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L McChesney

Publications and source records attributed to L McChesney.

At least 19 recordsLinked to original sources
PubMed2001

Differential expression of metallopanstimulin/S27 ribosomal protein in hepatic regeneration and neoplasia.

We have previously shown that human metallopanstimulin-1 (MPS-1) is a ubiquitous 9.4-kd multifunctional ribosomal S27/nuclear "zinc finger" protein that is expressed at high levels in a wide variety of actively proliferating cells and tumor tissues. In this study, we examined the expression of MPS-1 in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Tissue samples were obtained at the time of tumor resection, needle biopsy, or liver transplantation. MPS- 1 was studied by immunohistochemistry by use of specific antibodies to the N-terminus of MPS-1 in a biotin/streptavidin-amplified system. In chronic hepatitis, hepatocytes had very weak MPS-1 immunostaining. In contrast, hepatocytes in regenerating cirrhotic nodules stained strongly for MPS-1. In well-differentiated hepatocellular carcinoma, MPS-1 presence was intense at the periphery of the malignant nodule. In poorly differentiated hepatocellular carcinoma, MPS-1 presence was notably intense in malignant hepatocytes invading the septal tissues, in close contact with neovascular structures. These results suggest that MPS-1 may be involved in both progression toward malignancy in regenerating cirrhotic nodules and in subsequent steps of hepatocarcinogenesis.

Antibodies↗
PubMed1998

Histological characterization and pharmacological control of chronic rejection in xenogeneic and allogeneic heart transplantation.

BACKGROUND: Chronic allograft rejection remains a major barrier to successful long-term allograft transplantation in humans. Chronic allograft rejection is characterized by the appearance of arterial lesions with concentric intimal thickening. This study investigates the development and control of chronic rejection in hamster cardiac xenografts transplanted into Lewis rats. METHODS: Chronic rejection in the xenograft model involves transplantation of hamster hearts into Lewis rats treated with leflunomide (Lef) continuously at 15 mg/kg/day. The allograft model involves transplantation of Lewis hearts into Fisher-334 rats treated with cyclosporine (CsA) at 2.5 mg/kg for 5 days. RESULTS: The average scores of arterial intimal thickening on day 45 after transplantation were 1.89+/-0.43 in the xenograft and 2.50+/-0.72 in the allograft. The basic pathology of both xenografts and allografts undergoing chronic rejection was arterial intimal thickening comprising smooth muscle cell proliferation, mononuclear cell infiltration, and fibrosis. The majority of cells infiltrating the arterial intima and myocardium were T cells and macrophages. Compared with the allograft, intimal edema, matrix deposition and fibrinoid necrosis were specifically presented in the xenografts and generally involved the larger arteries. The predominant isotype of antibody deposited was IgM in xenografts and IgG in allografts. When combined Lef and CsA therapy was initiated on day 45 after transplantation, the changes of chronic rejection were reversed in both xenografts and allografts by day 90. The scores of intimal thickening were significantly reduced to 0.97+/-0.45 and 1.48+/-0.56, respectively. CONCLUSIONS: We conclude that chronic rejection can be induced in xenografts under conditions of inadequate immunosuppression. Chronic rejection in xenografts involves arterial lesions that bear some histological similarities to, as well as differences from, those observed in chronically rejected allografts. Finally, combination therapy with CsA and Lef reduced the incidence and severity of the intimal lesions in both chronically rejecting xenografts and allografts.

Animals↗
PubMed1998

Immunosuppression preventing concordant xenogeneic islet graft rejection is not sufficient to prevent recurrence of autoimmune diabetes in nonobese diabetic mice.

BACKGROUND: We and others have reported previously that the immunosuppressant, leflunomide (Lef), can prevent allogeneic and xenogeneic islet graft rejection in streptozocin (STZ)-induced diabetic animals. However, whether Lef required to prevent islet graft rejection is sufficient to prevent the recurrence of autoimmune diabetes has not been addressed. METHODS: The effect of Lef on concordant xenogeneic islet graft in STZ-induced diabetic mice and autoimmune nonobese diabetic (NOD) mice were studied. Then, whether Lef prevents the onset of spontaneous diabetes in young NOD mice and the recurrence of diabetes after major histocompatibility complex (MHC)-matched islet transplantation in diabetic NOD mice were investigated. RESULTS: In STZ-induced diabetic BALB/c mice, Lef treatment significantly prolonged rat islet graft survival. However, Lef could not significantly prolong rat islet graft survival in autoimmune diabetic NOD mice. For prevention studies, treatment with Lef at 30 mg/ kg/day from 4 weeks to 20 weeks of age significantly reduced the incidence of spontaneous diabetes in NOD mice. However, when the NOD mice were treated from 8 to 24 weeks of age, the incidence of spontaneous diabetes was not significantly reduced as compared to the incidence of diabetes in the untreated female NOD mice at 28 weeks of age. Finally, in the MHC-matched islet transplant model, Lef could not significantly prolong MHC-matched nonobese diabetes-resistant mice islet graft survival in NOD mice. CONCLUSIONS: Lef preventing concordant xenogeneic islet graft rejection is not sufficient to prevent the recurrence of autoimmune diabetes in NOD mice. We believe that controlling autoimmunity after islet transplantation will lead the way to promote successful clinical islet transplantation in the future.

Animals↗
PubMed1997

Prolongation of rat islet allograft survival by the immunosuppressive agent leflunomide.

The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2 +/- 0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0 +/- 1.6, 29.8 +/- 3.7, and 29.0 +/- 5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21 +/- 3.5 days. When CsA (5 mg/ kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8 -/+ 4.7 and 36.0 -/+ 6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/ day, MSTs were further increased to 45.8 -/+ 8.8 or 37.4 -/+ 4.7 days, respectively. Graft MST was 56.4 -/+ 9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2 -/+ 0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8 -/+ 1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its immunosuppressive effect was improved when combined with CsA.

Animals↗
PubMed1997

In vivo effects of leflunomide on normal pancreatic islet and syngeneic islet graft function.

Leflunomide (Lef) is a novel immunosuppressant that can prevent islet allograft and xenograft rejection. In this study, we investigated the in vivo effects of Lef on the function of normal pancreatic islets and syngeneic islet grafts in rats and compared its effect to cyclosporine (CsA) and FK506. Different groups of rats were treated with Lef (10 and 20 mg/kg/day), CsA (20 mg/kg/day), or FK506 (2 mg/kg/day). After 4 and 6 weeks, nonfasting blood glucose (BG) levels of all the treatment groups were not different from that of the control group. Intravenous glucose tolerance test revealed that the rate of glucose disappearance was normal in Lef-treated groups. However, the rate of glucose disappearance in the CsA- and FK506-treated rats was impaired. In contrast, long-term (7 months) treatment of rats with CsA (10 mg/kg/day) resulted in five of seven rats developing hyperglycemia. However, normal BG was observed in all rats treated for 7 months with Lef (10 mg/kg/day). In the second experimental model, streptozocin-induced diabetic ACI rats were grafted with an average of 1200 syngeneic islets into the liver or kidney capsule. Diabetes in these ACI recipients was stably reversed for 6 months, then these rats were treated with Lef (20 mg/kg/day), CsA (20 mg/kg/day), and FK506 (2 mg/kg/day). After 14 days of treatment, nonfasting BG levels were significantly increased in rats treated with CsA (before: 105 +/- 2.9 mg/ dl, after: 275.8 +/- 60 mg/dl) as well as in rats treated with FK506 (before: 108 +/- 2.4 mg/dl, after: 209 +/- 10.1 mg/dl). In contrast, the BG levels of the Lef-treated rats were indistinguishable from those of the untreated control groups. Site of transplantation, i.e., liver and kidney, did not affect the results. Our results indicating that Lef has no diabetogenic property in vivo lends support to the promise that leflunomide may be effective for clinical islet transplantation.

Animals↗
PubMed1996

Feasibility of using a swine portal vein containing a metallic stent for creating a portacaval shunt.

RATIONALE AND OBJECTIVES: We evaluated the feasibility of using a metallic stented portal vein as a conduit for portacaval shunt in pigs. METHODS: A metallic self-expanding stent was placed in the portal vein of five pigs under combined ultrasound and fluoroscopic guidance via a percutaneous transhepatic approach. After 6 weeks, a portacaval shunt was performed using the stented portal vein as a conduit. A single angiogram followed immediately by sacrifice and histologic examination was performed on each pig at a varying time interval postshunt. RESULTS: One pig died 3 days after the shunt procedure because of a presumed surgical technical failure and a consequent thrombosed portal vein. Angiographic patency of the portacaval shunt was confirmed in the four remaining pigs. Postmortem histologic evaluation showed more complete endothelialization and subintimal organization in the more chronic stents. Thrombus occurred only in the stent of the pig that died. There was no significant luminal obstruction in the other four stents. CONCLUSION: Our results suggest that a stented portal vein can be used successfully as a conduit for portacaval shunt in pigs.

Angiography↗
PubMed1995

Pharmacologically induced regression of chronic transplant rejection.

Chronic rejection, characterized by a progressive obliterative arteriopathy, is a major cause of graft failure in long-surviving human transplants for which there is no effective treatment. Leflunomide, an isoxazol derivative, has been shown to be a novel immunomodulatory drug that profoundly suppresses the immune response. In this study, 58 Fisher-344 rats received cardiac transplantation from Lewis rats. All the recipients were given CsA at 2.5 mg/kg for 5 days postoperatively. Without further treatments, the arterial intima was progressively injured by mononuclear cell infiltration and Ab deposition. Smooth muscle cell and fibroblast proliferation in the intima became a predominant phenomenon by day 90. CsA was ineffective in controlling the progress of arterial intimal thickening when treatment began on day 30. Leflunomide at 5 mg/kg failed to control arterial intimal thickening by day 60 when therapy began on day 30. However, the progress of arterial intimal thickening was significantly inhibited by day 90 when the dosage of leflunomide had been increased to 10 mg/kg on day 60. Combined therapy with leflunomide and CsA at 5 mg/kg for 30 days dramatically reversed the arterial thickening by day 60. After increasing the dosages of both leflunomide and CsA to 10 mg/kg on day 60, the combination therapy steadily controlled the chronic rejection. Only the combination therapy significantly down-regulated circulating antidonor IgM and IgG titers. In rat smooth muscle cell culture, this same drug combination had a synergistic inhibitory effect on proliferation. Therefore, the combination therapy of leflunomide and CsA could reverse and control the progress of chronic rejection, while leflunomide, at higher dosage as a monotherapy, could stabilize chronic rejection in this model. The mechanism of the regression of chronic rejection by leflunomide and cyclosporine may be related to their in vitro abilities to control not only lymphocyte but smooth muscle cell proliferation, as well. The synergistic effect of these two drugs on vascular smooth muscle cell proliferation in vitro may be an important part of this novel activity. This unique feature holds intriguing possibilities for treating established chronic rejection.

Animals↗
PubMed1995

A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation.

Nonanastomotic strictures after liver transplantations are a source of significant morbidity, often necessitating retransplantation. The purpose of this study was twofold: first to identify features associated with the development of this lesion; second, to make technical modifications that will decrease the incidence of this problem. In the first part of this study, 15 of 131 patients were diagnosed with nonanastomotic biliary stricture. A stepwise logistic-regression analysis associated donor cold ischemic time and dopamine dose with the development of nonanastomotic biliary strictures. All these patients had arterial reconstruction after partial revascularization of the liver with portal venous blood. Because the bile duct receives its blood supply from only the hepatic artery, we hypothesized that the prolonged period of warm ischemia from staged reconstruction of the vascular supply would promote the development of this lesion. In a second part of this study, the stricture rate in 45 patients with simultaneous revascularization using both the hepatic artery and portal vein was compared with that in 83 patients from the first part of this study initially revascularized with portal venous blood. All patients in the second study had grafts preserved using UW solution. Only 1 patient with simultaneous revascularization developed a nonanastomotic biliary stricture. Because we were unable to identify any significant complications related to this method of revascularization, we propose that the hepatic artery and portal vein should be released simultaneously, especially in patients receiving a graft with prolonged storage time.

Adenosine↗
PubMed1994

Leflunomide controls rejection in hamster to rat cardiac xenografts.

Leflunomide is an isoxazole derivative that has the ability to prevent acute rejection of cardiac, renal, and skin transplants in strongly rejecting rat models. Furthermore, leflunomide is able to interact synergistically with CsA to inhibit allograft rejection and also reverse ongoing allograft rejection. In vitro studies suggest that the mechanism of action of leflunomide is via an interruption of cytokine signaling in T cells. This study defines the ability of leflunomide to prevent and reverse rejection of concordant xenografts. One hundred nine adult Lewis rats in 13 groups received abdominal heterotopic cardiac transplants from Golden Syrian hamsters. The xenograft survived 3.9 +/-0.3 days without treatment. When leflunomide was given at 2.5, 5, 10, 15, or 20 mg/kg by gavage daily, the cardiac xenograft survivals were 5.0 +/- 0.6, 8.0 +/- 3.0, 52.0 +/- 20.2, 76.5 +/- 21.14, and 58.9 +/- 28.1 days, respectively. The survival rates were 4.0 +/- 0 and 27.7 +/- 28.7 days when CsA was given at 10 and 20 mg/kg i.m., respectively. The combination of CsA at 10 mg/kg with leflunomide at 10 mg/kg or 5 mg/kg prolonged cardiac xenograft survival to 106.0 +/- 50.2 days and > 90 days, respectively. There were no observable side effects in the latter combination. Histologic studies of untreated graft hearts 4 days after transplantation revealed infarction of myocardium and severe RBC extravasation. In contrast, the rejected hamster hearts from long-term survivors showed massive mononuclear cell infiltration and myocardium fibrosis in contrast to the early rejected picture. Therapy with leflunomide begun on day 2 reversed these rejection responses by day 6. In addition, the increase in allospecific IgM titers observed on day 2 was reversed, and the allospecific IgM to IgG isotype switch that occurred in untreated animals was prevented by leflunomide. These observations demonstrate that leflunomide, at nontoxic doses, effectively controlled acute rejection of concordant xenografts and synergistic immunosuppressive effect was achieved with leflunomide and CsA.

Animals↗
PubMed1994

Leflunomide in experimental transplantation. Control of rejection and alloantibody production, reversal of acute rejection, and interaction with cyclosporine.

Leflunomide is a compound recently shown to reduce T and B cell-mediated responses in a number of experimental rat, mouse, and human systems. To explore its potential as an immunosuppressant, we studied leflunomide in 128 Brown-Norway/Lewis cardiac transplants and in 48 unoperated Lewis rats. At doses ranging from 0.63 mg/kg to 10 mg/kg given for 7 days, leflunomide significantly prolonged graft survival compared with controls. When cyclosporine or leflunomide was given for 21 days at a dose of 5 mg/kg, indefinite graft survival occurred in 3/6 animals receiving leflunomide but in none of the 21-day cyclosporine-treated animals. When acute rejection was allowed to develop for four days in untreated rats, leflunomide but not cyclosporine reversed the rejection, returning histology to a normal appearance by seven days. Alloantibody responses measured in microcytoxicity assays as well as total allospecific IgG and IgM in the rejecting animals also were returned to baseline levels by leflunomide but not cyclosporine. When both drugs were used together, a synergistic effect was observed at low doses of both drugs. Pharmacokinetics studies showed that their combined use for up to 28 days did not affect the trough levels of cyclosporine or cyclosporine elimination, suggesting that the synergistic effect was not caused by reduced elimination. The toxicity of each drug was negligible in a group of 32 rats receiving the drugs alone or in combination as measured by serial observation of general appearance, testing of serum ALT, AST, bilirubin, creatinine, white blood cell counts, hemoglobin, and gross necropsy appearance. Weight gain was slightly reduced by both drugs but combined drug use did not alter the pattern. The results of these experiments show leflunomide to be a potent, well-tolerated immunosuppressant, synergistic in its activity with cyclosporine, and would seem to encourage a closer look at this drug for potential use in man.

Abdomen↗