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J D Perkins

Publications and source records attributed to J D Perkins.

At least 19 recordsLinked to original sources
PubMed2006

The role of Foxp3+ regulatory T cells in liver transplant tolerance.

The liver has long been considered a tolerogenic organ that favors the induction of peripheral tolerance. The mechanisms underlying liver tolerogenicity remain largely undefined. In this study, we characterized Foxp3-expressing CD4+ CD25+ regulatory T cells (Treg) in liver allograft recipients and examined the role of Treg in inherent liver tolerogenicity by employing the mouse spontaneous liver transplant tolerance model. Orthotopic liver transplantation was performed from C57BL/10 (H2b) to C3H/HeJ (H2k) mice. The percentage of CD4+ CD25+ Treg was expanded in the liver grafts and recipient spleens from day 5 up to day 100 posttransplantation, associated with high intracellular Foxp3 and CTLA4 expression. Immunohistochemistry further demonstrated significant numbers of Foxp3+ cells in the liver grafts and recipient spleens and increased transforming growth factor beta expression in the recipient spleens throughout the time courses. Adoptive transfer of spleen cells from the long-term liver allograft survivors significantly prolonged donor heart graft survival. Depletion of recipient CD4+ CD25+ Treg using anti-CD25 monoclonal antibody (250 microg/d) induced acute liver allograft rejection, associated with elevated anti-donor T-cell proliferative responses, CTL and natural killer activities, enhanced interleukin (IL)-2, interferon-gamma, IL-10, and decreased IL-4 production, and decreased T-cell apoptotic activity in anti-CD25-treated recipients. Moreover, CTLA4 blockade by anti-CTLA4 monoclonal antibody administration exacerbated liver graft rejection when combined with anti-CD25 monoclonal antibody. Thus, Foxp3+ CD4+ CD25+ Treg appear to underpin spontaneous acceptance of major histocompatability complex- mismatched liver allografts in mice. CTLA4, IL-4, and apoptosis of alloreactive T cells appear to contribute to the function of Treg and regulation of graft outcome.

Animals↗
PubMed2006

Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance.

Liver allografts are accepted spontaneously in all mouse strain combinations without immunosuppressive therapy. The mechanisms underlying this phenomenon remain largely undefined. In this study, we examined the effect of CD4+ CD25+ T regulatory cells (Treg) on the induction of mouse liver transplant tolerance. Orthotopic liver transplantation was performed from B10 (H2b) to C3H (H2k) mice. Depleting rat anti-mouse CD25 mAb (PC61) was given to the donors or recipients (250 microg/d IP) pretransplant or to the recipients postoperatively. At day 5 posttransplantation, both effector T cells (mainly CD8) and CD4+ CD25+ Treg were increased in the liver allografts and host spleens compared to naïve mice. Anti-CD25 mAb administration, either pretransplantation or posttransplantation, reduced the ratio of CD4+ CD25+ Treg to the CD3 T cells of liver grafts and recipient spleens and induced liver allograft acute rejection compared to IgG treatment. Anti-CD25 mAb administration elevated anti-donor T-cell proliferative responses and CTL and NK activities of graft infiltrates and host splenocytes; reduced CTLA4, Foxp3, and IDO mRNA levels; increased IL-10 and IFN-gamma; and decreased IL-4 mRNA levels in the livers or host spleens. The number of apoptotic T cells was reduced significantly in the liver grafts and treated host spleens. Therefore, anti-CD25 mAb administration changed the balance of CD4+ CD25+ Treg to activated T cells of liver graft recipients, preventing liver transplant tolerance. This was associated with enhanced anti-donor immune reactivity, downregulated Treg gene expression, and reduced T cell apoptosis in the grafts and host spleens.

Animals↗
PubMed2005

Demonstration of regional differences in equine ventricular myocardial velocity in normal 2-year-old Thoroughbreds with Doppler tissue imaging.

REASONS FOR PERFORMING STUDY: Doppler tissue imaging (DTI) is a novel noninvasive method by which myocardial velocity can be assessed directly and it allows regional, rather than global, cardiac function to be evaluated. HYPOTHESIS: That regional differences in myocardial velocities exist within the equine ventricle. OBJECTIVES: To develop a repeatable examination technique for DTI in horses, describe DTI findings in various regions of the normal equine ventricle, compare colour (CDTI) and spectral (SDTI) techniques of DTI, and document regional differences in myocardial velocity. METHODS: Five regions of the ventricles (right ventricular wall, interventricular septum and left, right and caudal regions of the left ventricle) were evaluated using SDTI and CDTI in 20 clinically normal Thoroughbreds age 2 years. Individual repeatability of the method was determined by examination of one 6-year-old Thoroughbred on 6 occasions. RESULTS: Three major movements were observed in the ventricular walls in systole, early diastole and late diastole. The interventricular septum had a complex pattern of movement. The left region of the left ventricle and interventricular septum had the most rapid movement. The individual repeatability of CDTI was poor, while in systole and early diastole, but not late diastole, SDTI produced repeatable estimates of maximal myocardial velocity. The different velocity estimates obtained with SDTI and CDTI are not interchangeable. Regional differences in the peak mean and maximal myocardial velocities were found in systole and early diastole (P<0.05), but were not identified in late diastole. CONCLUSIONS: The SDTI modality appears to produce the most repeatable data. There are regional differences in myocardial velocity within the equine ventricles for systole and early diastole. POTENTIAL RELEVANCE: DTI shows potential as a tool for studying regional myocardial movement both in clinical cases suspected of having myocardial dysfunction and in a research setting. In particular, SDTI offers potential as a direct and noninvasive means to study early diastolic function of the equine ventricles.

Animals↗
PubMed2001

Rescue of acute portal vein thrombosis after liver transplantation using a cavoportal shunt at re-transplantation.

BACKGROUND: Portal vein thrombosis is a rare but devastating complication following orthotopic liver transplantation. Fulminant liver failure ensues with acute portal vein thrombosis after transplantation limiting the treatment options. METHODS: We successfully re-transplanted a 46-year-old female patient who developed acute portal vein thrombosis 19 d after orthotopic liver transplantation. Vascular reconstruction included a cavoportal shunt to augment portal blood flow. RESULTS: Twelve months after re-transplantation this patient lives independently and enjoys excellent liver allograft function. CONCLUSIONS: Cavoportal shunt can augment portal blood flow in adult recipients of orthotopic liver transplants. This technique can be successfully employed during re-transplantation when portal blood flow is inadequate to maintain patency.

Female↗
PubMed2000

Functional and histopathological evidence of cardiac parasympathetic dysautonomia in equine grass sickness.

The parasympathetic terminal cardiac ganglia were examined in three normal horses and in five horses with grass sickness. Histopathological changes, consistent with those observed in other ganglia of horses with grass sickness, were identified in the terminal cardiac ganglia of the affected horses. A functional analysis of cardiac autonomic control by time domain analysis (TDA) of heart rate variability was applied to eight horses with grass sickness, and double-paired to 16 normal horses on the basis of their age, sex and breed, and the time of day at which the electrocardiographs were obtained. There were statistically significant differences between the normal and the affected horses in terms of the triangular index (P=0.01), a geometric method of TDA, the sNN100 index (P=0.009), a statistical method of TDA, and the R to R interval (P<0.0005). These results indicate that there is a pathological and functional parasympathetic decentralisation to the heart in equine grass sickness.

Animals↗
PubMed2000

Hyperbilirubinemia and cholestatic liver injury in hepatitis C-infected liver transplant recipients.

OBJECTIVE: A cholestatic pattern of liver injury has been observed in liver transplant recipients with rapidly progressive hepatitis C. We assessed the frequency and causes of cholestasis in hepatitis C-infected liver transplant patients, and evaluated the clinical and pathological course of those with cholestatic hepatitis C. METHODS: Sixty-nine sequential liver transplant recipients who had detectable hepatitis C viremia were studied retrospectively. Records and diagnostic tests were examined from patients who developed hyperbilirubinemia. RESULTS: Hyperbilirubinemia occurred in 33 of 69 (48%) hepatitis C-infected liver transplant patients. A thorough evaluation including review of clinical and laboratory data, ultrasound with Doppler, cholangiogram, and liver biopsy identified causes of hyperbilirubinemia other than hepatitis C in 26 of 33 patients. Seven patients developed cholestatic hepatitis C characterized by histological features of recurrent hepatitis C and cholestatic liver injury with ballooning of centrilobular hepatocytes, bile ductular proliferation, and canalicular cholestasis, in the absence of other causes of cholestasis. Five progressed rapidly to bridging fibrosis and two died of complications related to liver failure. Four patients with cholestatic hepatitis C showed extended survival after the onset of hyperbilirubinemia. CONCLUSIONS: 1) Hepatitis C is a relatively infrequent cause of cholestasis in liver transplant recipients. 2) The diagnosis of cholestatic hepatitis C requires a multimodality approach to exclude other causes of cholestasis. 3) Cholestatic hepatitis C ranges in severity and is not always associated with rapid development of graft failure, although significant histological abnormalities are frequent.

Adult↗
PubMed1998

Recombinant human tumor necrosis factor receptor Fc fusion protein therapy in kidney transplant recipients undergoing OKT3 induction therapy.

BACKGROUND: Initial doses of OKT3 are associated with a cytokine-induced acute clinical syndrome (ACS). This study assessed the safety of a recombinant human tumor necrosis factor receptor fusion protein (TNFR:Fc) given to minimize OKT3-ACS symptoms in renal allograft recipients undergoing induction therapy. METHODS: Sixteen patients were randomized into treatment or control groups. Treated patients received TNFR:Fc 1 hr before OKT3 on days 0 and 3. Patients were monitored after transplant for OKT3-ACS symptoms. Levels of cytokines, serum creatinine, and C-reactive protein were followed. RESULTS: Patients receiving TNFR:Fc had lower OKT3-ACS symptoms as measured by a scoring system. There was a higher incidence of infection in treated patients (10/12) compared to controls (1/4) in the 3 months after transplant, but the etiology of this difference was unclear. There were no significant differences in cytokine profiles. CONCLUSIONS: TNFR:Fc is well tolerated by renal transplant patients receiving OKT3 induction therapy and modestly decreases the symptoms associated with OKT3-ACS.

Acute Disease↗
PubMed1998

End-stage liver disease without hemochromatosis associated with elevated hepatic iron index.

BACKGROUND/AIMS: The utility of standard diagnostic tests for hereditary hemochromatosis in end-stage liver disease is unknown. A homozygous mutation (Cys 282 Tyr) has been identified in most patients with hereditary hemochromatosis. We examined whether serum iron studies and hepatic iron measurement distinguish end-stage liver disease patients with Cys 282 Tyr-associated hereditary hemochromatosis. METHODS: Serum iron, total iron binding capacity, and ferritin were measured in 106 cirrhotic patients prior to liver transplantation. Hepatic iron concentration and hepatic iron index were measured from explant liver tissue. Genotyping was performed on explant liver tissue in patients with an elevated hepatic iron index (>1.9). RESULTS: Thirty-three of 106 (31%) patients had elevated serum iron studies suggestive of hereditary hemochromatosis. Only four of 33 (12%) had a mean hepatic iron index >1.9, and none of the four patients was homozygous for Cys 282 Tyr. All four had liver disease due to hepatitis C and/or alcohol. CONCLUSIONS: (i) Serum transferrin saturation and hepatic iron index lack specificity for hereditary hemochromatosis in end-stage liver disease. (ii) Genotyping for Cys 282 Tyr may provide the best method to identify hereditary hemochromatosis in the setting of end-stage liver disease.

Female↗
PubMed1998

Donor-recipient sharing of HLA class II alleles predicts earlier recurrence and accelerated progression of hepatitis C following liver transplantation.

Both direct viral cytopathic effects and host immune responses appear to be important in the pathogenesis of hepatitis C virus (HCV) infection. Liver transplantation provides a means to explore the role of the immune system in the development of HCV-related liver damage through comparing the natural history of HCV in patients with different degrees of donor-recipient human leukocyte antigen (HLA) matching. We evaluated 36 patients with recurrent hepatitis C viremia following liver transplantation to determine whether hepatocellular injury or progression to bridging fibrosis occur more rapidly when donor and recipients share HLA alleles. HLA typing for the HLA-A and HLA-B loci was performed by serological techniques and PCR-based oligotyping was used to type alleles of the DRB1, DRB3, DQA1, and DQB1 loci. A median of eight liver biopsies, obtained during a median follow-up of 36 months, were reviewed per patient. Donor-recipient sharing of alleles of HLA-DQB1 or DRB1 was associated with more rapid development of recurrent hepatitis by univariate analysis (chi2=5.7, P=0.02 and chi2=5.54, P=0.02 respectively). However, only sharing of HLA-DRB1 alleles was identified as an independent predictor of reduced time to recurrent histologic injury by multivariate analysis (chi2 =5.74, P=0.02). Furthermore, sharing of HLA-DRB3 and histologic evidence of rejection were associated with more rapid progression to bridging fibrosis both by univariate methods (chi2=4.12, P=0.04 and chi2=4.66, P=0.03 respectively), and by multivariate analysis (chi2=13.01, P=0.001). These findings suggest that HLA class II-restricted immune responses may contribute to the pathogenesis of HCV-related liver injury in liver transplant recipients.

Adult↗
PubMed1998

Listeria infection after liver transplantation: report of a case and review of the literature.

Listeria monocytogenes is a well-recognized cause of bacteremia and meningitis in immunocompromised individuals, including recipients of solid organ transplants, but has only rarely been reported following orthotopic liver transplantation (OLT). Most previously reported cases of listeriosis occurred months to years following liver transplantation; we describe a case of listeriosis that occurred within 1 wk of liver transplantation, shortly after discontinuation of trimethoprim-sulfamethoxazole prophylaxis, and review the English literature on Listeria infection after OLT. The patient developed abdominal pain and fever that suggested a bile leak, but was definitively diagnosed with Listeria infection by blood culture. The infection was successfully treated with 3 wk of intravenous ampicillin. We conclude that serious systemic infection with Listeria monocytogenes is uncommon following OLT, may occur early in the postoperative period, and responds well to treatment with high dose ampicillin.

Adult↗
PubMed1998

Multigene tracking of hepatitis C virus quasispecies after liver transplantation: correlation of genetic diversification in the envelope region with asymptomatic or mild disease patterns.

To investigate the role of hepatitis C virus (HCV) quasispecies mutation in the pathogenesis of HCV infection, we analyzed changes in the genetic diversity of HCV genomes in 22 patients before and after liver transplantation by using heteroduplex mobility assay (HMA) technology. All patients were infected with HCV genotype 1 and developed high-titer posttransplant viremia. Each patient was classified according to the severity of posttransplant hepatitis, as assessed by standard biochemical and histological criteria. HCV quasispecies were characterized by HMA analysis of eight separate subgenomic regions of HCV, which collectively comprise 44% of the entire genome. The glycoprotein genes E1 and E2, as well as the nonstructural protein genes NS2 and NS3, had the greatest genetic divergence after liver transplantation (the change in the heteroduplex mobility ratio [HMR] ranged from 2.5 to 7.0%). In contrast, genes encoding the core, NS4, and NS5b proteins had the least amount of genetic divergence after liver transplantation (range, 0.3 to 1.2%). The E1/E2 region showed the greatest change in genetic diversity after liver transplantation, and the change in HMRs was 2.5- to 3.3-fold greater in patients with asymptomatic or moderate disease than in those with severe disease. The E1-5' region of HCV quasispecies isolated from patients in the asymptomatic group had a significantly greater degree of diversification after liver transplantation than the same regions of HCV quasispecies isolated from patients in the severe disease group (P = 0.05). While changes in the genetic diversity of some nonstructural genes were also greater in asymptomatic patients or in patients with mild disease than in patients with severe disease, the results were not significant. Data from this cohort demonstrate that greater rates of HCV quasispecies diversification are associated with mild or moderate liver disease activity in this immunosuppressed population.

Base Sequence↗
PubMed1998

Bilateral ruptured tubo-ovarian abscesses following bilateral tubal ligation several years earlier.

The occurrence of pelvic inflammatory disease and tubo-ovarian abscesses previously has been regarded as essentially nonexistent in the patient who has undergone tubal sterilization, although there have been isolated reports in the literature. This case describes a patient who underwent tubal ligation approximately 6 years prior to presenting with bilateral ruptured tubo-ovarian abscesses. The patient underwent emergency surgery and had an uneventful recovery. Theoretically, although bilateral tubal ligation should preclude the development of pelvic inflammatory disease, it is a diagnosis that should be considered in the patient presenting with lower pelvic and abdominal pain.

Abscess↗
PubMed1997

Renal disease in hepatitis C-positive liver transplant recipients.

Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.

Adult↗
PubMed1997

Hepatitis G virus co-infection does not alter the course of recurrent hepatitis C virus infection in liver transplantation recipients.

Although hepatitis G virus infection (HGV) is usually asymptomatic, it has been associated with mild hepatic injury. Whether hepatitis G co-infection alters the natural history of other viral hepatitis infections remains to be determined. In the present study, we investigated whether hepatitis G impacts on the time to recurrent hepatitis or on the time to progression to fibrosis in hepatitis C-infected patients who undergo liver transplantation. Forty-five liver transplantation recipients with persistent hepatitis C viremia by polymerase chain reaction (PCR) were evaluated. Stored sera obtained before and after liver transplantation was tested for HGV RNA by reverse transcriptase (RT)-PCR using primers to the 5' region of the HGV genome. A median of eight serial liver biopsy specimens were reviewed per patient. The prevalence of HGV co-infection was 21% before transplantation and 22% following transplantation. During a median follow-up of 29 months, 78% (35/45) of patients with hepatitis C viremia developed histological features of recurrent hepatitis. Fifty-one percent (23/45) progressed to fibrous portal expansion and 16% (7/45) developed bridging fibrosis. Comparisons of patients with and without hepatitis G co-infection following transplantation showed no significant difference in time to recurrent hepatitis, fibrous portal expansion, bridging fibrosis, or of allograft or patient survival. In conclusion, hepatitis G co-infection does not seem to impact on the time to recurrent hepatitis C or progression of hepatitis C-related histological injury after liver transplantation.

Flaviviridae↗
PubMed1997

Histological and clinical outcome after liver transplantation for hepatitis C.

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.

Adolescent↗
PubMed1997

Induction immunosuppressive therapy is associated with a low rejection rate after liver transplantation.

Despite advances in immunosuppression, allograft rejection occurs frequently after liver transplantation. The use of induction therapy with cytolytic antibodies may decrease the frequency of rejection in liver transplant recipients, but may also increase the rate of cytomegalovirus (CMV) infection. It has been our center's strategy to use induction therapy in our liver transplant recipients. To determine the outcome of our strategy, we retrospectively reviewed all liver transplants performed in the first 5 yr of our liver transplant program. The frequency of acute rejection in the first year after liver transplantation was only 34% in patients who received induction therapy. The type of induction therapy antibody did not affect the rejection rate. Clinically significant CMV infection (requiring treatment) occurred in 22% of patients. These results suggest that use of induction therapy with cytolytic antibodies does not lead to a high incidence of CMV infection and decreases the incidence of rejection after liver transplantation.

Acute Disease↗
PubMed1997

Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.

Cytochrome P450 3A (CYP3A) metabolizes a diverse array of clinically important drugs. For some of these (e.g., cyclosporine, verapamil, midazolam), CYP3A in the intestinal mucosa contributes to their extensive and variable first-pass extraction. To further characterize this phenomenon, we measured CYP3A content and catalytic activity toward the probe substrate midazolam in mucosa isolated from duodenal, jejunal and ileal sections of 20 human donor intestines. For comparison, the same measurements were performed for 20 human donor livers, eight of which were obtained from the same donors as eight of the intestines. Excellent correlations existed between homogenate and microsomal CYP3A content for the three intestinal regions. Median microsomal CYP3A content was greatest in the duodenum and lowest in the ileum (31 vs. 17 pmol/mg of protein). With respect to midazolam 1'-hydroxylation kinetics, the median Km for each intestinal region was similar to the median hepatic Km, approximately 4 microM. In contrast, the median Vmax decreased from liver to duodenum to jejunum to ileum (850 vs. 644 vs. 426 vs. 68 pmol/min/mg). Intrinsic clearance (Vmax/Km) followed a similar trend for the intestinal regions; median duodenal intrinsic clearance was comparable to hepatic intrinsic clearance (157 and 200 microl/min/mg, respectively). Vmax correlated with CYP3A content for all tissues except the ileum. Duodenal and jejunal Vmax and CYP3A content varied by >30-fold among donors. Microsomes prepared from every other 1-foot section of six intestines were also analyzed for CYP3A as well as for two coenzymes. In general, CYP3A activity, CYP3A content and CYP reductase activity rose slightly from duodenum to middle jejunum and then declined to distal jejunum and ileum. Cytochrome b5 content and cytochrome b5 reductase activity varied little throughout the intestinal tract. Regional intrinsic midazolam 1'-hydroxylation clearance was greatest for the jejunum, followed by the duodenum and ileum (144, 50 and 19 ml/min, respectively). Collectively, these results demonstrate that the upper small intestine serves as the major site for intestinal CYP3A-mediated first-pass metabolism and provides a rationale for interindividual differences in oral bioavailability for some CYP3A substrates.

Aryl Hydrocarbon Hydroxylases↗