摘要:

The pathophysiology of ischemia-reperfusion renal injury is mediated, in part, by the generation of the vasoconstricting prostanoid thromboxane A2(TXA2). This study was undertaken to evaluate the renoprotective effects, as well as the optimal timing and dosage, of a selective thromboxane synthetase inhibitor, OKY-046, in a unilateral nephrectomized, 60 min ischemia, 72 hr reperfusion, rodent model. Forty-one rats were subjected to right nephrectomy only (group A), or right nephrectomy with 60 min of left renal ischemia and treatment with inactive vehicle only (group B), or 2 mg/kg or 4 mg/kg of OKY-046 administered intravenously before (groups C and D) or after (groups E and F) pedicle clamping. Outcome variables included animal survival; change in kidney weight; 0, 24, and 72 hr plasma creatinine (CR); urea nitrogen (BUN); thromboxane B2(TXB2) and 6-keto prostaglandin F1 alpha(6 kPGF2 alpha) levels; creatinine clearance (CRCL); and histologic evidence of renal injury. Animal survival and postperfusion kidney weight were not significantly different among the groups. However, renal functional parameters were significantly improved with the 2 mg/kg dose of OKY-046 administered after renal ischemia (group B 72 hr Cr=8.01±1.1 mg% vs. group E=3.99±1.5 mg%; and group B 72 hr BUN=241.3±32.8 mg% vs. group E=52.6±22.5 mg%). The CRCL was also improved in group E vs. group B, although these results did not reach statistical significance(group B=0.069 ml/min vs. group E=0.194 ml/min). The 24 hr TXB2levels were significantly increased in group B(0 hr=754.1±219.4 pg/ml vs. 24 hr=2055.9±550.0 pg/ml), and pre- or posttreatment with OKY-046 abrogated this increase (group C 0 hr=517.1±80.9 pg/ml vs. 24 hr=384.7±251.5 pg/ml, and group E 0 hr=781.6±390.4 pg/ml vs. 24 hr=183.0±81.4 pg/ml). The 24 hr 6 kPGF1alphalevels decreased in all groups, whereas 72 hr 6 kPGF1alphalevels increased above baseline in groups A, C, and E, but not in group B. These data demonstrate the beneficial effects of thromboxane A2 synthesis inhibition in the setting of ischemia-reperfusion injury and suggest that this renoprotection correlates with late vasodilatory prostanoid synthesis.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The chronic increase of pulmonary vascular resistance after lung transplantation is only partly due to an active increase in baseline vasomotor tone, but the nature of the acute pulmonary hypertension after ischemia and reperfusion is not known. We studied the effects of sodium nitroprusside on pulmonary hemodynamics during reperfusion in porcine left lung allotransplants. In twelve pigs (weight: 18 to 24 kg) pulmonary arteries of the native and the transplanted lung were cannulated for right-heart bypass. The total blood flow was 2 L/min. Flow distribution between the lungs was measured at equal mean pulmonary artery pressure, and pulmonary vascular resistance at equal and constant flow-i.e., 1 L/min to each lung. After baseline measurements sodium nitroprusside (1, 3, and 9 μg/kg/min) was administered to six animals (SNP group). The control group(n=6) received an equal amount of the vehicle. After 30 min of discontinuation of the drug infusion, the schedule was repeated. In the transplanted lung, pulmonary vascular resistance decreased in all animals during the first hour of reperfusion. During the second drug infusion pulmonary vascular resistance was significantly lower in the SNP group compared with the control group only at the highest infusion rate of the drug(9 μg/kg/min), which also induced a 44% decrease in systemic vascular resistance. Arterial oxygen tension remained comparable in the two groups throughout the study. Our data suggest that other factors besides active vasoconstriction may contribute to the acute increase of pulmonary vascular resistance after lung transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Chronic graft rejection is now a major barrier to the long-term survival of cardiac transplants. A major hallmark of chronic rejection is intimal thickening of arteries in the graft leading to vascular occlusion. Current animal models of chronic rejection generally utilize immunosuppression to prevent acute rejection of grafts disparate at major histocompatibility antigens or graft disparities involving minor histocompatibility antigens alone. In the present communication we describe a new model of chronic rejection involving grafting of PVG-R23 hearts into PVG-RT1urecipients. The R23 hearts, which differ from the RT1urecipients at class II MHC, are rejected with a chronic time course and demonstrate extensive severe vascular myointimal proliferation within the coronary arteries. Furthermore we demonstrate for the first time that donor-specific blood transfusion can prevent chronic rejection and the intimal thickening of the coronary arteries.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The purpose of this study was to investigate whether treatment with TCV-309, a PAF antagonist, improves life-sustaining function of renal grafts that have suffered warm ischemia (WI) prior to cold storage (CS) and whether TCV-309 influences leukocyte sequestration in tissues. Syngeneic kidneys with 20 min of WI and 24 hr of CS were transplanted into bilateral nephrectomized rats. In the treated group, TCV-309 was administered (i.v. 1 mg/kg) 5 min before reperfusion. Rats in the control group received saline. On day 14, 80% rats survived in the treated group, which was higher than the controls (0%). At 24 hr of reperfusion, myeloperoxidase (MPO) activity, a marker enzyme for PMNs, in the treated kidney was significantly lower than the controls, but did not differ from the normal values. The MPO activity in the controls was higher than the normal values. In conclusion, the PAF antagonist improves posttransplant function of rat kidneys subjected to a period of WI and CS. PMNs are involved in postischemic renal injury, which is, at least partially, mediated by PAF. The effectiveness of PAF antagonist in treatment of recipients may lead to its clinical application in transplantation of ischemically injured kidneys.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We have previously reported the adverse effects of cyclosporine on small intestine transplant physiology. In this study, we report for the first time the effect of tacrolimus (FK) on graft intestinal blood flow and intramural distribution, vascular resistance, and absorptive function. Isogeneic small intestine transplantation was performed in Lewis rats. Animals were grouped based upon the following treatment schedules: no treatment for 1 week in group 1; 0.6 ml/kg/day i.m. polyethylene glycol (PEG) for 1 week in group 2; 2 mg/kg/day i.m. FK for 1 week in group 3; 0.6 ml/kg/day PEG for 1 week and then 0.3 ml/kg/day for 5 weeks in group 4; 2 mg/kg/day FK for 1 week and then 1 mg/kg/day for 5 weeks in group 5. Group 6 was the same as in group 5 but FK was withdrawn for 1 week prior to assessment. Maltose absorption was measured to evaluate graft absorptive function. Blood flow and its intramural distribution to mucosal and serosal/muscularis layers were determined using the radioactive microsphere technique. Perfusion pressure was measured to calculate vascular resistance. One week of FK administration in group 3 did not change graft hemodynamics and absorption significantly. Prolonged FK treatment up to 6 weeks in group 5 resulted in a significant increase in mucosal vascular resistance (71.0±9.6 versus 47.7±6.7 U/g,P<0.01) and significant decreases in mucosal blood flow (1.14±0.15 versus 1.69±0.24 ml/g/min,P<0.01) and maltose absorption (30 min after loading: 155.4±26.9 versus 216.4±29.6,P<0.01; 60 min after loading: 172.9±24.5 versus 229.1±32.6 glucose mg/dlP<0.01). The serosal/muscularis layer remained relatively unaffected. Withdrawal of FK for 1 week after prolonged treatment in group 6 resulted in restorations of all parameters measured to normal ranges. We conclude that a short course of FK is safe, but prolonged FK administration has harmful effects on the hemodynamics and function of small intestinal transplants. Complete recovery is achieved when FK is discontinued.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We hypothesized that, following experimental small bowel transplantation, immunosuppressive therapy initiated on the day of the initial rise in serum intestinal fatty acid-binding protein (I-FABP) would result in graft salvage. In previously published work, we showed that I-FABP was not detectable in the serum of isografted Lewis rats, but could be measured in the peripheral circulation during small bowel allograft rejection. A clinically useful method to monitor transplanted allografts for rejection should detect the problem early in its evolution so that treatment to reverse the process would salvage a functional organ. Lewis rats served as recipients of LBNF1out-of-continuity small bowel allografts and were studied in two groups: group I (control) received no immunosuppression and group II received cyclosporine (CsA, 15 mg/kg/d, p.o.) when I-FABP rose to≥ 80 ng/ml. Serum I-FABP was measured daily until the time of sacrifice. Full-thickness graft biopsies were obtained on postoperative days 3(baseline), 6 or 7 (elevated I-FABP), 10, and 14 (sacrifice). Following transplantation baseline serum I-FABP (day 2 or 3) averaged ≤ 10.0 ng/ml. I-FABP remained at baseline through day 5 (range 0-50 ng/ml) in all animals and then rose abruptly on either day 6 or 7 (range 86-150 ng/ml;P< 0.001 vs. baseline). Histology on day 6 or 7 revealed a mild-to-moderate cellular rejection. Cyclosporine therapy reversed the rejection reaction and restored the bowel to normal histology. Serum I-FABP returned to baseline. In untreated animals, serum I-FABP remained elevated for several days and then returned to baseline levels coincident with fulminant rejection and mucosal sloughing. I-FABP was released into the peripheral circulation early in the evolution of acute rejection in this model of small bowel transplantation. Immunosuppressive therapy initiated when elevated levels of I-FABP were detected in the serum resulted in graft salvage. Cyclosporine immunotherapy consistently reversed rejection in this model. This article represents the first report of salvage of small bowel allografts when immunosuppressive therapy was instituted prospectively on the basis of a serum marker. Immunoreactive I-FABP appears to hold significant potential as a bio-chemical screening tool for acute rejection occurring in small bowel allografts.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Nineteen LEW rats with long-surviving (> 100 days) (DA × LEW)F1kidney allografts were generated by treating the recipients with cyclosporine for 14 days after grafting. All rats were monitored after transplantation for the development of antibodies to intact donor class I MHC molecules. Cyclosporine completely suppressed the early antibody response to intact DA class I MHC molecules in all 19 LEW rats. However, 17 of the 19 rats developed antibodies between four and six weeks after grafting-i.e., between two and four weeks after the cessation of cyclosporine therapy, and maintained high levels of antibody to the donor class I molecules in spite of the long-term presence of the allograft. The 2 rats that did not produce antibodies to donor class I MHC molecules, along with one of the 17 that did produce antibodies, were immunized with a synthetic peptide corresponding to a region of the DA class I MHC molecule known to be recognized by LEW CD4+ T cells via the indirect recognition pathway. All 3 long survivors developed self APC-dependent CD4+ T cell proliferation to the immunizing donor peptides, and strong antibody responses to these peptides. However, none of these long survivors suffered rejection episodes as a consequence of the peptide immunization. In one of the two long-surviving rats without antibodies to intact donor class I MHC molecules at the time of peptide priming, the peptide priming resulted in the prompt development of strong antibodies to intact donor class I molecules. However, the other of these 2 rats did not produce such antibodies after peptide priming. Thus in this model of kidney allograft tolerance, with long-term exposure of the recipient's immune system to donor antigens without evidence of rejection, none of the animals develops tolerance for the indirect T cell recognition of donor class I MHC antigens. In occasional animals, B cells potentially reactive to intact donor class I molecules are present and are adequately exposed to antigen but are quiescent because of the absence of T cell help, perhaps as a consequence of reversible T cell suppression or anergy. In other occasional animals, B cell nonreactivity (anergy or tolerance) to intact donor class I molecules appears to develop.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Transplantation of human fetal pancreas (HFP) is being considered as a potential treatment for insulin-dependent diabetes mellitus (IDDM). Therefore, it is necessary to have an experimental model of HFP-specific allograft rejection in order to understand all the factors that contribute to allograft rejection, and in which to test potential immunomodulatory protocols. The severe combined immunodeficient (SCID) mouse provides such a model. Previously, it has been reported that human allograft rejection can be observed in SCID mice engrafted with human lymphocytes. However, graft rejection is inconsistent and depends on both the number of lymphocytes injected and on the activation state. Here, we describe a model in which SCID mice are injected intraperitoneally with donor-specific lymphocytes generated by an in vitro culture period with irradiated donor splenocytes. Injection of the donor-sensitized PBL results in an acute rejection of HFP allografts (as early as 4 days posttransplant). This model does not require the establishment of chimerism in the SCID mice, as demonstrated by the lack of detectable human CD45 cells in the peripheral blood of rejecting mice. Allograft rejection was due to human CD4+and CD8+cells, as determined by immunohistochemical analysis of graft-infiltrating cells. The advantages of this model include the potential to specifically manipulate either the phenotype of the responding cells or the mechanism in which the responding population is generated. This model can provide a rapid method to test the efficacy of immunomodulatory regimens designed to protect allografts from an acute rejection response.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Murine OKT3 monoclonal antibodies function as an immunosuppressant drug for organ transplant recipients. A contraindication to retreatment may develop, however, because a high proportion of OKT3-treated patients form anti-OKT3 antibodies. Previous data have shown that only antiidiotypic IgG antibodies can negate the beneficial effect of the drug. Eighty-two OKT3-treated transplanted patients were tested by ELISA for IgG, IgM, and IgA anti-OKT3 antibodies and compared with 200 controls. The anti-OKT3 antibody-positive sera were screened additionally by flow cytometry for the presence of antiidiotypic activity by measuring Ortho OKT3-FITC activity on a CD3-positive cell line, Jurkat, before and after incubation with serial dilutions of patient and control sera. Forty-four of 82 patients developed antibodies to OKT3, 20 manifested IgG, 20 produced both IgG and IgA, and 4 IgA only. We never detected IgM anti-OKT3. Of the 44 anti-OKT3-positive patient sera, 25 showed antiidiotypic specificity. Two IgG-IgA anti-OKT3-positive patient sera were IgG-depleted by Protein G. Both continued to exhibit antiidiotypic IgA activity. IgA anti-OKT3 was associated with low serum OKT3 levels and lack of ability of OKT3 to lower total CD3 cell numbers to therapeutic levels. This is the first report of IgA anti-OKT3 antibody in transplant recipients. Isotype IgA anti-OKT3 was observed in 54% of the patients whose sera tested positive for anti-OKT3 by ELISA. The IgG/IgA anti-OKT3-positive patient sera tested continued to exhibit antiidiotypic OKT3 reactivity when depleted of IgG. We urge that OKT3-treated patients be monitored routinely for IgA anti-OKT3 antibodies to avoid the expense and potential complications of retreatment with this drug in sensitized patients.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 ± 9.3 vs. 236.5 ± 11.9 mg/dl,P< 0.02), LDL levels(107.9 ± 6.6 vs. 149.6 ± 10.7 mg/dl,P< 0.002), and triglyceride levels (118.8 ± 14.2 vs. 157.2 ± 13.8 mg/dl,P< 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%,P= 0.01), the incidence of multiple rejections episodes (P< 0.05), and the use of both pulse methylprednisolone(P= 0.01) and OKT3 (P= 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 ± 1.6 vs. 20.0 ± 2.0% lysis of K562 target cells,P< 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression.

ISSN:0041-1337    

出版商:OVID    

年代:1996

数据来源: OVID