through November 2013 or until they experienced graft loss or death. Patient follow-up averaged 6.7 years with 108 or 43% developing BOS2. The average time to BOS2 was 4 years with a median of 3 years. The rate of BOS2 was similar in recipients of single and bilateral lung transplants. There was no HLA-DR bias (donor or recipient HLA-DR type) in risk of BOS2 when all BOS2 events were considered. However, when only early BOS2 (developing by year 3 post transplant, n=52 subjects) was considered, there was a significantly higher frequency of HLA-DR15 (p=0.004) and HLA-DR13 (p=0.02) amongst the DONORs of these recipients. Conclusions: Receipt of a healthy lung from a HLA-DR15-expressing donor increases the risk of early severe BOS. These results are consistent with the hypothesis that HLA-DR15 in the lung donor heightens the risk of de novo autoimmunity to colV and hence BOS2 risk. At present it is not known what the increased incidence of early BOS2 in recipients with DR13 expressing donors means.

Liver allograft pathology in healthy pediatric liver transplant recipients

Liver transplantation offers excellent results for children with end-stage liver disease, and efforts should be directed toward maintaining long-term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low-maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long-term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term.

Association between a TGFBR2 Gene Polymorphism (rs2228048, Asn389Asn) and Acute Rejection in Korean Kidney Transplantation Recipients

Transforming growth factor-β (TGF-β) signaling transduction initiates TGF-β activation, resulting in activation of TGF-β receptor II (TGFBR2). Any quantitative and qualitative changes in TGFBR2 are expected to affect the TGF-β signaling pathway, which occupies a central position with respect to the regulation of cell growth, differentiation, apoptosis, immune reaction, angiogenesis and extracellular matrix formation. Recent studies have shown that TGF-β1 gene polymorphisms may confer susceptibility to early acute and chronic allograft rejection in kidney transplantation recipients. In this study, we assessed whether polymorphisms of the TGFBR2 gene were associated with susceptibility to kidney transplantation rejection. A total of 347 renal allograft recipients transplanted at three centers in Korea were analyzed. Three SNPs (rs764522, rs3087465, rs2228048) of the TGFBR2 gene were genotyped from genomic DNA with direct sequencing. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. A total of 63 patients (18%) developed acute rejection (AR). There were no significant differences in age, sex, number of HLA mismatches, cause of renal failure, or immunosuppressant regimen between the AR and non-AR group. The synonymous SNP rs2228048 was significantly associated with AR (p = 0.020 in recessive model, and p = 0.036 in log-additive model. The allele frequencies of rs2228048 were different between the AR and non-AR group (p = 0.026). These results suggest that the synonymous TGFBR2 gene SNP rs2228048 may be associated with the development of AR in Korean kidney transplantation recipients.Authors Yeong-Hoon Kim and Tae Hee Kim contributed equally to this work and are considered co-first authors.

Chronic Antibody-Mediated Rejection in Rat Orthotopic Liver Transplantation

Introduction: In chronic rejection in Banff schema for liver allograft rejection, the early and late chronic rejection has been defined. However, the pathological characteristics of chronic antibody-mediated rejection in liver allogarfts have not been fully investigated. In the present study, we examined the pathology of chronic antibody-mediated rejection using rat liver transplantation. Method: Orthotopic liver transplantation was performed from Lewis (RT1l) to BN (RT1n) rats without immunosspression. In this allogenic combination, the liver grfts transplantated with hepatic artery reconstruction could survive more than 100 days, although the grafts transplanted without hepatic artery reconstruction were rejected by day 35 with extensive T cell-mediated and antibody-mediated rejection. We studied Lewis liver grafts that were transplnated into BN rats with hepatic artery reconstruction, focusing on the pathological characteristics of chronic rejection accompanied with chronic antibody-mediated rejection in liver grafts. Results: The grafts transplanted with hepatic artery reconstruction could survived more than 100 days with mild graft dysfunction (T-Bil 0.4 ± 0.1 mg/dl, AST 198.1 ± 19.9 mg/dl), after the eraly severe T cell- and antibody-mediated rejection and graft dysfunction (T-Bil 4.9 ± 1.4 mg/dl, AST 420.8 ± 134.4 mg/dl). Between day 7 and day 28, in addition to the development of T cell-mediated rejection, the deposition of IgM and IgG was detected on endothelial cells in portal veins and hepatic arteries, epithelial cells in bile ducts, and hepatic cells in lobules. After day 28, T cell-mediated rejection gradually subsided but continued more than day 100. The deposition of IgM and IgG was also contnued mainly on endothelial cells in portal veins and hepatic arteries, suggesting the development of chronic antibody-mediated rejection. In light and electron microscopic studies at more than day 100, most prominent features were persistent endothelial cell injuries in portal veins and hepatic arteries with obliterative vasculopathy, diffuse sinusoidal fibrosis, and obstructive cholangiopathy and ductopenia. Conclusion: In chronic liver allograft rejection, chronic antibodymediated rejection could develop with graft dysfunction. The pathological characteristics of chronic rejection accompanied with chronic antibodymediated rejection were similar features as late chronic rejection, but they progressed within short periods with typical obliterative vasculopathy and ductopenia. This animal model is useful for the evaluation of the mechanism and pathological characteristics of chronic antibodymediated liver allograft rejection.