Pharmacogenomics and lung transplantation: clinical implications.
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ATP Binding Cassette Transporter, Subfamily B↗
Biomedical subjects
A Zeevi
Publications and source records attributed to A Zeevi.
Voriconazole prophylaxis in lung transplant recipients.
Lung transplant recipients have one of the highest rates of invasive aspergillosis (IA) in solid organ transplantation. We used a single center, nonrandomized, retrospective, sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole (n = 65) or targeted prophylaxis (n = 30) with itraconazole +/- inhaled amphotericin in patients at high risk (pre- or posttransplant Aspergillus colonization [except Aspergillus niger]). The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis (1.5% vs. 23%; p = 0.001). Twenty-nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole. A three-fold or higher increase in liver enzymes was noted in 37-60% of patients receiving voriconazole prophylaxis as compared to 15-41% of patients in the targeted prophylaxis cohort. Fourteen percent in the voriconazole group as compared to 8% in the targeted prophylaxis group had to discontinue antifungal medications due to side effects. Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients. Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity.
Antifungal Agents↗
C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody.
UNLABELLED: The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts, but remains controversial in lung transplantation (LTX). METHODS: C4d deposition was assessed by immunohistochemistry in 192 lung transplant biopsies from 32 patients. ELISA analysis was performed on 415 serum samples in those 32 temporally and rejection-grade matched LTX patients; 16 patients developed HLA-Ab, while the other 16 patients remained negative. The specificity of C4d staining was further compared in 18 additional LTX patients without HLA-Ab or acute cellular rejection (ACR), but in the presence of CMV-pneumonitis or reperfusion injury. RESULTS: Specific subendothelial C4d deposition was seen in 5 of 16 (31%) patients with HLA-Ab and was absent in 16 patients without HLA-Ab (p<0.05). All patients with specific C4d deposition exhibited donor-specific HLA-Ab. There were 13 patients with bronchiolitis obliterans syndrome in the group of 16 HLA-Ab positive patients, versus 2/16 in ELISA-negative patients (p<0.005). One of 7 patients with CMV pneumonitis and 2 of 11 patients with reperfusion injury also showed C4d positivity (not statistically significant). CONCLUSIONS: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy nature, low sensitivity, and specificity of C4d staining might limit clinical use in protocol biopsies. However, in patients with decreasing pulmonary function, refractory ACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR.
Acute Disease↗
Steroid-free tacrolimus monotherapy after pretransplantation thymoglobulin or Campath and laparoscopy in living donor renal transplantation.
Living donor renal transplantation was performed under a regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. From October 9, 2002, to December 31, 2004, 196 consecutive, unselected laparoscopic live donor nephrectomies resulting in 196 living donor renal transplantations were performed. Recipients were pretreated with rabbit antithymocyte globulin (thymoglobulin; 24 patients or [12%]) or Campath 1H (alemtuzumab; 166 patients [85%]), or were not in protocol (6 patients [3%]), and were given postoperative steroid-free low-dose tacrolimus immunosuppressive monotherapy with subsequent weaning. There was no donor mortality. Major and minor donor morbidities were 2.6% and 4.2%, respectively. Laparoscopic live donor nephrectomy recipient outcomes with a mean follow-up of 401 days included (1) recipient and graft survival of 99.0% and 97.4%, respectively; (2) no ureteral stenosis; (3) 0.5% delayed graft function, from recurrent focal segmental glomerulosclinosis; and (4) no vascular thrombosis. The incidence of acute rejection at 30, 90, and 401 days was 1.5%, 3.8%, and 11.2% (all 196 recipients), 0%, 25%, and 29.2% (thymoglobulin recipients), and 1.8%, 3.9%, and 8.4% (Campath 1H recipients), respectively. Sixty-six patients (33.7%) are receiving spaced-dose immunosuppressive monotherapy. The mean creatinine concentration in all recipients was 1.5 +/- 1.1 mg/dL. There were no instances of cytomegalovirus tissue invasive disease or posttransplantation lymphoproliferative disease. The incidence of new-onset posttransplantation insulin-dependent diabetes was 0.5%. At current follow-up, the use of Campath 1H rather than thymoglobulin for pretreatment seems to have significantly improved the efficacy of our regimen.
Adult↗
The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients.
Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.
Adult↗
Measurement of basal, substrate induced and total P-glycoprotein activity in bronchoalveolar lavage T-cell subsets.
BACKGROUND: P-glycoprotein (P-gp) is a member of the ABC transporter superfamily. P-gp activity can be detected by measuring efflux of fluorescent substrates such as rhodamine 123 (R123). Our objectives were to evaluate P-gp activity in T cells freshly isolated from bronchoalveolar lavage (BAL) and to develop a strategy to distinguish between basal, in vitro substrate-induced, and total P-gp activities. METHODS: Cells were obtained from blood (n = 44) and BAL (n = 34), stained for expression of CD3, CD4, CD8, and CD14, and incubated with R123 (0.13 microM) +/- cyclosporine (5 microM), a specific P-gp inhibitor. P-gp activity was detected as median fluorescence intensity (MFI) and percentage of cells falling below a pre-established cutoff. RESULTS: BAL T cells displayed significant basal P-gp activity, which was most apparent when measured as percentage below the cutoff. Induced activity (difference between P-gp activity measured after load and efflux) was determined equally well when using the MFI or the percentage below cutoff parameter. Total activity was represented by the efflux parameters (MFI or percentage below cutoff) or by the activity-time area under the curve (AUC) method. The two efflux parameters correlated well but were insensitive to the time-dependent nature of dye efflux. In the AUC method, two samples with identical R123 brightness or percentage below cutoff after dye efflux can have very different total activities, depending on their basal activity. The AUC method was also most sensitive in distinguishing between P-gp activity in peripheral blood and resident lung T cells. Application of this methodology to the comparison of P-gp activity in BAL and peripheral CD8+ T cells best revealed the elevated total P-gp activity in BAL T cells. CONCLUSIONS: We have systematically evaluated several methodologies for analysis of P-gp activity and arrived at a novel and robust strategy amenable to standardization and evaluation of the effects of P-gp modulators in vivo and in vitro.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The impact of pharmacogenomic factors on steroid dependency in pediatric heart transplant patients using logistic regression analysis.
Many pharmacogenomic predictors of drug response are now available, and include both drug metabolism-disposition factors and drug targets. Information on statistical approaches to analyzing large clinical data sets in relation to genetic polymorphisms is limited. The objective of this study was to evaluate whether logistic regression could identify pharmacogenomic predictors of outcome in a large data set in a complex transplant patient population. Seventy pediatric heart transplant patients were studied. Patients were followed for at least 1 yr post-transplantation as outpatients, and weaned from corticosteroids if clinically appropriate. Logistic regression analysis was used to identify the predictors of steroid dependency. The dependent variable was the presence or absence of steroid therapy at 1 yr post-transplantation. The independent variables were the patients' transplant age, gender, MDR1 C3435T and G2677T, CYP3A53B and cytokine polymorphisms. By chi-square test for the MDR1 C3435T polymorphism, 12 of 18 (67%) patients in the CC group were still on prednisone, whereas only 18 of 47 (38%) of the CT/TT group were still receiving prednisone (p = 0.04). For the IL-10 groups, two of 15 patients with the high producer genotype (13.3%) remained on prednisone, in comparison with 16 of 28 patients with the intermediate producer genotype (57.1%) and 15 of 26 patients with the low producer genotype (57.7%, p = 0.01). Logistic regression analysis confirmed MDR1 C3435T (p = 0.021), and IL-10 polymorphisms (intermediate producer genotype p = 0.015; low producer genotype p = 0.013) as independent risk factors for steroid dependency at 1 yr after transplantation. This approach identifies pharmacogenomic factors, which can be studied more extensively in larger data sets, and used in prospective studies to individualize immunosuppressive therapy following solid organ transplantation.
Adolescent↗
T-helper cell responses in liver transplant recipients: correlation with cytomegalovirus and other major infections.
Mitogen concanavalin A (ConA) response and cytomegalovirus (CMV)-specific memory response were assessed in 24 liver transplant recipients and compared with healthy subjects. Transplant recipients as compared to healthy subjects had a lower CMV memory response at 2 weeks (P=0.023), and at 1 month (P=0.06), but a comparable response at 3 months. CMV recipient+/donor+(R+/D+) patients had the greatest increase in CMV-specific memory response at 2-3 months as compared to all other groups. Within this R+/D+ group, CMV-specific memory response was significantly more robust in patients who never had CMV infection as compared to those who developed CMV infection (P=0.035). ConA response at 2 weeks was significantly lower in patients with major infections as compared to those without them (SI 5.4 vs. 38.1, P=0.039). Thus, reconstitution of CMV-specific T-helper cell response was distinct for subsets of liver transplant recipients based on the recipient and donor CMV serostatus. Impairment in proliferative response to ConA identified a subgroup of patients with major infections after liver transplantation.
Antibodies, Viral↗
Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.
The majority of patients who develop bronchiolitis obliterans, after lung transplantation, die within 2-3 yrs after onset since treatment with conventional immunosuppression is typically ineffective. A case/control study was conducted in lung transplant recipients with biopsy-documented bronchiolitis obliterans to determine whether aerosol cyclosporin use contributed to increased survival. The cases comprised 39 transplant recipients who received open-label aerosol cyclosporin treatment in addition to conventional immunosuppression. The controls were transplant recipients treated with conventional immunosuppression alone. There were 51 controls from the University of Pittsburgh Medical Center and 100 from a large multicentric database (Novartis Lung Transplant Database). Forced expiratory volume in one second expressed as a percentage of the predicted value was an independent predictor of survival in all patients with bronchiolitis obliterans. Cox proportional-hazards analysis revealed a survival advantage for aerosol cyclosporin cases compared to the Pittsburgh control group. A survival advantage was also seen when comparing study cases to multicentric controls. Aerosol cyclosporin, given with conventional immunosuppression to lung transplant recipients with bronchiolitis obliterans, provides a survival advantage over conventional therapy alone.
Administration, Inhalation↗
Preservation of post-transplant lung function with aerosol cyclosporin.
Post-lung transplant use of aerosol cyclosporin (ACsA) is considered by examining the relationship between deposited aerosol dose and effect. In a sub-study of placebo controlled trials of ACsA as a rejection prophylaxis, 15 drug subjects received aerosol dose quantification tests to gage their ability to effectively deposit the nebulised drug in their transplanted lung(s). A total of seven placebo subjects received mock deposition tests. The deposited doses and mock doses were compared to changes in the forced expiratory volume in one second, at six time points during the 2-yr trial period (ACsA was started within 6 weeks post-transplant). Linear relationships were demonstrated between deposited dose and improvement in lung function in the drug subjects at all intervals. Mock dose data from placebo subjects did not demonstrate similar correlation. Based on these results, subjects were grouped by dose and compared. Subjects depositing > or = 5 mg of the drug in the periphery of their transplant(s) had improving pulmonary function on average. Low-dose and placebo subjects demonstrated declines, more A2-A4 rejection events in the latter portion of the trial, and more chronic rejection beyond the end of the trial. A dose-to-effect relationship is demonstrated for aerosol cyclosporin in terms of pulmonary function and biopsy proven rejection.
Administration, Inhalation↗
Real-time monitoring of acute liver-allograft rejection using the Banff schema.
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.
Acute Disease↗
Persistent lack of human herpesvirus-6 specific T-helper cell response in liver transplant recipients.
BACKGROUND: Specific immunologic defects predisposing to human herpesvirus-6 (HHV-6), e.g. the role of HHV-6 specific T-helper cell memory response in liver transplant recipients, have not been assessed. METHODS: T-helper function (mitogen ConA response) as a marker of overall immunocompetence and T-helper response (memory response) specific to HHV-6 and cytomegalovirus (CMV) were assessed in 15 liver transplant recipients and compared with 25 healthy subjects. Samples were tested pretransplant, at 2 weeks, 1 month, 2-3 months, and 1 year posttransplantation. Stimulation index (SI) >3 was considered a positive response. RESULTS: Seven percent (1/15) of the transplant recipients at any time posttransplantation, as compared to 64% (16/25) of the healthy subjects, had a positive HHV-6 memory response (P = 0.00065). HHV-6-specific memory response in transplant recipients at 2 weeks (SI 1.43), 1 month (SI 1.1), and 2-3 months (SI 1.3) was significantly more suppressed than in healthy subjects (SI 17.5, P = 0.0001). Although transplant recipients as compared to healthy subjects also had a lower CMV-specific memory response posttransplant (P = 0.0439), CMV-specific memory response recovered significantly at 1 month (P = 0.03) and at 2-3 months (P = 0.027) as compared to that at 2 weeks. However, HHV-6 memory response was persistently absent up to 2-3 months with partial recovery at 1 year; 7% of the patients at 2-3 months, but 25% at 1 year had a positive HHV-6 specific memory response. Forty percent (6/15) of the patients developed HHV-6 viremia a mean of 4 weeks posttransplant. Patients with HHV-6 viremia had greater suppression of HHV-6 memory response at 1 month than those without viremia (mean SI, 0.96 vs. 1.3, P = 0.08). All but one of the patients had a positive ConA response. CONCLUSION: Prolonged suppression of HHV-6 memory response, but not overall T-helper cell function was documented and may play a role in the pathogenesis of HHV-6 infection in liver transplant recipients. Memory response to CMV after liver transplantation was significantly more robust than to HHV-6.
Herpesvirus 6, Human↗
The immunosuppressant drug FK506 is a potent trophic agent for human fetal neurons.
FK506 is a potent immunosuppressive drug used to prevent rejection post-organ transplantation. It is activated upon binding to members of the immunophilin chaperone proteins (e.g. FK506-binding protein, FKBP 12). Studies of the distribution of FKBP12 reveal that it is enriched in neurons throughout the central and peripheral nervous system. In vitro, FK506 augments neurite outgrowth; in animal models, it enhances axonal re-growth and functional recovery following lesioning. The effects on human neurons and glial cells have not yet been studied. Using immunofluorescent laser scanning confocal microscopy we demonstrate that in human fetal brain cultures FK506 significantly increases cell numbers, including neurons, and the expression of the neuronal marker MAP-2. This suggests that the drug has a potent effect in stimulating neuronal survival, proliferation and dendrite extension. Interestingly, in combination with brain-derived neurotrophic factor, FK506 induces a prominent decrease in glial fibrillary acidic protein expression, which indicates an inhibitory effect on astrogliosis in vitro. Our data support a potential role for FK506 and its analogues in the treatment of neurodegenerative disorders.
Astrocytes↗
Rare-event analysis of circulating human dendritic cell subsets and their presumptive mouse counterparts.
BACKGROUND: Considerable interest has focused recently on murine CD8alpha- and CD8alpha+ dendritic cell (DC) subsets, because of their roles in initiating and regulating immune responses. Attention has also centered on their presumed human counterparts, DC1 and DC2, respectively, and their precursors. Identification and quantification of these subsets in the blood may be crucial to understanding and monitoring of their immunologic significance, particularly in humans, where blood may be the only tissue readily or routinely available. METHODS: Leukocytes were isolated from anticoagulated human or mouse (C57BL/10J) blood using conventional procedures. Four-color, rare-event, flow cytometric analysis was used to identify DC1 precursors (pDC1; lineage [lin]- CD4+ CD11c+ HLA-DR+) or DC2 precursors (pDC2; lin- CD4+ CD11c- CD123(hi) [IL-3Ralpha(hi)] HLA-DR+) in normal humans. In mice, CD8alpha+ (CD11b(lo), CD11c+) and CD8alpha- (CD11b(hi), CD11c+) DC subsets were identified both in normal animals and after administration of the potent DC growth factor, fms-like tyrosine kinase 3 ligand (Flt3L). RESULTS: All human subjects examined had discrete populations of pDC1 and pDC2 comprising approximately 0.6% and 0.1% of blood mononuclear cells. CD8alpha- and CD8alpha+ DC constituted approximately 0.75% and 0.2%, respectively, of blood mononuclear cells in normal mice, and 12% and 0.5%, respectively, in Flt3L-treated animals. Flt3L administration substantially increased the absolute numbers of circulating CD11c+ DC by approximately 200-fold. CONCLUSIONS: In addition to pDC1 and CD8alpha- DC, pDC2 and CD8alpha+ DC can be identified in normal human or mouse blood, respectively. Monitoring and isolation or characterization of these cells may provide novel insights into their functional significance in transplantation and other clinical conditions.
Adjuvants, Immunologic↗
The epidemiology of parainfluenza virus infection in lung transplant recipients.
Human parainfluenza virus (HPIV) is a common cause of seasonal respiratory tract infections. However, little is known about the clinical presentation and impact of HPIV infections in lung transplant recipients. We reviewed HPIV infections at the University of Pittsburgh Medical Center. From January 1990 through May 2000, 32 cases of HPIV infection were identified. HPIV infection was found in 24 lung transplant recipients (75%), all of whom were included in the study group. Diagnosis was established at a median of 2.1 years after transplantation (range, 0.6-5 years). Presenting symptoms included cough (17 patients), shortness of breath (16), and temperature elevation (4). Respiratory failure occurred in 5 patients (21%). The HPIV serotypes were HPIV-1 (7 patients), HPIV-2 (2), and HPIV-3 (15 [63%]). Twenty-two patients underwent transbronchial biopsy, and 18 (82%) showed signs of acute allograft rejection. Seven patients (32%) subsequently were found to have bronchiolitis obliterans.
Humans↗
Monitoring the patient off immunosuppression. Conceptual framework for a proposed tolerance assay study in liver transplant recipients.
The mission of the recently established Immune Tolerance Network includes the development of protocols for the induction of transplant tolerance in organ allograft recipients and the development of assays that correlate with and may be predictive of the tolerant state. The state of clinical organ transplant tolerance seems to already exist in a small minority of conventionally immunosuppressed liver and, more rarely, kidney transplant patients. Immunosuppressive drug therapy has been withdrawn from these patients for a variety of reasons, including protocolized weaning for a uniquely large group of liver patients at the University of Pittsburgh. In this study, we propose to evaluate the validity of a variety of in vitro immunologic and molecular biologic tests that may correlate with, and be predictive of, the state of organ transplant tolerance in stable liver patients off immunosuppression. Only peripheral blood will be available for the execution of these tests. Both adult and pediatric liver graft recipients will be studied, in comparison to appropriate controls. We shall examine circulating dendritic cell (DC) subsets [precursor (p) DC1 and p DC2] including cells of donor origin, and assess both the frequency and function of donor-reactive T cells by ELISPOT and by trans-vivo delayed-type hypersensitivity analysis in a surrogate murine model. Cytokine gene polymorphism and alloantibody titers will also be investigated. It is anticipated that the results obtained may provide physicians with a tolerance assay "profile" that may determine those patients from whom immunosuppressive therapy may be safely withdrawn.
Abatacept↗
Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus.
AIMS: The role of sirolimus (SRL) as a rescue agent (n=42) and as a component of primary immunosuppression (n=8) was evaluated in a mixed population of 50 transplanted children receiving tacrolimus (liver: 26, heart: 5, intestinal: 5, liver-intestine: 9, lung: 1, bone marrow: 1, liver-kidney: 1, multivisceral: 1). Rescue indications for tacrolimus (TAC) failure were recurrent acute rejection and acute rejection complicating withdrawal of immunosuppression in posttransplant lymphoproliferative disorder (PTLD). Rescue indications for TAC toxicity were nephrotoxicity, pancreatitis, seizures, hypertrophic cardiomyopathy, and graft-versus-host disease. RESULTS: Mean age at rescue was 11.5 years and mean follow-up was 204 (range 18-800) days. As primary immunosuppression, SRL+TAC prevented early acute rejection in 7/8 children. The indication for rescue resolved in 33/42 children. In children with TAC toxicity, this was associated with decrease in TAC doses by 50%, significant improvements in renal function, and continuing decline in Epstein-Barr virus (EBV) viral load in PTLD patients. Serious adverse events led to discontinuation of SRL in 9/42 rescue patients, 3 of them also experienced acute rejection. Three additional children also experienced acute rejection on SRL therapy (overall incidence 6/50, 12%). Pharmacokinetic analysis in the first week of SRL administration suggested a short half-life (11.8+/-5.5 hr, n=21). CONCLUSIONS: SRL and reduced-dose TAC may achieve adequate immunosuppression without compromising renal function or enhancing EBV viremia significantly.
Acute Disease↗
Long-term survival of rat cardiac allografts by intrathymic plus portal venous injections of donor bone marrow cells and short-term tacrolimus immunosuppression.
Intrathymic (IT) or portal venous (PV) injection of donor antigens has been shown to prolong organ acceptance in low responder rat strain combinations. We determined whether a combination of these strategies would prolong cardiac allograft survival in high responder combinations. Wistar Furth rats received 1 x 10(8) ACI rat bone marrow cells (BMCs) via IT, intravenous (IV), PV, IV + PV, IT + IV or IT + PV route at the time of ACI cardiac transplantation. Without tacrolimus (FK), all grafts were acutely rejected. With FK immunosuppression (1.5 mg/kg per day, I. M., days 0-4), single BMC injection did not increase graft survival beyond 93 days, whereas 70% of grafts survived indefinitely ( > 150 days) when IT and PV BMCs were combined. Animals receiving IT and PV BMCs also had less allograft vasculopathy. Thus, IT and PV injections of donor BMCs under a brief course of FK synergistically improve cardiac allograft survival.
Animals↗