OBJECTIVE: To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation. METHODS: Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema. RESULTS: Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ²=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01). CONCLUSIONS AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.
Animals ; Benzamides ; Graft Rejection/prevention & control* ; Graft Survival ; Liver/pathology* ; Liver Transplantation ; Mechanistic Target of Rapamycin Complex 1 ; Morpholines ; Pyrimidines ; Rats ; Rats, Inbred Lew

Bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HSCT) is a major cause of morbidity and mortality with limited treatment options. Lung transplantation (LTX) has been rarely reported as a treatment option for selected HSCT recipients with this problem. In the present study, we reported six patients who underwent LTX due to BOS after HSCT (two females, four males) from January 2012 to December 2014 in our center. The median time from HSCT to diagnosis of BOS was 2.5 years (ranging from 1 to 5 years). At a median time of 4 years (ranging from 2 to 5 years) after diagnosis of BOS, four patients received bilateral sequential LTX, and two patients received single LTX. One of the recipients suffered from mild acute rejection after LTX, another suffered from primary lung graft dysfunction on post-operation day 2, and three experienced fungal infections. The median time for follow-up after LTX was 19.5 months (ranging from 12 to 39 months). At present, all patients are alive with good functional capacity and no relapse of BOS and hematologic malignancy conditions. Patients who received bilateral LTX have better pulmonary functions than patients who received single LTX.
Adolescent ; Adult ; Bronchiolitis Obliterans ; etiology ; surgery ; Female ; Graft Rejection ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Lung ; diagnostic imaging ; pathology ; Lung Transplantation ; Male ; Mycoses ; Tomography, X-Ray Computed ; Young Adult

OBJECTIVETo study the clinical and histopathologic features of post-transplant kidney biopsy tissues from pediatric C-III donors.

METHODSThe clinical and pathologic features of 20 cases (22 case-times) of renal transplant biopsies from pediatric cadaveric donors were analyzed by light microscopy and immunohistochemistry according to the Banff system of working classification of renal allograft pathology. Biopsies were compared to those from adult C-III donors and adult cadaveric donors.

RESULTSSixteen cases (72.7%) showed renal allograft drug toxicity damage by Tacrolimus, seven cases (31.8%) showed degeneration and necrosis of renal tubular epithelial cells, four cases (18.2%) showed T cell-mediated acute rejection and six cases (27.3%) showed renal interstitial inflammation. There were two cases (9.1%) of renal dysplasia and one case (4.5%) of renal infarction. There was insufficient evidence for diagnosis of renal allograft nephropathy. Compared to post-transplant kidney from adult C-III donors, the proportion of drug toxicity damage was higher (P<0.05). Compared to post-transplant kidney from adult cadavers, the proportions of drug toxicity damage, degeneration and necrosis of renal tubular epithelial cells were higher (P<0.05) while the proportion of acute rejection was lower (P<0.05).

CONCLUSIONSThe pathologic changes in the post-transplant kidneys from pediatric donors are different from those from adult donors. Optimal long-term outcome can be accomplished by effective treatment based on timely or procedural biopsy.

Adult ; Age Factors ; Biopsy ; Cadaver ; Child ; Graft Rejection ; pathology ; Humans ; Immunohistochemistry ; Immunosuppressive Agents ; adverse effects ; Infarction ; pathology ; Kidney ; blood supply ; drug effects ; pathology ; Kidney Transplantation ; Kidney Tubules ; drug effects ; pathology ; Necrosis ; Tacrolimus ; adverse effects ; Transplantation, Homologous ; Treatment Outcome

OBJECTIVE: To explore the effect of pre-transplant donor specific antibody (DSA) on antibody-mediated rejection (AMR) and function of transplanted kidney.
 METHODS: A total of 88 cases of renal transplant recipients were selected. Before surgery, DSA was examined by Luminex liquid phase chip in renal transplant recipients. The recipients were divided into a DSA positive group (n=20) and a DSA negative group (n=68). The follow-up time was 2 years. After the operation, the pathologic morphology of the transplanted kidney was evaluated and classified according to the Banff 2005 standard. The situation for the transplanted kidney was evaluated.
 RESULTS: The incidence of AMR in the DSA positive group and negative group was 20% and 1.5%, respectively, with significant difference between them (P<0.01). The incidence of graft loss in the DSA positive group and negative group was 15% and 1.5%, respectively, with significant difference between them (P<0.05). The pre-transplant DSA associated with AMR at multiple mean fluorescence intensity (MFI) was obvious different from that without AMR (P<0.01). Receiver operating characteristic (ROC) curves showed that the maximal MFI threshold for recipients with AMR was 7909.5 after renal transplantation. There was no significant difference in the delayed recovery of renal graft function (DGF) between the 2 groups (P>0.05).
 CONCLUSION The detection of DSA level before renal transplantation can predict the risk of AMR and the function of transplanted kidney. The MFI intercept point of the highest DSA (MFI>
7909.5) can be used to predict the risk of AMR.
Antibody Specificity ; Graft Rejection ; Humans ; Incidence ; Isoantibodies ; blood ; Kidney ; pathology ; Kidney Transplantation ; ROC Curve

BACKGROUND: Angiotensin II type 1 receptor (AT1R) is responsible for cardiovascular effects mediated by angiotensin II. This study aimed to investigate the impact of antibodies directed against AT1R (anti-AT1R) in renal allograft rejection. METHODS: We evaluated 53 patients who had biopsy-proven rejection including antibody-mediated rejection (AMR) (N=22), T-cell-mediated rejection (TCMR) (N=29), and mixed AMR and TCMR (N=2). Donor specific HLA antibodies (DSA) and anti-AT1Rs were simultaneously determined. RESULTS: Anti-AT1Rs were detected in 9.4% (5/53) of rejection patients (one with acute AMR, two with chronic active AMR, one with acute TCMR, and one with mixed acute AMR & TCMR). HLA antibodies and DSA were detected in 75.5% (40/53) and 49.1% (26/53) of patients, respectively. There was no significant difference in transplant characteristics between anti-AT1R(+) and anti-AT1R(-) patients except for the association of HLA class-I DSA(+) and anti-AT1R(+). Four of five anti-AT1R(+) patients had DSA and were also found to have AMR. A single anti-AT1R(+)/DSA(-) patient developed acute TCMR. Detection rates of DSA, HLA antibodies, or anti-AT1R were not different between AMR and TCMR. However, DSA(+)/anti-AT1R(+) was more frequently found in AMR than in TCMR (P=0.036). Patients with anti-AT1R showed a greater tendency to develop high-grade rejection as Banff IIA/IIB or AMR. CONCLUSIONS: The presence of anti-AT1R was significantly associated with HLA class-I DSA in renal allograft rejection patients. Both anti-AT1R and DSA positivity was associated with AMR in patients with renal allograft rejection.
Adult ; Antibodies/blood ; Female ; Graft Rejection/*etiology ; HLA Antigens/immunology ; Humans ; Kidney/pathology ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Receptor, Angiotensin, Type 1/*immunology ; Tissue Donors ; Transplantation, Homologous

Since the introduction of pancreas transplantation more than 40 years ago, surgical techniques and immunosuppressive regiments have improved and both have contributed to increase the number and success rate of this procedure. However, graft survival corresponds to early diagnosis of organ-related complications. Thus, knowledge of the transplantation procedure and postoperative image anatomy are basic requirements for radiologists. In this article, we demonstrate the imaging spectrum of pancreas transplantation with enteric exocrine drainage.
Adult ; Anastomosis, Surgical/methods ; Diagnostic Imaging/methods ; Drainage/methods ; Female ; Graft Rejection/pathology ; Graft Survival ; Humans ; Iliac Artery/radiography/surgery ; Immunosuppressive Agents ; Kidney Transplantation ; Male ; *Medical Illustration ; Mesenteric Artery, Superior/radiography/surgery ; Middle Aged ; Pancreas/*blood supply/radiography ; Pancreas Transplantation/adverse effects/*methods ; Pancreatitis, Graft/etiology ; Portal Vein/radiography/surgery ; Postoperative Complications/radiography ; Postoperative Hemorrhage/etiology ; Survival Rate

BACKGROUND/AIMS: The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT). METHODS: Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT. RESULTS: In the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively. CONCLUSIONS: A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.
Adult ; Aged ; Area Under Curve ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Gastrointestinal Diseases/etiology ; Graft Rejection/prevention & control ; Humans ; Immunosuppressive Agents/blood/*pharmacokinetics ; Leukopenia/etiology ; Liver/pathology ; Liver Failure/*therapy ; *Liver Transplantation ; Male ; Middle Aged ; Mycophenolic Acid/adverse effects/*analogs & derivatives/blood/pharmacokinetics ; ROC Curve ; Retrospective Studies ; Tacrolimus/therapeutic use ; Tissue Donors

OBJECTIVETo investigate the pathological and immunological changes of renal grafts in recipients experiencing graft rejection.

METHODSThe clinicopathologic data of 56 renal needle biopsy samples obtained from renal transplant recipients were analyzed retrospectively. The specimens were classified histopathologically according to the Banff 2009 classification system and analyzed by immunohistochemical labeling and immunofluorescence.

RESULTSIn the 56 recipients, 1 (1.79%) experienced hyperacute rejection, 8 (14.29%) had suspected acute rejection, 12 (21.43%) developed acute T-cell rejection, 6 (10.71%) had acute antibody-mediated rejection, 2 (3.57%) had acute T-cell rejection with acute antibody-mediated rejection, 12 (21.43%) had chronic active T cell-mediated rejection, 2 (3.57%) had chronic active antibody-mediated rejection, 2 (3.57%) had chronic active T cell-mediated rejection with antibody-mediated rejection, 8 (14.29%) had non-specific interstitial fibrosis and tubular atrophy, and 3 (5.36%) had normal graft function. The expression levels of immune markers CD3, CD4, CD8, CD20, GrB and perforin differed with the types of T cell-mediated graft rejection, and the positivity and expression levels of these markers tended to increased with the severity of graft rejection. The expression of C4d was positive in all cases with antibody-mediated graft rejection.

CONCLUSIONSThe pathological characteristics of the renal biopsy specimens and expression levels of the immune markers allow timely and accurate evaluation of graft rejection type to provide a reliable pathological and etiological basis for clinical treatment and prognostic assessment.

Adolescent ; Adult ; Aged ; Female ; Graft Rejection ; immunology ; pathology ; Graft Survival ; Humans ; Kidney ; immunology ; pathology ; Kidney Transplantation ; adverse effects ; Male ; Middle Aged ; Retrospective Studies ; Young Adult

Recent data suggest that activation of aryl hydrocarbon receptor (AhR) by its high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in expansion of regulatory T (Treg) cells and suppresses the development of autoimmune and allergic diseases in several models. Treg cells have been increasingly documented to suppress allograft rejection and even to establish stable long-term graft acceptance. However, the involvement of TCDD in the regulation of solid organ transplantation rejection is largely unknown. Here, we examined whether activation of AhR with TCDD altered cardiac allograft rejection in an allogeneic heart transplant model. Recipient C57BL/6 (H-2b) mice were administrated with a single intraperitoneal injection of TCDD, and the murine cardiac transplant models from BALB/c (H-2d) to C57BL/6 (H-2b) were built 24 h later. The complete cessation of cardiac contractility was defined as the observation endpoint. The effect of TCDD on T-cell proliferation was assessed by mixed lymphocyte reaction (MLR). Histological and immunohistochemical analyses were performed to estimate the severity of rejection. The phenotype and cytokine profile of lymphocytes were analyzed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Activation of AhR remarkably prolonged the survival of cardiac allografts to more than 20 days. In vitro, TCDD ugregulated the frequency of CD4+CD25+Foxp3+ Treg cells and suppressed the proliferation of T lymphocytes. In vivo, the prolonged survival time was associated with increased number of Treg cells in allografts and spleens. Furthermore, the secretion of interferon-γ (IFN-γ) and interleukin-17 (IL-17) was reduced to less than 50% of that of the PBS treatment control group by TCDD treatment, whereas IL-10 was elevated to 10-fold of that of the PBS treatment control group. Collectively, our data indicate that activation of AhR with a single dose of TCDD significantly prolonged the survival of fully allogeneic cardiac grafts, and the mechanism underlying this effect might be involved in the induction of Treg cells.
Animals ; Graft Rejection ; immunology ; pathology ; prevention & control ; Graft Survival ; drug effects ; immunology ; Heart Transplantation ; adverse effects ; methods ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Polychlorinated Dibenzodioxins ; pharmacology ; Receptors, Aryl Hydrocarbon ; immunology ; T-Lymphocytes ; immunology ; pathology ; T-Lymphocytes, Regulatory ; immunology ; pathology

INTRODUCTIONRenal transplant rejection involves both immunological and non-immunological factors. The objective of the present study was to investigate the association between immunological factors, such as serum interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α), and non-immunological parameters, such as age, serum creatinine (SCr), creatinine clearance (CrCl) and dyslipidaemia, in renal transplant recipients (RTRs).

METHODSThis study included 90 RTRs and 90 healthy controls. Biochemical parameters, including serum IL-6 and TNF-α, were estimated using standard protocols. CrCl was calculated using the Cockroft-Gault equation, and the type of rejection was confirmed on biopsy. Student's t-test and univariate and multivariate analyses were performed using the Statistical Package for the Social Sciences for Windows version 15.

RESULTSThe mean levels of serum IL-6 and TNF-αwere significantly higher in RTRs than in the control group (p < 0.001). These parameters were also found to be significantly different between the transplant rejection (TR) and transplant stable (TS) groups (p < 0.001). CrCl was significantly decreased in the TR group when compared to the TS group (p < 0.001). The two cytokines, IL-6 and TNF-α, correlated significantly with all metabolic parameters, such as SCr, CrCl and dyslipidaemia. Multiple regression analysis showed that TNF-α and CrCl were the strongest predictors of IL-6.

CONCLUSIONWe conclude that immunological factors, as well as non-immunological factors such as CrCl, SCr and dyslipidaemia, play important roles in the pathogenesis of graft rejection and renal graft dysfunction.

Adult ; Biomarkers ; blood ; Biopsy ; Creatinine ; blood ; Female ; Follow-Up Studies ; Graft Rejection ; blood ; pathology ; Humans ; Interleukin-6 ; blood ; Kidney ; pathology ; Kidney Transplantation ; Male ; Predictive Value of Tests ; Retrospective Studies ; Time Factors ; Tumor Necrosis Factor-alpha ; blood