Lesser reduction in bone mineral density by the immunosuppressant, FK506, compared with cyclosporine in rats

BACKGROUND: Posttransplantation osteopenia leading to osteoporosis induced commonly by treatment with immunosuppressants including cyclosporine (CsA) is a severe complication and results in lowering the quality of life in patients receiving organ transplantation. FK506 is a newly developed immunosuppressant and is currently being used for the prevention of rejection after organ transplantation. In this study, to investigate whether FK506 as well as CsA would cause osteopenia or not, we evaluated the effect of FK506 on bone mineral density and several parameters relevant to bone metabolism in comparison with that of CsA using normal rats. METHODS: Ten-week-old male Sprague-Dawley rats were treated with FK506 (vehicle, 1 mg/kg, and 3.2 mg/kg) or CsA (vehicle, 10 mg/kg, and 32 mg/kg) by daily oral gavage for 28 days. Bone mineral density of the femur, plasma insulin-like growth factor I (IGF-I), and urinary deoxypyridinoline were determined by peripheral quantitative computerized tomography, radioimmunoassay, and enzyme-linked immunosorbent assay, respectively. RESULTS: The reduction in bone mineral density of the femur was observed in both FK506- and CsA-treated rats. The reduction in CsA-treated rats, however, was statistically significant and strikingly severe, whereas that in FK506-treated rats was much less severe than CsA. Plasma IGF-I levels were significantly elevated in FK506-treated rats but not in CsAtreated rats. Urinary deoxypyridinoline levels were unchanged in FK506-treated rats but elevated in CsA-treated rats. CONCLUSIONS: Compared with CsA, FK506 does not appear to induce severe osteopenia by high-turnover bone metabolism in the rat by mediating via IGF-I induction in part. The results suggest that FK506 may exert favorable effects on bone metabolism in patients with organ transplantation compared with CsA. To assess this idea, further clinical investigations focused on bone metabolism will be required.     

The role of graft and host accommodation in a hamster-to-rat cardiac transplantation model

BACKGROUND: We evaluated the importance and mechanism of graft and host accommodation in hamster-to-rat cardiac xenotransplantation models. METHODS: To evaluate graft accommodation, accommodated hamster grafts (Group 2) were transplanted to na?ve host rats treated with FK506, and compared with na?ve hamster grafts (Group 1). To evaluate host accommodation, three groups were evaluated: naive hamster hearts were transplanted to na?ve hosts treated with FK506 (Group 3: 0.5 mg/kg, Group 4: 1.0 mg/kg) and splenectomy, and compared with accommodating hosts (Group 5) with FK506 0.5 mg/kg and splenectomy. We examined graft survival, histopathology, antihamster antibodies and B-1 cells in blood. RESULTS: Graft survival in Group 2 (3.4+/-0.9 days) was not significantly different from that in Group 1 (2.8+/-0.4 days). Graft survival in Groups 4 and 5 (>30 days) was significantly prolonged compared with that in Group 3 (6.0+/-0.7 days). Histopathology of Groups 1-3 showed humoral rejection, whereas Groups 4 and 5 showed normal histology and expression of protective genes. In Groups 1-3, antihamster immunoglobulin (Ig) M and B-1 cells increased significantly compared to Groups 4 and 5, where IgM and B-1 cells remained low or were reduced. CONCLUSIONS: Host accommodation was more important than graft accommodation. Accommodating grafts expressing protective genes were rejected with an elevation of both IgM and B-1 cells. In accommodated hosts, both IgM and B-1 cells decreased, suggesting that B-1 cells may be responsible for the production of antihamster antibodies. These results suggest that sufficient suppression of B-1 cells, resulting in decreased titers of antihamster antibodies, may play an important role in host accommodation.     

Immunosuppressive activity, lymphocyte subset analysis, and acute toxicity of FK-506 in the rat. A comparative and combination study with cyclosporine

The immunosuppressive and toxic properties of the recently discovered macrolide antibiotic FK506 were examined in comparison and in conjunction with cyclosporine administration in the rat. Male Sprague-Dawley rats were immunized systemically with sheep erythrocytes and received, from the same time, either FK506 (1 mg/kg/day) intramuscularly or CsA (25 mg/kg/day) by gavage, or both drugs in combination. Seven days after immunization, the splenic plaque-forming cell response and circulating antibody titers were reduced greater than 90% in animals receiving either FK506 or CsA and in the drug combination group. These immunosuppressive effects of FK506 and CsA were accompanied by significant increases in the incidences of splenic OX-8+ cells and by corresponding reductions in the W3/25+:OX-8+ ratio. No further changes in T cell populations were observed in animals given both drugs. A progressive monocytosis was found in response to CsA, but not in FK506-treated rats. Increases in plasma urea were observed in FK-506 and drug-combination or CsA-treated rats on day 7, whereas creatinine levels were raised only in the FK-506 groups. Elevated bilirubin levels and alterations in liver enzyme activities were observed in CsA-treated rats by day 4, whereas FK-506 alone produced no similar effects. CsA-treated rats also exhibited elevated blood and urinary glucose levels from day 4. No biochemical evidence of additive drug toxicity was detected. The only histological abnormalities observed were thymic medullary atrophy in all drug-treated animals, together with very minor reductions in bone marrow cellularity in a proportion of those rats given FK-506. These findings show that, at the dosage selected, the powerful immunosuppressive activities of FK-506 were associated with little evidence of acute toxicity and with no indications of additive toxicity with CsA.     

FK506--its influence on anti-class 1 MHC alloantibody responses to blood transfusions.

The influence of FK506 on in vivo alloantibody responses to major histocompatability class 1 antigens was investigated in inbred rat strains, and compared with the effect of cyclosporine. AO rats received transfusions of DA blood on days 0 and 7. From days 0 to 14 the rats also received, daily, either FK506 0.3 mg/kg suspended in saline or dissolved in olive oil, or CsA 10 mg/kg. The administration of FK506 suspended in saline at the time of blood transfusion completely abrogated the development of anti-MHC class 1 alloantibodies as detected by indirect hemagglutination (IHA)* and 51Cr release complement dependent cytotoxicity assays (CDC). Isotyping studies showed that FK506 suspended in saline suppressed IgM production and inhibited the switch to IgG production. Similar responses were seen in CsA-treated animals. In contrast, rats treated with FK506 dissolved in olive oil developed high titers of anti-class 1 alloantibodies. On days 49 and 56 the rats were challenged with further DA blood transfusions given without immunosuppression. In the groups given FK506 suspended in saline or CsA, cytotoxic antibodies did not develop; low titer antibodies were, however, detected by IHA in the animals that had previously received FK506 suspended in saline. The results indicate that FK506, in common with CsA, inhibits anti-class 1 MHC alloantibody production, and at the same time enables the development of tolerance. The vehicle in which FK506 is administered is, however, critical to its efficacy at the low doses used. These results may be of relevance to clinical transplantation as similar antibodies mediate hyperacute renal allograft rejection in man.     

Structural skeletal impairment induced by immunosuppressive therapy in rats: cyclosporine A vs tacrolimus

The exact role of immunosuppressive drugs in the development of osteoporosis and pathologic fractures frequently reported in patients following organ transplantation is still not known. In two experiments, the effects of immunosuppressive drugs were studied on growing rats allocated randomly into five groups of eight rats each which received either FK506 (1.5 mg/kg or 3 mg/kg) or cyclosporine A (15 mg/kg or 30 mg/kg) for 28 days by daily oral gavage. In experiment I ( n=40), bone mineral content (BMC) of the femur by dual energy X-ray absorptiometry (DXA), and bone ash weight were measured. In experiment II ( n=40), stereologic measurements of decalcified tibiae were carried out. The BMC and ash weight values of the whole femur were significantly lower both in the low- and high-dose FK506 groups as well as in the high-dose CsA group. Decalcified sections showed lower volume density of trabecular bone of the tibial metaphysis in both CsA-treated groups and in the high-dose FK506 group. Furthermore, the volume density of the hypertrophic zone volume of the growth plate was higher in high-dose CsA-treated rats. Our data demonstrate that both CsA and FK506 have adverse effects on bone and that high doses of CsA or FK506 alter both cortical and trabecular bone with subsequent osteopenia. In addition, CsA-treated groups showed histological changes in some aspect resembling rickets/osteomalacia.     

Cyclosporine A mediates fibroproliferation through epithelial cells

BACKGROUND: Obliterative bronchiolitis (OB) is the major cause of morbidity and mortality after lung transplantation. The potential role of immunosuppressive drugs in the development of OB is uncertain, but there are limited data indicating that cyclosporine A (CsA) may have a direct fibrogenic effect on various human cell types. Epithelium-fibroblast interactions have been suggested to play a crucial role in the course of fibroproliferation, which is a major feature of OB. METHODS: We studied the effect of CsA and FK506 on primary human lung fibroblast proliferation in a human epithelial-fibroblast interactive model. RESULTS: Clinically relevant concentrations of CsA (0.1-1 microg/mL) and FK506 (0.001-0.01 microg/mL) did not affect fibroblast proliferation in monocultures. Conditioned medium (CM) from untreated epithelial cells (Calu-3) stimulated fibroblast proliferation. CM from FK506-treated (0.001-0.1 microg/mL) epithelial cells had no significant additive effect on fibroblast proliferation compared with CM of untreated epithelial cells. In contrast, CM obtained from epithelial cells treated with 0.1 microg/mL CsA significantly enhanced fibroblast proliferation compared with CM of untreated epithelial cells. This proliferative effect of 0.1 microg/mL CsA was mediated by epithelial-derived factors greater than 100 kDa. CONCLUSIONS: These data demonstrate that a clinically relevant concentration of CsA stimulates fibroblast proliferation through mediators produced by airway epithelial cells, raising the possibility that CsA may contribute to the development of OB after lung transplantation.     

FK 506 reverses acute graft-versus-host disease after allogeneic bone marrow transplantation in rats.

Severe graft-versus-host disease was induced by transplantation of ACI rat bone marrow and spleen cells into irradiated Lewis rat recipients. Treatment with FK 506 or cyclosporine A (CsA) was started after clinical and histologic evidence of acute GVHD was present. A 14-day course of FK 506 at 1.0 mg/kg/day could rescue 100% of the animals suffering from GVHD. In contrast only one half of the animals treated with CsA at a high dose of 25 mg/kg/day recovered. After cessation of immunosuppressive therapy, FK 506-treated animals displayed a marked prolonged disease-free interval as compared to CsA-treated bone marrow recipients. Recurrence of the disease in these animals could be prevented when FK 506 treatment was continued after the induction period with a low maintenance dose of 0.1 mg/kg/day every other day.     

Cytomegalovirus infection and posttransplant lymphoproliferative disease in renal transplant recipients: results of the U.S. multicenter FK506 Kidney Transplant Study Group.

BACKGROUND: The recent U.S. multicenter randomized trial of FK506 versus cyclosporine (CsA) demonstrated equivalent patient and graft survival in patients treated with FK506 and statistically fewer rejection episodes in the first year posttransplant. METHODS: To determine if more effective posttransplant immunosuppression was associated with an increased risk of cytomegalovirus (CMV) or posttransplant lymphoproliferative disease (PTLD), we examined the incidence of these two opportunistic infections during 3 years of follow-up. RESULTS: CMV infection occurred in 40 (19.5%) FK506 and 40 (19.3%) CsA-treated patients. The incidence of CMV disease was 9.3% in FK506 and 6.8% in CsA-treated recipients; the most common site of CMV disease was the gastrointestinal tract. A multivariate analysis of several risk factors demonstrated that a CMV- recipient of a CMV+ donor was at greatest risk for CMV infection. The incidence of posttransplant lymphoproliferative disease was equal in the two treatment arms: six CsA- and five FK506-treated recipients. CONCLUSIONS: The results of this study suggest that the superior efficacy of FK506 in the prevention of acute rejection was not associated with an increased risk of CMV or posttransplant lymphoproliferative disease compared with CsA.     

A crucial effect of splenectomy on prolonging cardiac xenograft survival in combination with cyclosporine

In this study we investigated the effect of splenectomy in combination with cyclosporine (CsA) on survival of heterotopic cardiac xenografts from hamster to rat. A 12-fold prolongation of mean cardiac xenograft survival, to 41 days, was accomplished with the combined therapy. In both untreated controls and CsA-treated recipients rejection occurred in 3 days. Splenectomy by itself prolonged xenograft function to 5 days. Evidence of humoral-mediated rejection in this cross-species combination was given for the extensive thrombosis and hemorrhage in the subepicardial area, the appearance of lymphocytotoxic titers just before graft function ceased, and the presence of IgM deposits in subepicardial vessels of the xenograft. CsA by itself could not modify this pattern of rejection. Splenectomy decreased antibody formation significantly and rejection became more cellular in nature. The regimen of splenectomy in association with CsA suppressed antibody titers and produced a CsA dose-dependent prolongation of xenograft survival. Thus, a complementary or synergistic effect is the result of the immunosuppressive regimen of splenectomy and CsA in hamster-to-rat cardiac xenografts. In this study the effect of splenectomy in controlling the humoral response in concordant xenografts and its role in future clinical xenografting is emphasized.     

Heart and liver xenotransplantation under low-dose tacrolimus: graft survival after withdrawal of immunosuppression

BACKGROUND: The hamster-to-rat xenotransplantation model is a useful model to investigate the features of extended host response to long-surviving xenografts. Early xenoantibody responses are T-cell independent and resistant to tacrolimus. Treatment with the combination of mofetil mycophenolate plus FK506 avoids acute xenograft rejection completely, but after withdrawal of immunosuppression hamster grafts are rejected by a process called late xenograft rejection (LXR). METHODS: Hamster hearts and livers were transplanted into Lewis rats. Grafted rats were treated with mofetil mycophenolate (25 mg/kg/day) for 8 days and FK506 (0.2 mg/kg/day) for 31 days. Serum IgM and IgG levels were determined by flow cytometry and interferon-gamma levels by ELISA. IgM, IgG, and C3 deposits were measured in tissue by immunofluorescence, and leukocyte infiltration was measured by immunoperoxidase staining. Results. Survival of heart and liver xenografts in the rats was 48+/-4 days and 63+/-8 days, respectively. After cessation of all immunosuppression, hearts were rejected in 18+/-4 days and livers in 33+/-8 days. Production sequences of xenoantibodies in the two organs differed substantially, especially 7 days after transplantation and at the moment of rejection. Quantification of interferon-gamma levels indicated that there were no significant changes after transplantation. Histological and immunohistochemical studies showed signs of humoral mechanism of LXR in rats undergoing heart transplantation and cellular mechanism of LXR in those that received a liver transplant. Conclusions. These observations suggest that rejection in the hamster-to-rat heart xenotransplantation model is mediated by a T cell-independent B-cell response to which a T cell-dependent B-cell response is added in LXR. In the liver xenotransplantation model, our hypothesis is that LXR is mediated by a mixed cell mechanism, involving lymphocytes CD4+ CD45RC+, macrophages, and cytotoxic T lymphocytes. In summary, we have demonstrated and compared the peculiar features of LXR in two different organs.     

Efficacy of rapamycin and FK 506 in prolonging rat hind limb allograft survival.

OBJECTIVE: Graft rejection and the toxicity of current immunosuppressive regimens preclude the application of microsurgical advances to transplantation of limbs or other nonessential parts. If limb transplantation is to become a clinical reality, newer, safer, more effective immunosuppressive agents are needed. SUMMARY BACKGROUND DATA: Rapamycin (RPM) and FK 506 are fungal macrolide antibiotics with effective immunosuppressive properties demonstrated in several animal models. RPM is more potent and effective than is FK 506 in rat cardiac allografts and has demonstrated synergy with cyclosporine (CsA) in limb allograft models. METHODS: An orthotopic rat hind limb allograft model (Brown-Norway [RT-1n] to Lewis [RT-1(1)] rats was used. RPM (doses, 3.0, 4.5, and 6.0 mg/kg/day) was administered intraperitoneally on postoperative days 1 to 14. FK 506 (6 mg/kg/day) was administered orally on postoperative 1 to 14 and 1 to 90 and at rejection onset (10 mg/kg/day for salvage). CsA with RPM (postoperative days 1 to 14) was used to assess synergy, with CsA alone serving as the control. Other controls included untreated and placebo-treated allografted animals. The permutation test and Mann-Whitney test were applied to the data. RESULTS: The mean survival times were assessed as follows: (1) control (placebo, untreated), 5 days; (2) RPM groups, 9.5, 10.6, and 8.7 days; (3) 14-day FK 506, 28 days; (4) 90-day FK 506, > 90 days; (5) CsA, 17.3 days; and (6) CsA with RPM, 19.3 days. FK 506 significantly prolonged graft survival compared with RPM (Permutation Test, p < 0.001 and Mann-Whitney Test, p < 0.05). FK 506 salvage reversed early rejection. High-dose RPM produced significant toxicity. Synergy between CsA and RPM was not demonstrated. CONCLUSIONS: FK 506 prolongs allograft survival, reverses early rejection, and prevents rejection without clinical toxicity when given continually. RPM does not prevent rejection in this model and produces significant toxicity at high doses. FK 506 may be a first step in making limb transplantation a clinical reality in reconstructive surgery.     

环孢素A及FK506对人肝癌细胞株增殖的影响

目的:探讨免疫抑制剂环孢素(CsA)及他克莫司(FK506)对肝癌细胞增殖的影响及可能机制。方法:采用噻唑蓝(MTT)比色法观察CsA及FK506对QGY鄄7701、QGY鄄7703、SMMC鄄7721和BEL鄄7402等4株肝癌细胞增殖的影响。还应用Hoechst33258荧光染料涂片,在荧光显微镜下观察用药组细胞的形态学改变。结果:随着作用时间延长,10μM的CsA对4株肝癌细胞均呈现明显的生长抑制效应(P<0.01),而0.5μM的FK506与对照组相比,其生长抑制作用不明显(P>0.05)。荧光显微镜下CsA用药组肝癌细胞呈现凋亡改变;而FK506用药组与对照组无显著差异。结论:免疫抑制剂CsA非但未促进体外肝癌细胞生长,相反呈明显的抑制效应。FK506尽管未呈现对肝癌细胞增殖的抑制效应,也未显示有生长促进作用。CsA对肝癌细胞的增殖抑制作用与诱导癌细胞发生凋亡有关。     

Xenograft survival in two species combinations using total-lymphoid irradiation and cyclosporine

Total lymphoid irradiation (TLI) has profound immunosuppressive actions and has been applied successfully to allotransplantation but not xenotransplantation. Cyclosporine (CsA) has not generally permitted successful xenotransplantation of organs but has not been used in combination with TLI. TLI and CsA were given alone and in combination to rats that were recipients of hamster or rabbit cardiac xenografts. Combined TLI and CsA prolonged survival of hamster-to-rat cardiac xenografts from three days in untreated controls to greater than 100 days in most recipients. TLI alone significantly prolonged rabbit to rat xenograft survival with doubling of survival time. However, combined treatment did not significantly prolong rabbit-to-rat cardiac xenograft survival compared with TLI alone. The hamster and rat are phylogenetically closely related. Transplants from hamsters to rat are concordant xenografts since the time course of unmodified rejection is similar to first-set rejection of allografts. Although the rabbit-to-rat transplant is also between concordant species (average survival of untreated controls: 3.2 days) the rabbit and rat are more distantly related. These results suggest that TLI is an effective immunosuppressant when applied to cardiac xenotransplants in these animal models; that the choice of species critically affects xenograft survival when TLI and/or CsA are used for immunosuppression; and that the closely related species combination tested has markedly prolonged (greater than 100 days) survival using combined TLI and CsA.     

Skin allograft survival and analysis of renal parameters after FTY720 + tacrolimus treatment in mice

Calcineurin inhibitors such as cyclosporine (CsA) and tacrolimus (FK506) show similar efficacy to prevent rejection within the first year after organ transplantation. However, their use is limited by side effects, such as kidney damage, hypertension, new-onset diabetes, and hyperlipidemia. The consensus opinion suggests that compared with CsA, FK506 has fewer negative effects on blood pressure, serum lipids, and renal function. Nevertheless, FK506 use is associated with a higher incidence of posttransplantation diabetes mellitus. FTY720 is a new compound that has shown beneficial effects in animal models of rejection in transplantation, ischemia/reperfusion injury, autoimmune diseases, and tumor development. Our aim was to investigate whether FTY720 + tacrolimus association could provide additional immunosuppression without causing renal toxicity. FTY720 as a monotherapy or in association with FK506 was administered to C57BL/6 mice for 21 days to prevent skin graft rejection and to evaluate renal function and structure. Increased skin allograft survival in the FTY720 + FK506 group was associated with decreased cell numbers in the spleen, blood, and axillary lymph nodes. Changes in major histocompatibility complex (MHC) class II and intercellular adhesion molecule-1 (ICAM-1) expressions in splenocytes were also found in this group. The major effects already described for FK506 (diabetes) or FTY720 (lymphopenia) were observed after 21 days administration even when the drugs were associated. FTY720 associated with FK506 caused fewer changes in kidney structure, and blood glucose levels were lower than in FK506 monotherapy.     

Allogeneic hepatocyte transplantation using fk 506

Hepatocyte transplantation is an intriguing alternative to orthotopic liver transplantation. While engraftment of syngeneic hepatocytes can be achieved with relative ease, engraftment of allogeneic hepatocytes has been far more complicated. We used FK 506 (Tacrolimus), a novel and highly efficient immunosuppressant, which has been reported to augment liver regeneration in rats. Recipients of isolated syngeneic (LEW) and allogeneic (Wistar F.) rat hepatocytes (major histocompatibility barrier) recieved different immunosuppressive regiments with FK 506 or Cyclosporine A (CsA). Mature syngeneic hepatocytes could be retrieved up to post op day 300 with the lowest number of hepatocytes on post op day 20. Following allogeneic transplantation, no mature hepatocytes could be identified after post op day 10, though ductular like structures within the spleen were found in FK 506 but not CsA-treated animals. The epithelial cells of ductular like structures exhibit cytological features of CK-19 positive cells. Our results suggest that under CsA or FK 506 immunosuppression long-term survival of mature allogeneic hepatocytes within the spleen cannot be achieved across a major histocompatibility barrier though FK 506 allows engraftment of allogeneic donor type ductular cells.     

Nephrotoxicity after orthotopic liver transplantation in cyclosporin A and FK 506-treated patients

Abstract Nephrotoxicity represents a serious side-effect of immunosuppression following orthotopic liver transplantation. In order to preserve the therapeutic potential of cyclosporin (CsA) and FK 506 in human liver transplantation and to differentiate the nephrotoxic action of either drug in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 randomly assigned to CsA- and 61 to FK 506-based immunosuppression. Early postoperative renal insufficiency (between PODO and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (36.7%) and FK 506 (42.6%). Early postoperative acute renal failure (ARF; SCr > 3 mg/dl) occurred in 18.3%, regardless of the immunosuppressive management. Approximately 50% of patients with ARF required hemodialysis (CsA: 11.7%; and FK 506: 8.3%). Mean onset of hemodialysis in CsA-treated patients was POD1 and in FK 506-treated patients, POD 6, which demonstrated a different time course of drug-pecific nephrotoxicity of CsA and FK 506 in early ARF. All patients with early postoperative ARF requiring hemodialysis survived more than 1 year (100% survival). New onset of late ARF (between POD 30 and 365), however, occurred in 6.5% under FK 506 and in 1.7% under CsA immunosuppression due to severe infections with the multiple organ failure syndrome. This observation was consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Mortality of patients with late ARF requiring hemodialysis was 100%. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK 506-treated patients, and represented a slowly progressing form of drug-pecific nephrotoxicity. These preliminary results demonstrated a similar outcome in terms of early and late nephrotoxicity, but longer follow-up will delineate its overall efficacy and toxicity in humans.     

他克莫司和环孢素A对肾移植术后患者肝功能影响的临床比较观察

目的:研究和比较他克莫司（FK506）以及环孢素A（CsA)对肾移植术后患者肝功能的影响。方法：将肾移植术后患者随机分为FK506组和CsA组,FK506组8例,CsA组26例。CsA组中出现肝功能异常的6例患者用FK506进行替换治疗。两组均联合应用霉酚酸酯（MMF）和泼尼松（Pred)。结果：观察6个月,FK506组和CsA组中急性排斥的发生率差异 不显著;FK506组中未发现肝功能异常患者,CsA组中有6例患者肝功能异常;肝功能异常的6例患者用FK506替换CsA后,总胆红素（TBIL）、直接胆红素（DBIL）、丙氨酸转氨酶（ALT）相继转为正常。结论：FK506免疫抑制剂效果与CsA相似,但对肝功能影响甚微,适合应用于术前有肝功损害或术后应用CsA后出现肝功能异常倾向的患者。     

Prolonged survival of donor-specific rat intestinal allograft by administration of bone-marrow-derived immature dendritic cells

It has been reported that intraportal administration of donor antigens induced donor-specific hyporesponsiveness. We studied here the effects of transplantation of BM-derived immature dendritic cells (imDCs) and mature DCs (mDCs) via portal vein on rat small intestinal allograft survival. This study comprised four treatment groups: 1) untreated controls; 2) FK506 alone; 3) intraportal donor-specific BM-derived imDCs transplantation+FK506; 4) mDCs/Tx+FK506. Allograft survival was minimal in control group (5.2+/-0.8 days) and maximal in imDC+FK506 group (28.4+/-3.0 days). The rats in mDC+FK506 group showed systemic inflammatory reaction due to GVHR, and died within 10 days after transplantation. The in vitro MLR reaction using imDCs was also strongly inhibited both in direct and indirect recognition pathways. The impact of imDCs for the specific induction of transplant tolerance may suggest that immunization with donor-specific imDCs has therapeutic potential in organ transplantation.     

Prolongation of lung xenograft survival in rats with a short course of deoxyspergualin and cyclosporin A

The efficacy of 15-deoxyspergualin (DSG), cyclosporin A (CyA), and splenectomy-alone or in combination-in prologing the survival of concordant lung xenotransplants was studied in the hamster-to-rat model. In the untreated group, rejection occurred within 3 days, with an elevation of lymphocytotoxic antibody titers. The rejected lung revealed that ED1+cells were more prevalent than MRC OX8+cells in the perivascular infiltrates. In the DSG group, the antibody response was suppressed and median survival increased to 7.5 days. The rejected lungs demonstrated a highly significant depression in ED1+cellular infiltration and a moderate MRC OX8+cellular infiltration. When maintenance CyA was combined with a short course of DSG, survival dramatically increased to beyond 100 days. There were no deposits of IgM, IgG, or C3 or of any cell infiltrate in the grafts of two animals sacrificed 107 and 119 days post-transplantation. We conclude that initial treatment with DSG combined with continuous CyA can suppress acute rejection in the hamster-to-rat lung xenograft model, resulting in longterm graft survival.     

Aorta transplantation as a model to study hyperacute, acute, and chronic rejection of xenografts

Abstract: To explore the mechanism of rejection of vascularized xenografts, we performed discordant and concordant transplantation of aortic grafts. Forty-one guinea pig-to-rat and 50 hamster-to-rat aortic transplantations were performed successfully. Recipient rats were either untreated or treated three times per week with 10 mg/kg of cyclosporine (CsA) starting the day before transplantation. Recipients were sacrificed at various timepoints after transplantation and the grafts were processed for histology and immunohistochemistry. Guinea pig aortic grafts were rejected hyperacutely in both the control and CsA treated group. Four hours after transplantation all endothelial cells and some of the medial smooth muscle cells had disappeared. Seven days after transplantation the media were totally acellular, whereas the adventitia was enlarged due to infiltrating cells, consisting mainly of macrophages. At day 56, only traces of the original graft could be identified.
Hamster aortic grafts developed signs of chronic rejection. In control rats, the intimal lesions could already be demonstrated in 17% of the rats at day 14, and in all rats from day 28. CsA treatment inhibited the development of the intimal lesions. At days 56 and 84 the difference in intimal thickness between the control group and the CsA treated group was statistically significant. The cellularity of the media of the hamster grafts remained constant during the first 21 days in both groups but declined sharply thereafter as a consequence of migration or necrosis of myocytes. The thickness of the adventitia in both groups increased after transplantation, due to infiltrating macrophages and T cells, reaching a peak at day 14. In conclusion, the aorta transplantation model provides useful information with regard to the development of chronic rejection in concordant grafts. Discordant aortic grafts are rejected hyperacutely just like discordant heart grafts.