ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Untreated anephric LEW rats die ca. 9 days following transplantation of LBNF1 kidney allografts. Although treatment with ART-18, a mouse antirat IL-2R mAb (300 μg/kg/day x 10days), prolonged graft survival to ca. 3 weeks, the severely impaired renal function was comparable to untreated controls (creatinine levels 3–5 mg/dl). In contrast, simultaneous infusion of ART-18 and a very low dose of CsA (0.75 mg/kg x 10days), marginally effective on its own, resulted in survival of >45 days; the grafts exhibited relatively good function comparable to that in rats treated with full-dose (15 mg/kg/day) CsA. This beneficial biological effect did not depend upon elevated CsA trough levels in animals conditioned with both modalities. The CD4:CD8 ratio at the graft site was lowest (0.3–0.4) in recipients treated with ART-18 + CsA. Synergy between the two agents has been demonstrated by adoptive transfer studies in which nonspecific suppression has been conferred selectively by cells infiltrating kidney grafts in rats given ART-18 and CsA in concert but not separately (LBNF1and WF test cardiac allograft survival ca. 12 days). In contrast, suppression in the recipient spleens was donor-specific; both CD4 and CD8 cells prolonged test graft survival. Immunohistological evaluation of renal allografts revealed that therapy with ART-18 or low-dose CsA alone failed to deplete IL-2R+cells and prevent production of IL-2, IFN-g, and TNF. In contrast, the frequency of infiltrating IL-2R+cells and elaboration of endogenous cytokines in non-uremic hosts receiving combination therapy was greatly depressed, stressing again synergistic interaction between ART-18 and CsA. Additionally, markedly reduced class II antigen induction, XL-fibrin deposition, and glomerulitis may also contribute to prolonged survival and satisfactory function of kidney allografts in this animal group.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Brief exposure (30 min) of isolated islets to 0.5 μg/ml cyclosporine leads to alterations in the insulin secretory response to selected stimuli. When glucose is used as the secretagogue, cyclosporine slightly stimulates insulin release at substimulatory concentrations of the hexose. The inhibitory effect predominates, however, at stimulatory concentrations of glucose with a threshold at 6 mmol/L glucose and maximal inhibition of 33.5 mmol/L glucose. By contrast, insulin release induced by 17 mmol/L arginine is not affected. Cyclosporine also inhibits by 66% the insulin secretory response to 100 nmol/L phorbol 12-myristate 13-acetate, suggesting that either cyclosporine interferes with phorbol ester action on β cells or the action site is located beyond the protein kinase C activation. On the other hand ionomycin-stimulated insulin response is also blocked by cyclosporine, indicating that insulin release induced by transient changes in cytosolic Ca++is also affected.The evidence gathered here suggests that the inhibitory effect of cyclosporine on insulin release is apparent when glucose is used as a fuel stimulant and is reversed following removal of the stimulant. This effect is not reversed by using substances known to activate the protein kinase C or the Ca++-dependent branches of the stimulus-secretion coupling system in β cells, indicating that the site of action of cyclosporine on pancreatic islets might be located in distal steps of the stimulus-secretion coupling of glucose-induced insulin release.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Cardiac transplantation between inbred rat strains that differ for weak histocompatibility antigens is associated with the development of arteriosclerosis in the arteries of the donor graft myocardium. The lesions are seen in donor/recipient pairs that differ for both MHC and non-MHC histocompatibility antigens that apparently stimulate a low-level, chronic rejection of the donor heart graft. The arteriosclerosis associated with this chronic rejection consists of a diffuse, concentric proliferation of the intima and pathologically resembles the lesions observed in the coronary arteries of long-term human cardiac graft recipients.We have recently examined the influence of positive and negative manipulation of the host immune response on the development of the graft arteriosclerosis. Our results demonstrate that delayed harvest of the cardiac grafts or immunization with donor skin grafts or splenic lymphocytes increases the sensitivity of the recipient to the donor heart graftsand, under conditions that allow for the long-term survival of the graftincreases the severity of the arteriosclerotic lesions. Alternatively, suppression of the host immune responses with cyclosporine or FK506, substantially reduces the arteriosclerotic changes. These results suggest that control of accelerated graft arteriosclerosis in long-term human cardiac recipient may require more careful and effective immunosuppression of the allograft reaction.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The clinical usefulness of Cyclosporine is limited by its intrinsic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitor U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2excretion compared with controls (48.2±3.1 vs. 24.2±2.6 ng/24 hr,P<0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P<0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Using an ex vivo liver sanguinous perfusion system, hemodynamic and biochemical changes of the porcine livers were studied, which were preserved cold (4°C) for 24 hr in University of Wisconsin solution and reperfused with normothermic (37°C) (n=8) or hypothermic (32°C) (n=8) blood for 3 hr. Six more livers were reperfused with normothermic blood (37°C) immediately after procurement as controls. The total hepatic blood flow was adjusted to 1 ml/min/g liver weight, in which hepatic artery and portal vein flows were administered at a 1:2 ratio. In livers stored cold for 24 hr in UW solution and perfused normothermically, a statistically higher hepatic artery resistance was exhibited at 30 and 60 min after reperfusion (P<0.05), and there was lower bile output (P<0.05) at 90 and 120 min as compared to the controls. In livers stored cold for 24 hr in UW solution and perfused hypothermically, as compared to ones perfused normothermically, statistically higher hepatic-artery and portal-vein resistances (P<0.05) were observed throughout the perfusion period and 60 min after reperfusion, respectively. In addition, bile output and oxygen consumption of these livers were statistically lower than those of ones perfused normothermically (P<0.05). In contrast, chemistries of the perfusate of livers perfused hypothermically were comparable to ones perfused normothermically. Histologic examination of the liver perfused hypothermically demonstrated hepatic arterial and/or portal venous congestion and mild-to-moderate hemorrhage in the portal triads. This study suggests that livers preserved for a prolonged period of time demonstrate a high hepatic arterial resistance shortly after revascularization, and that recipient hypothermia after revascularization may be a risk factor for the development of hepatic arterial thrombosis following liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

In this study we investigated cellular proliferation of T cells and macrophages at the site of rat cardiac allografts and determined the influence of immunosuppressive therapy on the proliferative characteristics of these cell types. A bromodeoxyuridine-labeling technique was used that allowed both the accurate detection of proliferative activity and the phenotypic characterization of cellular infiltrates within grafted tissues. In untreated recipients (BNLewis), T cytotoxic/suppressor cells as well as T helper cells showed proliferative activity at the site of the graft. The percentage of OX8-positive cells within the graft that showed proliferation ranged from 15% to 37%. The percentage of W3/25-positive cells within the graft that showed proliferation ranged from 25% to 30%. In contrast, macrophages hardly showed proliferative activity within the graft; only 1–4% of the macrophages stained positive for bromodeoxyuridine. From these observations it is concluded that the graft serves as a nonlymphoid tissue site, wherein lymphocytes can freely proliferate and expand.To study the influence of immunosuppressive therapy on cellular proliferation, the steroid budesonide, 120 μg/kg/day, was administered for 13 days (MST, 20 days). During effective immunosuppressive therapy, still a remarkable amount of infiltrating cells was present within the grafts. Moreover, immunosuppressive treatment did not primarily appear to affect the proliferative capacity of the individual cell types. OX8-positive cells as well as W3/25-positive cells clearly showed proliferative activity within the treated grafts. However, despite the presence of these proliferative cells, signs of graft destruction were absent during immunosuppressive therapy. This finding may shed new light on the effect of steroids at the site of the graft and their role in the prevention of tissue destruction.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Rat liver transplants were performed in order to assess the importance of the impermeant anion lactobionate and the trisaccharide raffinose on the effectiveness of a simplified variant of UW solution for liver preservation by simple cold storage. Rat livers were stored at 4°C for 18, 24, 30, or 40 hr in a modified UW solution or in one of three variants of UW in which one of these impermeants was replaced by another more permeable agent. Using modified UW solution (solution A), 50% (5/10) of rats receiving livers that had been preserved for 30 hr survived for more than 1 week; with solution B, which differs from A in the replacement of raffinose by glucose, the 1-week survival was 60% (6/10) after 30-hr preservation. Solution C, which is identical to A except for the replacement of lactobionate by gluconate, gave 20% (2/10) survival rate after 30-hr preservation. However, using solution D, which is identical to A except for substitution of chloride for lactobionate, none (0/8) of the rats receiving liver preserved for 30 hr survived. These results suggest that the inclusion of lactobionate as a major anion plays a crucial role in the effectiveness of UW solution, whereas raffinose can be replaced by more permeant glucose without deleterious effect.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The effect of total-lymphoid irradiation on survival of canine pancreas and kidney allografts was studied. TLI had a marked immunosuppressive effect as measured by in vitro immune responses and reduced circulating leukocytes. Despite the changes, median graft survival times for animals treated with 800 cGy (9 days) or 1800 cGy (9.5 days) were not significantly different from untreated control animals (7 days). The addition of low-dose antithymocyte globulin (10 mg/kg/day) on post-transplant days 0, 2, 4, 6, 8, and 10 had no measurable synergistic effect. Similarly, median segmental pancreas allograft survival times after 1700–2200 cGy of TLI treatment (16.5 days) were only marginally longer than those of untreated controls (9 days). The only animal to maintain a graft for greater than 200 days was matched to the donor in mixed lymphocyte culture (MLC). This animal was able to reject a third-party skin graft after 8 days while a graft from the original donor was still surviving after 21 days when the pancreas graft failed from a chronic-type rejection. These results indicate that TLI alone or in combination with ATG will not be predictably effective as a method of prolonging allograft survival. The role of matching major histocompatibility complex antigens in TLI treatment requires clarification.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

There are conflicting reports about the effects of administration of dopamine to brain-dead donors upon posttransplant organ function. This study compared the survival and serum creatinine levels in pigs that received renal grafts from untreated controls, from controls in which either the donor or donor and recipient received dopamine or from animals rendered brain dead for 16 hr by acute elevation of intracranial pressure, and given standard supportive treatment. In two additional groups, brain-dead donors were given dopamine or dopamine with triiodothyronine. Recipients of grafts from control animals or from brain-dead donors survived the 7-day period of study and showed minimal changes in serum creatinine. Recipients of grafts from brain-dead donors given dopamine however showed reduced survival and progressive increase in serum creatinine. This did not occur in the group given triiodothyronine concurrently with dopamine.It is suggested that if administration of dopamine is essential to treat donor hypotension, concurrent use of triiodothyronine may preserve posttransplant renal function.

ISSN:0041-1337    

出版商:OVID    

年代:1990

数据来源: OVID