ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The rejection of the transplanted allograft is dependent on T cell activation, which requires T cell receptor engagement by antigen and costimulatory signals delivered by T cell surface molecules such as CD28. CTLA4-Ig is a fusion protein that has previously been shown to block the CD28-mediated costimulatory signal and inhibit immune responses in vitro and in vivo. In this report we show that treatment of the C3H/He recipient of a BALB/c vascularized cardiac allograft with a 12-day course of CTLA4-Ig produced indefinite graft survival (>100 days) in the majority of recipients. In addition, these recipients demonstrated donor-specific transplantation tolerance when tested with donor-specific (BALB/c) and third-party (C57BL/10) skin grafts. These results demonstrate that CTLA4-Ig can induce transplantation tolerance in the adult murine cardiae allograft model.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

New concepts for the treatment of hepatitis B in immunocompromised patients are urgently needed. We describe our first experience with the new antiviral agent famciclovir in combination with a short course of prostaglandin E in a patient with severe hepatitis B after liver transplantation. Initial treatment with prostaglandin E reduced the inflammatory activity, as measured by transaminase activities, but did not affect viral replication. Consecutive long-term treatment with famciclovir further normalized liver function and profoundly suppressed viral replication. HBeAg and HBV-DNA -PCR all became negative and only HBsAg persisted. Histology documented marked reduction of cellular infiltration. The patient completely recovered and is back to regular work as a teacher.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In this study we present a comprehensive evaluation of the molecular interactions between human T cells and porcine aortic endothelial cells (PAEC) that contribute to human T cell activation. Binding assays demonstrated that porcine erythrocytes (E) and PAEC express ligand(s) for the human T cell glycoprotein CD2. Prior incubation of human T cells with a blocking monoclonal antibody directed against CD2 (αCD2-BL) completely inhibited T cell/E and T cell/PAEC interaction. Xenogeneic mixed lymphocyte reactions (XMLR) revealed that human PBMC, or highly purified T cells were activated by PAEC in the absence of human antigen-presenting cells (APC). Addition of αCD2-BL or αLFA-1 to these assays inhibited PAEC-mediated human T cell activation. Furthermore, we demonstrated that highly purified human CD4+ and CD8+ T cells proliferated in response to PAEC and that this response was blocked by monoclonal antibodies directed against LFA-1 and CD2. Addition of αSLA class I blocked the proliferation of CD8+ but not CD4+ T cells, indicating direct presentation of SLA class I antigens to human T cells. We have recently shown that expression of the human complement inhibitor (CD59) on PAEC (PAEC-LXSNCD59) rendered these cells resistant to human complement-mediated activation and lysis, suggesting that human CD59 expression on PAEC could be an effective therapy for hyperacute rejection (HAR). However, recent studies have shown that in addition to its role as a complement inhibitor, CD59 binds human T cell CD2 and contributes to T cell activation. We therefore examined whether human CD59 expression on PAEC augmented the human an-tiporcine T cell response. We demonstrated that human T cells do not display increased binding to or activation by PAEC-LXSNCD59 relative to PAEC controls. Taken together, our data establish that PAEC directly stimulate human T cells in vitro and that interactions between the human accessory molecules CD2, LFA-1 and their PAEC surface ligands contribute to human T cell activation. In addition, the expression of human CD59 on porcine donor organs may confer resistance to human complement-mediated HAR without exacerbating the human antiporcine cellular response.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Leflunomide is an isoxazole with newly discovered immunosuppressive properties. Its mechanism of action operates later in the cell cycle than cyclosporine and appears to interfere with lymphocyte IL-2 responsiveness. With the encouraging results from in vitro and small-animal studies, we subjected leflunomide to the rigorous canine renal transplantation model in a dose response protocol. Thirty-eight female mongrel dogs underwent renal transplantation and bilateral nephrectomy. Immunosuppression was stratified from controls with no immunosuppression to monotherapy with leflunomide at 2, 4, 8, and 16 mg/kg/day given orally and in a combination therapy with cyclosporine. To evaluate its toxicity while maintaining a low constant blood level, eight dogs were treated by continuous intravenous infusion at doses of 2, 4, 6, and 8 mg/kg/day. The mean survival time for nonimmuno suppressed controls (n=2) was 9 days, leflunomide 2 mg/kg/day (n=2) was 9 days, leflunomide 4 mg/kg/day (n=4) was 16 days, leflunomide 8 mg/kg/day (n=5) was 28 days, leflunomide 16 mg/kg/day (n=7) was 21 days. Cyclosporine alone at 10 mg/kg/day (n=4) resulted in a mean survival time of 13 days. The mean survival time with the combination of cyclosporine 10 mg/kg/day with leflunomide 4 mg/kg/day (n=6) was 68 days. The mean survival time for continuous intravenous leflunomide 2 mg/kg/day (n=2) was 10 days; for leflunomide 4 mg/kg/day, 20 days; for leflunomide 6 mg/kg/day, 14 days; and leflunomide 8 mg/kg/day, 21 days. The mean serum trough levels of leflunomide ranged from 10 μUg/ml at the 2 mg dose to 55 μUg/ml for the 16 mg dose, levels that have been well tolerated in man. Leflunomide at 16 mg/kg/day reliably prevented acute al-lograft rejection, but the dogs died of inanition with normal renal function. Leflunomide at a nontoxic dose of 4 mg/kg/day extended survival to 16 days, but all dogs died of rejection. A combination of inadequate doses of leflunomide (4 mg/kg/day) and cyclosporine (10 mg/kg/day) resulted in all animals having normal renal function and weight for 30 days. Even at a high dose of 16 mg/kg/day, no viral or bacterial infections were noted. These observations in a canine system add to the growing enthusiasm for the evaluation of leflunomide in human transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

A severe shortage of organs is perhaps the most important obstacle facing transplantation today. In an attempt to address this serious problem, several transplant centers have suggested a reconsideration of genetically unrelated living kidney donors. Recently, there have been reports of excellent results using such unconventional donors, and cogent arguments have been made that this approach is ethically acceptable, at least when the donor is motivated by altruism. To see what impact this new information has had on the transplant community, I mailed a questionnaire to all adult renal transplant centers in the United States asking for their views and practices regarding unrelated living kidney donation. Of the 127 (64%) responding, 88% would accept spouses as donors, 63% would accept friends, and 15% would even consider altruistic strangers. When compared with the results of a similar survey completed six years ago, it became clear that support for unrelated living kidney donation had increased, as the great majority of centers now believe that emotionally related donors are acceptable. On the other hand, while more of these donors are being used, they still account for only a small fraction of all kidney transplants. It appears that medical successes and favorable ethical arguments have generated broad support for some types of unrelated living donors, but more in principle than in practice, as there still seems

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Transforming growth factor beta (TGFβ1) is a prosclerotic cytokine implicated in several disease processes. Recent reports have demonstrated a role for TGFβ1in experimental models of glomerulonephritis, focusing attention on the relevance of TGFβ to renal fibrogenesis in human disease. The study reported here was designed to investigate whether circulating, active TGFβ1, could be detected in renal allograft recipients, and whether plasma levels correlated with episodes of rejection, a process involving both inflammation and fibrosis. We have developed an ELISA assay for active TGFβ1using commercially available antibodies, and measured plasma levels in 43 healthy controls, 11 patients with membranous nephropathy (MN) and impaired renal function, 17 transplant recipients with stable renal function, 27 patients with acute cellular rejection, 7 patients with chronic vascular rejection, and 10 patients with acute tubular necrosis and/or cyclosporine toxicity. In the last three groups diagnoses were biopsy-proved, and all samples were collected at the time of biopsy. TGFβ1was also measured in urine samples from 8, 11, 0, 9, 4, and 7 individuals, respectively, from each group. TGFβ1was not detected in plasma from any of the healthy controls or any of the MN patients, (detection limit of assay 0.1 ng/ml). By comparison, it was significantly increased in all groups of transplant recipients (unpairedttest,P<0.01), but there were no significant differences between the transplant groups. Plasma TGFβ1level did not correlate with renal function (estimated by either serum creatinine or reciprocal creatinine), kidney donor age, recipient age, time since transplantation, or cyclosporine plasma trough level. TGFβ1was found in every urine sample tested from healthy controls, with a range from 1 ng/ml to 35 ng/ml. Among the 20 transplant patient urines tested, 2 were negative, 18 were positive but within the range determined for the healthy controls. There were no significant differences between the groups.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

111In-labeled platelet scintigraphy was used to confirm immunological intolerance as the cause of prolonged febrile syndrome in hemodialyzed patients with a nonfunctioning renal allograft. Thirty-six patients with febrile syndrome (>38dGC) and a nonfunctioning renal graft were studied. Thirteen patients were under minimal steroids (5–10 mg/day) and 23 were free of immunosuppressive therapy. A control group of 6 patients without fever and with a nonfunctioning renal graft was also included. The labeling of autologous platelets with111In-mercaptopyridine was performed following a modified technique of Thakur. Scans were obtained at 24 and 48 hr after injection of 100–200 μUCi of111In-labeled platelets. A platelet uptake index (PUI) was calculated to evaluate the results of the scintigraphy. A PUI >1.5 at 24 or 48 hr was considered positive and suggestive of immunological activity in the nonfunctioning renal allograft. In the study group the PUI was considered positive in 26 patients and negative in 10. In 3 patients with positive PUI, fever disappeared after steroid treatment, and trans-plantectomy was performed in the remaining 23. In 8 of the 10 patients with a negative PUI, fever disappeared with antimicrobial therapy. In the control group, a negative PUI was obtained in all cases. The sensitivity of PUI in demonstrating immunological intolerance of the nonfunctioning renal allograft was 93% with a specificity of 100%. Our results suggest that this new approach with111In-labeled platelet scintigraphy may constitute a good marker for discriminating the origin of the febrile syndrome in patients with a nonfunctioning renal allograft. A positive PUI (>1.5) strongly suggested immunological intolerance of the nonfunctioning allograft.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

OG 37–325 (nva-cyclosporine, cyclosporine G) is structurally similar to cyclosporine A (CsA). We hypothesized that OG 37–325 may, therefore, be metabolized by P450 3A, an enzyme recently shown to metabolize CsA, To test this hypothesis, we employed the erythromycin breath test (ERMBT) to measure P450 3A activity on multiple occasions in twenty OG 37–325-treated renal transplant recipients. When stable dosing was achieved, there was a measured 6-fold variation in the ratio of 12-hr whole-blood parent compound trough concentration (ng/ml, HPLC) to daily OG 37–325 dose (mg/kg) ([OG 37–325]/dose). In support of our hypothesis, there was an inverse correlation between the ERMBT result and the [OG 37–325]/dose ratio (r=-0.71,P<0.001, n=20); that is, patients with higher P450 3A activity generally required higher OG 37–325 doses to attain target blood levels. We also found that intrapatient variation in the [OG 37–325]/dose ratio observed over the course of the study correlated with changes in the ERMBT results (r=-0.67,P=0.002). Inter- and intrapatient differences in [OG 37–325]/dose ratio were not predicted by patient age, serum cholesterol, blood hematocrit, or traditional liver chemistries. We conclude that P450 3A is generally rate limiting in the elimination of OG 37–325 in adult renal transplant recipients. Therefore, most drug interactions observed with CsA should also be expected with OG 37–325. We also conclude that intrapatient changes in OG 37–325 dosing requirements largely result from changes in P450 3A activity. The ERMBT may therefore provide useful information concerning patient compliance and may also serve as a useful guide to OG 37–325 dosing adjustments.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We retrospectively reviewed all (n=369) percutaneous renal allograft biopsies performed at our institution between 1987 and 1992, comparing 14-gauge Franklin-Silverman (internal diameter=2.0 mm, n=169) and 18-gauge automated (internal diameter =1.2 mm, n=200) core biopsy needles. Visualization method, specimen adequacy, and complications were grouped by needle type. Five or more glomeruli were present in 88.9% of specimens obtained with Franklin-Silverman needles and in 82.7% with automated needles. A histologic diagnosis was obtained in 94.1% and 95.5% of Franklin-Silverman and automated biopsies, respectively. A complication was detected in 27 Franklin-Silverman biopsies (16.0%) and in 21 automated biopsies (10.5%) (not significant [NS],P>0.05). Some procedures had more than one complication. Excluding asymptomatic gross hematuria, incidental hematomas, and incidental arteriovenous fistulas detected by routine ultrasonography, clinically significant complication rates were 6.5% for Franklin-Silverman biopsies and 2.5% for automated biopsies (NS). No allograft losses or patient deaths occurred as a result of allograft biopsy. Subgroup analysis of all biopsies performed with ultrasound marking alone (Franklin-Silverman, n=119; automated, n=148) revealed no significant (NS) difference in complication rates (15.1% vs. 10.8%). Additional subgroup analyses of palpation, ultrasound marking, and real-time ultrasonographic visualization techniques within each needle type also revealed no significant difference in the complication rate. Biopsy within 30 days of transplantation and no antihypertensive therapy were the only factors univariately associated (P<0.05) with an increased complication rate. Multivariate analysis found biopsy within 30 days of transplantation (P=0.007) was associated with the overall presence of one or more complications of any type. Type of needle (Franklin-Silverman vs. automated) achieved borderline significance (P=0.047) when time to biopsy was statistically adjusted for; the Franklin-Silverman needle had a higher complication rate.

ISSN:0041-1337    

出版商:OVID    

年代:1994

数据来源: OVID