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K M Olthoff

Publications and source records attributed to K M Olthoff.

46 records · Page 3Linked to original sources
PubMed1991

The role of tumor necrosis factor in allograft rejection. III. Evidence that anti-TNF antibody therapy prolongs allograft survival in rats with acute rejection.

We have previously demonstrated that TNF-alpha levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administration of anti-TNF-alpha or anti-TNF-beta antibodies prolonged graft survival in a rat heterotopic cardiac transplant model. This experiment was designed to evaluate anti-TNF therapy in the treatment of acute allograft rejection. Heterotopic cardiac transplants were performed using Buffalo donors and Lewis recipients. Histologic sections of transplanted grafts from untreated animals revealed significant rejection at day 4 with terminal rejection occurring on day 10.8 +/- 0.4. Animals in the experimental groups received antirejection therapy from postoperative days 4-13. Treatment with cyclosporine at 2 mg/kg/day prolonged graft survival to 16.5 +/- 2.0 days (P = 0.01 versus controls). Administration of polyclonal anti-TNF-alpha in combination with polyclonal anti-TNF-beta increased graft survival to 14.6 +/- 0.4 days (P less than 0.001 versus controls). Use of a monoclonal anti-TNF-alpha antibody was even more effective, with graft survival of 17.4 +/- 0.7 days (P less than 0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-alpha in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-alpha (5 micrograms/day, i.p.) markedly accelerated the time to graft failure (7.4 +/- 0.2 days, P less than 0.001 versus controls). Examination of explanted graft tissue on postoperative day 9 from animals treated with anti-TNF showed decreased mononuclear cell infiltrate when compared to untreated animals. Treatment with TNF-alpha markedly increased the inflammatory process. These results suggest that TNF may play a role in the pathogenesis of acute rejection.

Animals↗
PubMed1990

Is liver transplantation justified for the treatment of hepatic malignancies?

Twenty-eight patients received orthotopic liver transplants for malignant disease between February 1, 1984, and December 31, 1989. Preoperative diagnoses included hepatocellular carcinoma (n = 16), cholangiocarcinoma (n = 3), other primary hepatic tumors (n = 6), and metastatic diseases to the liver (n = 3). Overall actuarial survivals at 6 months, 1 year, and 5 years were 67.3%, 51%, and 31%, respectively. Long-term survival longer than 5 years was achieved in 3 patients. The recurrence rate in patients surviving longer than 3 months is 48% (median, 7 months). Hepatocellular carcinoma and cholangiocarcinoma had the poorest survival and highest recurrence rates. Specific prognostic factors correlating with survival or recurrence could not be elucidated. These results indicate that orthotopic liver transplants can provide long-term cure and palliation for malignant disease; however, patient selection is extremely important in predicting outcome.

Adenoma, Bile Duct↗
PubMed1990

Anti-tumor necrosis factor antibody enhances allograft survival in rats.

We have recently observed significantly elevated serum tumor necrosis factor-alpha (TNF-alpha) levels during human liver allograft rejection. Although increased TNF activity has been reported in rejecting rat cardiac and renal allografts, this represents the first report of an animal model utilizing immunotherapy directed against TNF. Intraabdominal heart transplants (Buffalo to Lewis) were performed. Cardiac rejection was defined as cessation of a palpable beat and confirmed at laparotomy. Control animals received no immunotherapy and experienced rejection on Postoperative Day 11 +/- 0.4 (mean +/- SEM). Experimental animals received immunotherapy either intraperitoneally (ip) or intravenously (iv) from Days 1 to 10. Intraperitoneally administered anti-TNF-alpha prolonged graft survival to 16 +/- 2.7 days (P less than 0.05 vs controls), iv administration prolonged survival to 15 +/- 1.4 days (P less than 0.004). Animals treated with ip anti-TNF-beta survived 17 +/- 1.7 days (P less than 0.002 vs controls). Conversely, administration of purified TNF-alpha to graft recipients decreased graft survival to 7 +/- 0.4 days (P less than 0.001 vs controls). Serum samples analyzed in an L929 bioassay showed increased cytotoxic activity in control animals, corresponding to an increase in circulating TNF. This activity was partially abrogated in animals receiving immunotherapy. These data demonstrate that circulating levels of TNF are increased during rejection. Immunotherapy with anti-TNF-alpha or anti-TNF-beta prolongs graft survival, suggesting that TNF may play a role in the pathogenesis of acute allograft rejection.

Animals↗
PubMed1990

Comparison of UW solution and Euro-Collins solutions for cold preservation of human liver grafts.

University of Wisconsin solution, a new organ preservation medium, is reported to extend the period of cold storage. In order to evaluate the efficacy of UW solution in human liver preservation we compared 58 donor liver grafts preserved in Euro-Collins (EC) solution. All livers were harvested in a similar manner. Donor and recipient characteristics in the two groups were comparable. The mean preservation time of the UW solution was 11.5 +/- 4.2 hr (range 3-20 hr), significantly longer than the EC mean preservation time of 4.9 +/- 1.6 hr (2-9.6 hr) (P = 0.0001). Evaluation of mean postoperative liver function tests and coagulation factors on days 1-7 showed no statistical difference between the two groups. There was one primary graft nonfunction in the EC group and none with the UW organs. Hepatic artery thrombosis was similar in each group. The incidence of early retransplantation was similar. Three-month graft survival was 81% in the UW group vs. 73% in the EC group. Patient survival at three months was 87% with the UW organs and 84% with the EC organs. We conclude that cold storage of liver grafts in the UW solution has allowed for significantly longer preservation, permitting transplantation to be performed under semielective conditions and procurement of organs from much further distances. Grafts stored in UW solution perform as well as those stored in Euro-Collins, with no significant difference in liver function abnormalities postoperatively.

Adenosine↗
PubMed1990

The role of tumor necrosis factor in allograft rejection. II. Evidence that antibody therapy against tumor necrosis factor-alpha and lymphotoxin enhances cardiac allograft survival in rats.

In the previous study we demonstrated that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. The current study was designed to investigate the efficacy of antibody therapy against tumor necrosis factor-alpha and lymphotoxin (LT) in a rat heterotropic cardiac transplant model utilizing Buffalo donors and Lewis recipients. Control animals received no immunotherapy and experienced rejection on postoperative day 11 +/- 0.4 (mean +/- SEM). Experimental animals received immunotherapy either intraperitoneal or intravenous from days 1 to 10. The i.p. administered anti-TNF-alpha prolonged graft survival to 16 +/- 2.7 days (P less than 0.05 vs. controls); the i.v. administration prolonged survival to 15 +/- 1.4 days (P less than 0.004). Animals treated with i.p. anti-LT survived 17 +/- 1.7 days (P less than 0.002 vs. controls). Combination immunotherapy of anti-TNF-alpha and anti-LT increased function to 21 +/- 2.2 days (P less than 0.001 vs controls). Conversely, administration of purified TNF-alpha or LT to graft recipients accelerated the time to rejection. Mean survival for both treatments was 7 days (P less than 0.001 vs. controls). Histologic examination of the transplanted cardiac tissue showed a typical pattern for acute rejection; there was no evidence of hemorrhagic or coagulative necrosis. In contrast, administration of purified TNF-alpha or LT to recipients of a syngeneic heart did not stimulate rejection. These data suggest that TNF-alpha and LT may play a role in the pathogenesis of acute allograft rejection. In addition, the mechanism appears to be distinct from that seen in TNF-alpha or LT-mediated cytotoxicity of tumor cells.

Animals↗
PubMed1990

The role of tumor necrosis factor in allograft rejection. I. Evidence that elevated levels of tumor necrosis factor-alpha predict rejection following orthotopic liver transplantation.

Plasma levels of tumor necrosis factor-alpha were measured in 50 adult patients following orthotopic liver transplantation. The mean (+/- SEM) plasma concentration of TNF-alpha was significantly higher in patients experiencing a rejection episode (941 +/- 83 pg/ml) than in those with a stable clinical course (240 +/- 6 pg/ml; P = 0.0001). Peak levels of TNF-alpha were usually found at the time of clinically diagnosed rejection, although elevated levels were observed 1-2 days earlier. First-week peak TNF-alpha levels were significantly higher in patients who suffered graft loss (2146 +/- 788 pg/ml) than in those who were discharged from the hospital without clinical evidence of rejection (581 +/- 93 pg/ml; P = 0.004). TNF-alpha levels were not correlated with white blood cell count (r2 = 0.004), cyclosporine levels (0.01), serum creatinine (0.002), serum bilirubin (0.05), serum SGOT (0.03), or SGPT (0.05). TNF-alpha levels were not elevated in four cases of viral hepatitis occurring after transplantation. We conclude that circulating levels of TNF-alpha are elevated during liver allograft rejection and may precede clinical manifestations. First-week TNF-alpha levels are also useful predictors of long-term graft outcome. Further investigation is required to determine whether this monokine is important in the actual pathogenesis of allograft rejection.

Adolescent↗
PubMed1988

Liver transplantation at UCLA: a report of clinical activities.

Liver transplantation has become a widely accepted form of therapy for many life-threatening liver illnesses. Since the introduction of CsA in 1980, numerous centers have opened and now more than 800 liver transplants are performed in the United States per year. In most large series, a 70% 5-year survival rate is seen. However, in terms of survival, hepatic transplantation for carcinoma continues to lag behind other diseases. In the absence of an available alternative treatment for this group of patients, vigorous investigation into prevention of recurrences following OLT is needed. Despite the proliferation of liver transplant programs, optimization of postoperative care remains a major challenge for those physicians who care for these patients. Too often, the diagnosis of rejection in contrast to infection is guided by clinical suspicion rather than firm evidence. Reversal of multiorgan dysfunction is often aggravated by the very immunosuppressants which allow transplantation. Maximizing graft acceptance and organ function while minimizing infectious complications remains the ultimate goal for transplant surgeons and is the key to further success.

Adolescent↗