Search PubMed⌕ Search

Biomedical subjects

S G Tullius

Publications and source records attributed to S G Tullius.

At least 37 records · Page 2Linked to original sources
PubMed2001

Improvements in early behavior of rat kidney allografts after treatment of the brain-dead donor.

OBJECTIVE: To improve the quality of organs from brain-dead donors by assessing the influence of alternative strategies on the early behavior of kidneys after transplantation into unmodified hosts. SUMMARY BACKGROUND DATA: Kidneys transplanted from living donors perform consistently better than those from cadaver sources. The authors have recently shown that donor brain death produces inflammatory changes in peripheral organs within hours, amplifies coincident ischemia-reperfusion injury, and accelerates acute and chronic rejection. Normalization of the graft by donor hormone treatment has hitherto been unsuccessful. METHODS: A standardized rat model of brain death was used. Experimental groups included recipients of allogeneic grafts from living and brain-dead donors (F344-->LEW). Donors were treated immediately after induction of brain death either with intravenous steroids, which block inflammatory cytokine release, or a soluble P-selectin glycoprotein ligand (sPSGL), which blocks initial selectin-mediated cellular adhesion. Kidney grafts were examined serially up to 10 days by morphology, immmunohistology, and reverse transcriptase-polymerase chain reaction. RESULTS: Overall survival of ummodified recipients of kidneys from brain-dead donors was significantly reduced versus living donors. Animals with organs from brain-dead donors that had received steroids or sPSGL survived significantly longer than those from untreated brain-dead donors. The intensity of ischemia-reperfusion injury and of acute rejection was reduced. Cellular infiltration and transcription of mRNA of representative proinflammatory mediators were diminished. CONCLUSIONS: Treatment of organ donors at the time of brain death markedly improves organ quality after kidney transplantation, upgrading it to that from a living donor.

Animals↗
PubMed2000

Quadruple tacrolimus-based induction therapy including azathioprine and ALG does not significantly improve outcome after liver transplantation when compared with standard induction with tacrolimus and steroids: results of a prospective, randomized trial.

BACKGROUND: Tacrolimus in combination with prednisolone has been proven to be a safe and effective immunosuppressive induction therapy in solid organ transplantation. However, it remains unclear whether a tacrolimus-based quadruple induction regimen with azathioprine and an antilymphocytic preparation could further improve the results after orthotopic liver transplantation. Therefore, we designed a prospective, randomized study to compare the immunosuppressive efficacy of dual (tacrolimus and prednisolone) and quadruple (tacrolimus, azathioprine, ALG Merieux and prednisolone) induction after liver transplantation. METHODS: After randomization, 120 consecutive patients of primary liver transplants were divided into the dual group (n=59) and the quadruple group (n=61) and followed for a minimum of 3 years. RESULTS: Patient survival at 3 years was 88.2% in the dual versus 94.9% in the quadruple group. Overall 25 patients in each group (41 and 42%, respectively) developed acute rejection. There was no difference in the number and severity of rejections. In each group only four patients required OKT3-therapy, however, although three of four patients in the quadruple group responded to OKT3 and cleared rejection, none of the four patients in the dual group were treated successfully with OKT3 (P<0.02). Rejection in these patients resolved only after additional treatment with mycophenolate mofetil. Adverse events and infections were equally distributed in both groups. Asymptomatic Cytomegalovirus infections were more common in the quadruple group (P<0.02). As of today, only one patient developed posttransplant lymphoproliferative disease (dual group). CONCLUSIONS: The data from our single-center study indicate that both tacrolimus-based dual and quadruple immunosuppressive induction regimens yield similar safety and effectiveness after liver transplantation.

Adult↗
PubMed2000

Mechanisms of tolerance induction in second renal allografts of a chronic rejection model.

In a previous experiment we demonstrated the induction of tolerance by the allograft itself. In this model of weak histoincompatibility, second grafts of donor origin replacing chronically rejected first renal allografts were accepted long term. Additionally grafted donor-specific hearts functioned indefinitely while adoptive transfer experiments demonstrated the development of donor-specific transferable tolerance. In the current experiment we compared intragraft gene expression of chronically rejected first and tolerant second grafts by RT-PCR. Second renal allografts of donor origin (F-344) replaced first grafts 2, 4, 8, 12, and 16 weeks after the initial engraftment. No immunosuppression was used during second engraftment. Grafts were followed by serial proteinuria; morphological and immunohistological studies (APAAP/infiltrating cells, ICAM-1, MHC II expression) and competitive RT-PCR analyses (expressed as arbitary units AU/cDNA) for relevant cells and cytokines (CD-3, IFNgamma, IL-10, and IL-4) were assessed by the end of the observation period (16 weeks). Macrophages/monocytes (ED-1+) and T-cells (CD-5 and CD-4+) infiltrated first allografts in high numbers by 12 weeks associated with strong structural signs of chronic graft rejection (ca. 30% arterio- and glomerulosclerosis, tubular atrophy and interstitial fibrosis). Cellular infiltrates in second grafts were prominent, however significantly reduced, while histological changes were minor. At cDNA levels, CD-3 transcripts were elevated in second renal allografts performed 2, 4, and 8 weeks after the initial engraftment while comparable levels were observed when second engraftment was performed after 12 and 16 weeks. Analyses of relevant cytokines demonstrated a TH1/TH2 shift independent from the time interval between first and second engraftment. These results emphasize the role of alloresponsiveness for the development of chronic graft dysfunction. Mechanisms of tolerance induction in our model are associated with a distinct alloresponsive pattern. A crucial role for regulatory T-cells is suggested.

Animals↗
PubMed2000

Treatment with a combined endothelin A/B-receptor antagonist does not prevent chronic renal allograft rejection in rats.

A markedly increased expression of endothelin (ET)-1 has been observed in renal allografts with chronic rejection, one of the most common causes of kidney graft loss. In this study we investigated the effect of treatment with a combined ET-A/B-receptor antagonist on the course of chronic renal allograft rejection. Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-to-Lewis isografts and uninephrectomized Lewis rats served as controls. Animals were treated with either the oral combined ET-A/B-receptor antagonist LU224332 (20 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light-microscopic evaluation and immunohistochemical assessment of cell-surface markers. Treatment with LU224332 did not improve survival after 24 weeks (0.47 vs. 0.38; p > 0.05 by log-rank test), nor did it have an influence on blood pressure, creatinine clearance, or proteinuria. Combined ET-A/B-receptor blockade was associated with a reduction of expression of cell-surface markers for macrophages (EDI), T-cells (R73), and major histocompatibility complex (MHC) II (F17-23-2), but did not lead to an improvement of histologic changes of chronic allograft rejection. Our data show that blocking both ET-A- and -B receptors, in opposition to a previously published beneficial effect of selective ET-A blockade, does not prevent the progression of chronic renal allograft rejection and does not prolong survival in this model. Functional integrity of the ET-B receptor therefore seems to play an important role in the nephroprotection provided by selective ET-A-receptor antagonists in chronic renal allograft nephropathy.

Animals↗
PubMed1999

Prevention of chronic renal allograft rejection in rats with an oral endothelin A receptor antagonist.

BACKGROUND: Chronic rejection is the most common cause of graft loss in renal transplantation. The pathomechanisms underlying chronic rejection are poorly understood, and no treatment has yet successfully been established. We hypothesized that, in analogy to models of reduced renal mass, the administration of a selective endothelin (ET) A receptor antagonist could improve the course of chronic rejection in renal allografts. METHODS: Experiments were performed in the Fisher-to-Lewis rat model of chronic rejection. Lewis-->Lewis isografts served as controls. Animals were treated with either the oral selective ET-A receptor antagonist LU135252 (50 mg/kg/day) or vehicle. Animal survival, blood pressure, creatinine clearance, proteinuria, and urinary ET excretion were investigated for 24 weeks. Kidneys were removed for light microscopical evaluation, determination of ET mRNA expression and tissue protein concentration, and immunohistochemical assessment of cell surface markers. RESULTS: Rats with chronic rejection showed an increase in renal ET mRNA synthesis and ET protein content. Treatment with LU135252 resulted in a significant improvement in survival after 24 weeks (0.92 vs. 0.38, P<0.01 by log-rank test). Creatinine clearance was higher in animals treated with the selective ET-A receptor antagonist (P<0.05). LU135252 had no influence on blood pressure and proteinuria. Selective ET-A blockade was associated with significantly less morphological changes and a significant reduction of expression of cell surface markers for macrophages (ED1), T cells (R73), and MHC II (F17-23-2). CONCLUSION: The renal ET-A system plays an important role in the pathomechanisms underlying chronic renal allograft rejection, because the treatment with a selective ET-A receptor antagonist dramatically improves the course of chronic renal failure after allograft transplantation. These results offer a novel therapeutical option for treatment of chronic renal allograft rejection, for which so far no therapy is known.

Administration, Oral↗
PubMed1999

[Lymphoepithelial carcinoma of the extrahepatic bile duct].

A 36-year-old female patient was transferred to our unit for surgical treatment of a biliary tract obstruction. ERC disclosed an obliteration of the common hepatic duct involving the hepatic bifurcation. Primary sclerotic cholangitis and carcinoma of the bile duct could not be confirmed histologically in the biopsy specimens. Tumor markers and autoimmune antibodies were normal. Histological examination of the ductus choledochus during the operation was not conclusive and a malignant lymphoma was considered. The macroscopic appearance comprised obliterative alterations extending to the right hepatic duct. Therefore, resection of the extrahepatic bile duct, right hemihepatectomy and hepaticojejunostomy were performed. The final histological statement revealed a lymphoepithelial carcinoma. The postoperative course of the patient was uneventful, and the patient is in good condition without any signs of recurrent disease 12 months after the operation. This tumor has been described as occurring as a neoplasm of the stomach and salivary glands exclusively and as being of low-grade malignancy. Additional histological evaluations confirmed the diagnosis of lymphoepithelial carcinoma.

Adult↗
PubMed1998

Prompt treatment of initial acute rejection episodes may improve long-term graft outcome.

Acute rejection episodes have been cited as a major immunological risk factor for the development of chronic rejection. To examine the influence of a single rejection event on ultimate graft outcome, acutely rejection rat kidney grafts were retransplanted sequentially into syngeneic rats and their functional and structural behavior assessed over time Early structural changes (days 3 and 4) were completely reversible, while signs of chronic rejection did become obvious during the long-term follow up. More advanced deteriorated grafts (days 5 and 7) were irreversibly damaged and the rats died shortly after retransplantation. Those results indicate the critical impact of acute rejection episodes on chronic graft rejection. Immediate and aggressive treatment of acute rejection episodes may remove this event as a risk factor for late deteriorating changes.

Acute Disease↗
PubMed1998

Recurrence-free survival after liver transplantation for small hepatocellular carcinoma.

Recurrence-free survival (RFS) in patients with small hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) was analyzed. From 1988 until 1996, 725 OLTs were performed in 669 patients. In 52 adults, HCC was confirmed histologically. OLT was limited to patients with small (< 5 cm) HCC with a maximum number of three nodules. Actuarial survival for these 52 patients at 1 and 5 years is 88% and 71%. RFS was defined as time until death without recurrence time until follow up with a diagnosis of recurrence, or, in patients without recurrence, time of last follow up. Overall, the 5-year RFS was 60%. Five-year RFS was less for bilobar compared to unilobar tumors (36% vs 70%), less for stage IVa tumors (UICC) compared to stage I-III tumors (17% vs 71%), and less for multiple compared to solitary tumors (54% vs 67%). In conclusion, potential cure may be achieved in more than 50% of all transplanted patients.

Actuarial Analysis↗
PubMed1998

Prevention of acute allograft rejection by antibody targeting of TIRC7, a novel T cell membrane protein.

A novel 75 kDa membrane protein, TIRC7, is described that exhibits a central role in T cell activation in vitro and in vivo. Modulation of TIRC7-mediated signals with specific anti-TIRC7 antibodies in vitro efficiently prevents human T cell proliferation and IL-2 secretion. Moreover, anti-TIRC7 antibodies specifically inhibit type 1 subset specific IFN-gamma expression but spare the type 2 cytokine IL-4. Diminished proliferation but not IFN-gamma secretion is reversible by exogenous rIL-2. An anti-TIRC7 antibody that cross-reacts with the 75 kDa rat homolog exhibits inhibition of rat alloimmune response in vitro and significantly prolongs kidney allograft survival in vivo. Targeting of TIRC7 may provide a novel therapeutic approach for modulation of the immune response.

Acute Disease↗