ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The effectiveness of rapamycin (RAPA) was examined for heart, kidney, and small bowel allografts in rats. Untreated or vehicle only–infused Wistar Furth (RT1u) recipients rejected Buffalo (RT1b) heart allografts within a mean survival time (MST) of 6.5±0.5 and 6.3±0.5 days, respectively. In contrast, a 14-day continuous intravenous (i.v.) infusion by an osmotic pump of 0.08 mg/kg/day RAPA to WFu recipients prolonged BUF heart allograft survival to an MST of 34.4±12.1 days (P=0.0001). There was a graded dose-response to 0.16 mg/kg (39.0±8.7 days; P=0.0001), 0.32 mg/kg (55.7±3.3 days; P=0.0001) and 0.8 mg/kg (48.0±3.6; P=0.0001). Furthermore, intraarterial/intragraft but not i.v. infusion of 0.02 mg/kg/day prolonged BUF heart allografts—namely, an MST of 14.6±1.4 days versus 8.6±2.6 days (P=0.0001), respectively. Local delivery doses of RAPA were about as effective as the same dose delivered i.v.: 0.08 mg/kg MST 37.0±18.3 days (P=0.0001); 0.32 mg/kg, 40.0±3.9 days (P=0.0001); and 0.8 mg/kg, 54.8±8.2 days (P=0.0001).Systemic i.v. RAPA therapy with 0.08 or 0.8 mg/kg/ day prolonged the survival of BUF kidney grafts in WFu recipients—namely, an MST of 52.7±42.7 (NS) and 90.2±62.4 (P=0.001) days, respectively, versus an MST of 11.6±1.5 days in control WFu recipients only infused with vehicle. While normal WFu rats reject heterotopic BUF small bowel allografts within an MST of 10.0 days, a 14-day course of i.v. RAPA treatment significantly (P=0.0001) prolonged small bowel allograft survival to an MST of 26.8±3.7 days.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The immunosuppressive activity of RS-61443, a semisynthetic derivative of mycophenolic acid, was examined in 33 canine renal allografts. Initial studies established that triple therapy consisting of 20 mg/kg RS-61443 in combination with 5 mg/kg cyclosporine and 0.1 mg/kg methylprednisolone was the optimal combination to prevent graft rejection. The median survival time was 8.1±1.2 days in dogs without treatment (n=5), 8.5±1.7 days in the treatment control group (CsA 5 mg/kg, MP 0.1 mg/kg; n=6), 36.0±9.6 days with RS-61443 monotherapy (40 mg/kg; n=6); and 122.4±38.75 days with triple therapy (n=16). Graft prolongation was statistically significant when compared with controls (P<0.05 and 0.002, respectively). Six recipients in the triple therapy group survived over 150 days without major adverse effects. Long-term administration of RS-61443 (20 mg/kg/day) did not cause nephrotoxicity, hematotoxicity, or hepatotoxicity, with the exception of a slight elevation of the alkaline phosphatase levels. Gastrointestinal symptoms including gastritis, diarrhea, and anorexia were common, especially under 40 mg/kg RS-61443 monotherapy, and appeared to be dose-related. Despite its immunosuppressive activity, an increased susceptibility to bacterial or viral infections was not observed. Histological studies of the kidney grafts revealed slight interstitial cell infiltration without vascular or glomerular damage.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We have examined the effects of prednisone, cyclosporine, azathioprine, and RBC-adsorbed goat antidog antilymphocyte globulin on islet graft function in totally pancreatectomized canines with purified, quantitatively defined, autologous, or allogeneic islets transplanted to the liver. The objectives were twofold: (1) to determine the potential detrimental effects to islet autograft function of the aforementioned agents, and (2) to determine the relative efficacy of the “nontoxic” agents in prolonging purified islet allograft function administered in doses that would be considered tolerable in human. The islet autograft studies demonstrated that prednisone given in doses of 1–2 mg/kg/day had a detrimental effect on islet autograft function, and that the combinations of immunosuppression involving CsA, azathioprine, and ALG were not detrimental to islet autograft function to the extent that hyperglycemia would ensue. In the subsequent allograft studies, three groups of canines received islet transplants: (1) controls (n=5; 7860±750 islets/kg/weight), (2) canines given CsA and azathioprine (n=6; 6810±890 islets/kg/body weight), and (3) canines given CsA, azathioprine, and RBC-adsorbed goat antidog ALG (n=8; 6540±710 islets/kg/body weight). The mean (±SE) day of rejection (serum glucose ±200 mg/dl) in the group of canine islet allograft recipients receiving CsA, azathioprine, and ALG was 11.8±1.4 days—significantly prolonged versus islet allograft recipients receiving no immunosuppression (mean survival 4.8±1.1 days, P<0.03), and versus allograft recipients receiving CsA/azathioprine without ALG (mean survival 4.41±1.4 days, P<0.05). Prednisone appears to be detrimental to islet graft function, even at low doses. ALG was not toxic, and significantly extended the survival of canine islet allografts. The inclusion of steroids as part of maintenance immunosuppression, or as treatment for acute rejection of islets, in human islet transplants should be reconsidered, whereas ALG or other antilymphocyte agents should continue to be used.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We have investigated a new hybrid artificial pancreas device to transplant islet allografts without immunosuppression. The device consists of a chamber through which passes a copolymer membrane connected to standard vascular grafts. Islets are placed inside the chamber but are outside of the blood stream. Nominal molecular porosity of 80,000 daltons permits free diffusion of nutrients and insulin across the membrane but inhibits the entry of immunoglobulins and immunocytes from the blood stream into the chamber.Initial studies focused on the technical feasibility of implanting the unseeded (no islets) devices. In 12 normal mongrel dogs, the arterial limb of the device was anastomosed end-to-end to the common iliac artery and the venous limb end-to-side to the common iliac vein. Vascular patency was monitored by an audible bruit over the device. Two devices currently remain patent at 388 and 421 days. The remaining experiments failed due to thrombosis and membrane rupture, with 2 failing as late as 170 and 279 days. In a second series, both arterial and venous anastomoses were done end-to-side and dogs were placed on low-dose aspirin therapy. All 8 dogs are currently maintaining patent unseeded devices (96–226 days postimplantation).Subsequent studies determined the function of devices seeded with isolated canine pancreatic islet allografts in totally pancreatectomized, severely diabetic dogs. Diabetes was controlled by once-a-day insulin injection. After 2–3 weeks of diabetic control, a seeded device was implanted. Diabetic control was monitored by fasting blood levels and postprandial and intravenous glucose tolerance tests, and vascular patency by the loudness of the bruit. In the first series of 6 dogs given seeded devices without aspirin, no significant function was discernible, with failure attributable to thrombosis, poor islet viability, and surgical complications. In the second series of 13 dogs given aspirin, 8 dogs have required an appreciably lower dose of injected insulin to maintain fasting blood glucose at acceptable levels. Of note are 4 dogs that required virtually no exogenous insulin for at least 3 weeks. One dog lost function on day 74 and another still requires no insulin at 267 days postimplantation. However, despite normal fasting glucose levels, the glucose tolerance tests showed delayed return to normal levels. Weight lost following pancreatectomy was rapidly regained in the presence of a functioning seeded device. Histologic examination of the removed devices revealed no signs of rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Transplantation of a Lewis rat small bowel allograft (SBTx) into Lewis x Brown Norway F1(LBNF1) hybrid recipients provokes lethal graft-versus-host disease. GVHD in F1hybrid rats inoculated with large number of parental lymphocytes may be abrogated by prior treatment of F1hybrids with a sublethal dose (SLD) of the same parental lymphocytes. Therefore, we sought to determine whether this type of immunomodulation would prevent GVHD after SBTx. We examined whether pretreatment of LBNF1recipients with a SLD of parental lymphocytes, or with a revascularized segment of parental small bowel, might ameliorate GVHD following transplantation of the entire parental small bowel. Nonpretreated LBNF1recipients died of GVHD after entire Lew SBTx; 95% of LBNF1recipients pretreated with SLD of Lew lymphocytes and 84% of LBNF1recipients first transplanted with a segment of Lew small bowel survived GVHD induced by entire Lew SBTx 10 days later. Of LBNF1recipients pretreated with SLD of Brown Norway lymphocytes or first transplanted with a segment of BN small bowel, none were protected from GVHD induced by entire Lew SBTx 10 days later. We concluded that pretreatment of LBNF1recipients either with an SLD of parental lymphocytes or with a segment of parental small bowel provides profound protection from the effects of GVHD following transplantation of an entire small bowel of the same parental strain specificity.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We have previously demonstrated that TNF-α levels are elevated in liver transplant patients experiencing acute rejection. In addition, prophylactic administrationof anti-TNF-α or anti-TNF-β 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-α in combination with polyclonal anti-TNF-β increased graft survival to 14.6±0.4 days (P<0.001 versus controls). Use of a monoclonal anti-TNF-α antibody was even more effective, with graft survival of 17.4±0.7 days (P<0.001 versus controls). Combination immunotherapy with monoclonal anti-TNF-α in conjunction with CsA extended survival to greater than 30 days. In contrast, recombinant TNF-α (5 μg/day, i.p.)

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The University of Wisconsin solution is considered the most effective universal flush and cold storage solution to date, and is now being widely applied clinically in organ transplantation. The results of this study show that Cardiosol, a modified cardioplegic solution containing 5% polyethylene glycol (PEG20M, MW 17,000 daltons), is significantly superior to UW (P<0.001) in the flush perfusion and hypothermic storage of pancreases for more than 36 hr prior to transplantation into streptozotocin-induced diabetic rats. When the pancreases were stored in Cardiosol, the 1-week survival rate was 7 of 10 (70%) after 24 hr of preservation; 7 of 12 (58%) after 36 hr; and 3 of 10 (30%) after 48 hr. In contrast, when the pancreases were stored in UW solution, the 1-week survival rate was 8 of 12 (67%) after 24 hr of preservation; after 36 hr, no animal survived (0 of 14). Intravenous glucose tolerance test K-values (decline in glucose concentration, percentage per minute) were normal in both groups receiving 24-hr-preserved pancreases, ranging from 2.60 to 4.16. Of interest, the peak insulin response 1 min following intravenous glucose was significantly higher (P<0.01) in the Cardiosol-preserved organs (303±29.8 μU/ml) (± SEM) than in the glands preserved in UW solution (112±47.9 μU/ml). We conclude that Cardiosol allows prolonged whole organ pancreas preservation in the rat transplant model.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Portacaval shunt (Eck fistula) in dogs causes hepatocyte atrophy and organelle disruption, as well as tripling of hepatocyte mitoses. After submitting dogs to this procedure, FK506 was infused into the tied-off left portal vein. The size, anatomic quality, and replication of hepatocytes were enhanced in the portion of liver infused with FK506, with a significant spillover effect in the noninfused portion. These hepatotrophic qualities of FK506 may explain part of FK506's efficacy for the treatment of chronic liver rejection. Also, the observations support a trial with this drug for the treatment of autoimmune liver diseases because, in addition to turning off the immunologic genesis of such disorders, repair and regeneration of the damaged liver may be augmented. Finally, these hepatrophic qualities are part of an emerging spectrum of biologic effects caused by drugs that may modulate the enzyme cis-trans peptidyl-prolyl isomerase (PPIase), the principal constituent of the cytosolic binding sites of FK506, repamycin, cyclosporine, and presumably other immunosuppressive drugs as yet undiscovered.

ISSN:0041-1337    

出版商:OVID    

年代:1991

数据来源: OVID