FK506和供体特异性输血在大鼠异位心脏移植中的作用

目的探讨FK506和供体特异性输血在大鼠异位心脏移植中的作用。方法利用大鼠异位心脏移植模型以了解在移植当天或移植术后第4日进行供者特异性输注（DST）的基础上,应用FK506能否延长移植物的存活。结果在移植当天行DST或单独用FK5061mg／kg连续10天,可将移植心中位存活时间从对照组的5天分别有效延长至7天和11天,而FK506与DST联合应用时并不产生增强效应。结论FK506和DST单独应用时虽均能延长大鼠同种移植心存活,但是它们没有协同作用。     

Prolongation of Rat Liver Graft Survival by Splenectomy Combined with Low Dose FK506 Therapy

Abstract: The effects of low dose FK506 therapy (0.1 mg/kg/day × 1 day) on graft survivals were analyzed, and the feasibility of splenectomy was assessed. ACI strain liver grafts were orthotopically implanted into LEW male rat recipients. In the control group, the survival period was 10.4 ± 1.4 days. In the group treated with splenectomy, the survival period was 13.4 ± 2.0 days. In the groups with low dose FK506 therapy, the survival periods were 22.7 ± 6.7 and 39.7 ± 6.3 days with or without splenectomy, respectively. Rats in the group with average dose FK.506 (1.0 mg/kg/day × 7 days) survived more than 100 days. In summary, the effect of low dose FK506 therapy was relatively limited. Splenectomy by itself was marginally effective; however, this effect was enhanced when combined with low dose FK.506 therapy.     

Limited effectiveness of FK506 administration for ongoing rejection in heterotopic rat heart transplantation

A comparison was made of the histological findings for myocardial tissue of heterotopic transplanted rat hearts administered with FK506. ACI rats were used as donors and Lewis rats as recipients. FK506 was used for 6 days except for group I (control group). Group II received 0.32 mg/kg/day of FK506 from the day of operation while group III was given the same dosage from the 4th day after transplantation. Group IV was given 1.28 mg/kg/day of the agent from the day of grafting and group V received the same dose from the 4th postoperative day. The graft survival time was longer for all groups given FK506, but was significantly longer only for groups administered with FK506 from the day of operation. Histological studies performed 10 and 20 days after transplantation showed that a moderate rejection was seen in about half of the grafts receiving FK506 from the 4th day after grafting. An ultra-structural study of these cases showed that infiltrating large lymphocytes still remained in the interstitial tissues and that the cytoplasmic organelles of the myocytes had been focally destroyed. These results suggest that, although FK506 suppressed any further rejection, the effect might be limited and the myocardial changes of the cardiac graft might persist even after administration for ongoing rejection.This work was supported by a Ministry of Education Grant (A) 03770873.     

Long‐term small bowel allograft function induced by short‐term FK 506 application is associated with split tolerance

Abstract Functional long‐term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high‐dose FK 506 has been shown to induce stable long‐term graft function. In order to examine whether this long‐term function is associated with donor‐specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One‐step orthotopic SBT was performed in the allogeneic Brown Norway (BN)‐to‐Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0‐5 in the rejection model and from days 0‐9 in the long‐term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long‐term functional model survived long term (> 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor‐specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely (> 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third‐party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor‐specific heart allografts.     

Suppression of liver allograft rejection by administration of 15-deoxyspergualin

In this experiment, the effect of the administration route-the hepatic artery, portal vein, or systemic circulation-of the immunosuppressive drug 15-deoxyspergualin (DSG) on the suppression of liver allograft rejection is investigated. A 3-day injection of DSG at a dose of 0.32–1.28 mg/kg per day into the systemic circulation of a rat that had received a liver transplant was not effective in prolonging liver graft survival (14.3±2.9 days vs. 14.1±2.5 days for controls). However, the administration of DSG into the portal vein following liver transplantation markedly prolonged survival for up to 24.9±10.0 days. Survival times were prolonged even more when the DSG was administered via the hepatic artery for 3 successive days after liver grafting (30.9±9.6 days). The concentration of DSG in the blood following the one-shot injection of DSG was highest when DSG was administered via the hepatic artery, intermediate when injected into the portal vein, and lowest when injected into the systemic vein. In conclusion, DSG can inhibit liver graft rejection more effectively via the hepatic arterial route than via the portal vein or systemic circulation.     

Efficacy of transient treatment with FK506 in the early phase on cyclophosphamide-induced bone marrow chimerism and transplant tolerance across MHC barriers

BACKGROUND: The use of mixed allogeneic bone marrow chimerism to induce donor-specific transplantation tolerance has been extensively demonstrated. In the present study, we assessed the effect of combined use of a short course of FK506 and a single-dose cyclophosphamide (CYP) on the induction of tolerance and development of GVHD after allogeneic BMT. MATERIALS AND METHODS: Lewis rat (RT1(l)) recipients received BMT from Brown Norway (RT1(n)) donors on the next day after injection of CYP at a dose of 200 mg/kg. The recipients were further treated with no FK506 (n = 8), 0.3 mg/kg/day FK506 on days 10-16 (n = 6), or the same dose of FK506 on days 0-6 (n = 6). In a subgroup of animals, heterotopic heart transplantation was performed to investigate transplantation tolerance. RESULTS: Six of eight recipient rats that did not receive FK506 died of severe GVHD, while high levels of chimerism were induced. Recipients of FK506 in the later phase developed mild transient GVHD around 2 to 3 weeks after BMT and recovered thereafter; however, the level of chimerism was significantly decreased (2.8 +/- 2.3% on day 100). Treatment with FK506 in the early phase completely prevented the development of GVHD and induced stable allogeneic chimerism in the long-term (13.8 +/- 8.3% on day 100). These recipients with stable chimerism accepted subsequent BN heart allografts indefinitely (>200 days x 5), while rejecting third-party (BUF) heart allografts by day 12. CONCLUSIONS: Early transient FK506 promotes the induction of stable bone marrow chimerism without GVHD after BMT with CYP pretreatment. The timing of treatment with FK506 is critical with a view to preventing GVHD and inducing stable long-lasting chimerism.     

Japanese study of kidney transplantation: 1. Results of early phase II study

For a 4-month period from July to October 1990, 37 primary renal transplant patients were enrolled in the early phase II study of FK506. An i. v. dose of FK 506 0.075 mg/kg twice a day was administered initially, and then in oral dose of 0.15 mg/kg twice a day followed. Prednisolone was started at 1 mg/kg daily as an additioned drug. Some 32 live related donors with one-mismatched haplotype of HLA and 5 cadaveric donors underwent transplantation. All patients are alive, and all kidney allografts are functioning. A correlation between the trough level of FK 506 in whole blood and acute rejection or adverse events was retrospectively investigated. There was a significant correlation between the trough level in whole blood and acute rejection or renal impairment. In conclusion, the therapeutic dose of FK 506 should be adjusted by monitoring the trough level in whole blood, the range of which might be recommended to be 15–20 ng/ml during the early phase after transplantation.     

Inhibition of Acute Rejection After Skin or Cardiac Transplantation by Administration of Donor Antigens in the Rat

Purpose We examined differences in host immunologic changes induced by the intravenous or intraportal administration of donor antigens at engrafting and evaluated their contribution to graft survival using a rat transplantation model.Methods Lewis rat recipients were given either an intravenous or intraportal injection of donor splenocytes (1 × 10⁸) immediately after receiving skin grafts from Brown Norway donors. The immunologic responses were analyzed by mixed lymphocyte reaction (MLR) and profiles of interferon-, interleukin (IL)-2, and IL-10 in MLR supernatants. The effect on cardiac transplantation of perioperative administration of low-dose FK506 (0.1mg/kg per day) was also examined.Results Mixed lymphocyte reactions using splenocytes and sera from recipients treated intraportally were greatly inhibited. Interferon-, IL-2, and IL-10 levels were significantly higher after intraportal treatment compared with intravenous treatment (P 0.05). When FK506 was injected from day 3, a significant enhancement of cardiac allograft survival was demonstrated by intraportal treatment (16.1 ± 2.9 days) in comparison to the non-treatment (13.0 ± 1.7 days, P 0.05) and intravenous treatment rats (11.7 ± 2.7 days, P 0.05).Conclusions The Th2 deviation induced with intraportal alloantigen administration immediately after engraftment was thus observed to produce a synergistic effect with immunosuppressant treatment to suppress acute rejection.     

Intraportal delivery of immunosuppression to intrahepatic islet allograft recipients

Local delivery of immunosuppressive agents may dampen local alloreactive events with avoidance of systemic toxicity. We investigated the innovative strategy of intraportal (IPO) delivery of three immunosuppressive agents in streptozotocin diabetic rat recipients of islet allografts (Lewis to Wistar-Furth) transplanted intrahepatically. IPO budesonide (BUD, 240 or 360 g/kg per day), a potent steroid, and cyclosporin (CyA, 2 or 4 mg/kg per day) did not prolong graft mean survival time [MST±standard deviation (SD)] as compared to nonimmunosuppressed recipients. Fourteen days of IPO FK 506 (0.16 mg/kg per day) significantly increased MST as compared with untreated controls (49±29 vs 7±1 days, P<0.01) and was more effective than intravenous (IV) FK 506 (17±7 days, P<0.01). When FK 506 was given for 28 days, the benefit of IPO over IV delivery was reaffirmed (MST 81±32 vs 34±4 days, P<0.01). The potential for toxicity was lessened by lower mean systemic levels in the IPO group as compared to the IV group (1.3±0.6 vs 3.5±0.9 ng/mg, P<0.02). The strategy of continuous IPO FK 506 was effective in the prevention of rejection of intrahepatic islet allografts.     

Changes in the mononuclear cell subpopulations of rat cardiac transplant recipients administered FK506 for the treatment of ongoing rejection

The inhibitory effect on ongoing rejection and the changes that occurred in mononuclear cell subpopulations were compared between four groups of rats treated with FK506 or steroids. Group 1 was given no immunosuppressive drugs, group 2 was given FK506 from the day of grafting, group 3 was commenced on FK506 on the 4th day after grafting, and group 4 was commenced on methylprednisolone (MP) on the 4th day after grafting. The garft survival times in groups 2 and 3 were significantly longer than those in groups 1 and 4, and there were fewer CD3⁺ and CD4⁺ T lymphocytes in the peripheral blood in the groups treated with immunosuppressive drugs than in group 1. In group 4, the levels in both the peripheral blood and thymus were significantly lower than those in the groups treated with FK506 despite the fact that graft rejection occurred soon after the discontinuation of steroid administration. Moreover, the levels of interleukin-2 receptors and macrophages in groups 2, 3, and 4 were significantly lower than that in group 1 postoperatively; however, the number of macrophages in groups 2 and 3 was significantly lower than that in group 4 on the 10th day after transplantation. The findings of this study demonstrated that FK506, even if administered after rejection has begun, might inhibit the subsequent extensive allograft rejection more specifically and effectively than steroids, and that the measurement of a marker for macrophages in the peripheral blood could be useful for the detection of rejection following allograft transplantation in rats.     

Two-year follow-up study of the efficacy and safety of FK 506 in kidney transplant patients

Abstract We conducted a 2-year follow-up study of the efficacy and safety of FK 506 in 104 kidney transplant patients at 32 sites in Japan. The initial daily oral dose of FK 506 was 0.3 mg/kg, which was gradually reduced to 0.15 mg/kg by month 10 and remained stable thereafter. The mean trough level of FK 506 in whole blood and the mean serum creatinine level in year 2 were 7.9 ng/ml and 1.9 mg/dl, respectively. Patient and graft survival rates for all patients were 97% and 92%, respectively. Forty-ix patients (44%) experienced rejection episodes, and 84% of these episodes occurred within 3 months after transplantation. The principal adverse reactions to FK 506 therapy were hyperglycaemia, renal dysfunction and hyperkalaemia. Most of these events were dose-dependent, and disappeared or ameliorated following reduction of the FK 506 dose.     

In vivo and in vitro mechanisms of cardiac allograft acceptance in the rat after short treatment with 15-deoxyspergualin

15-Deoxyspergualin (DSG) has been reported to be a useful immunosuppressive agent already used to inhibit acute rejection in clinical transplantation. In the present study, the survival of heart allograft in rats after a short course of DSG treatment and the mechanisms underlying DSG-induced heart allograft acceptance were studied. Male LEW rats were used as recipients. Male ACI and Wistar rats were used as donors and third-party donors, respectively. Survival of ACI heart grafts in LEW recipients treated with a short course of DSG starting on day 4 after grafting was markedly prolonged, with a mean survival time of 16.6±5.8 days and 29.8±3.0 days at doses of 2.5 mg/kg per day and 5 mg/kg per day, respectively. On day 20 after grafting, the mechanism of inducing allograft survival after DSG treatment at a dose of 5 mg/kg per day was analyzed by testing the activation of spleen cells or serum in several assay systems. Spleen cells from DSG-treated rats with surviving heart allografts showed almost no proliferative response against donor strain stimulator cells compared with controls. The cytotoxic activity towards donor strain target cells of spleen cells from DSG-treated rats with surviving heart allografts was lower than that of spleen cells from rats with rejected heart allografts. Adding various concentrations of spleen cells or serum from DSG-treated LEW rats with surviving ACI heart allografts to the mixed lymphocyte reaction when responder cells from normal LEW rats were exposed to irradiated ACI or Wistar (third-party) stimulator cells, revealed strong suppression in a cell-dose-dependent manner and a serum-dose-dependent manner. Moreover, transfer of 2.0x10⁸ spleen cells or 2 ml serum from DSG-treated LEW rats with surviving ACI heart allografts to irradiated grafted host did not prolong the survival either of ACI heart grafts or of thirdparty Wistar heart grafts. These results suggest that proliferative response and cytotoxic activity are decreased and suppressor cells and suppressor humoral factor(s) are induced by treatment with DSG in rats with surviving allografts.Abbreviotions DSG 15-Deoxyspergualin - MLR mixed lymphocyte reaction - CML cell-mediated lympholysis     

Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation

Abstract In order to avoid the side effects of tacrolimus (FK506), a low-dose FK506-based regimen was started from 1 June 1991. The dose was adjusted to maintain the FK506 whole blood trough level at 15–20 ng/ml for 7 days postoperatively, at 10–15 ng/ml for 2 months, and under 10 ng/ml thereafter. The graft survival rates at 3 years and 5 years were 87.8 and 82.3 % (FK506) vs 86.8 and 86.8% [cy-closporine (CyA)]. The incidence of acute rejection within the first 90 days was 31.6% in the FK506 group which was lower than the 57.1% of the CyA group ( P - 0.0585). Grades of acute rejection episodes over IIA in the FK506 group were 20 %, which was lower than the 37 % in the CyA group. The mean oral dosages of FK506 were 0.061 and 0.04 mg/kg per day at 3 and 5 years, respectively. The incidence of new onset diabetes was 27.8% in the FK506 group and 17.1 % in the CyA group. However, insulin therapy was withdrawn in all patients of the FK506 group within 5 months. The percentage of patients who required an antihypertensive agent was 28.6 % and 40 % in the FK506 group and 73.2% and 88 % in the CyA group at 1 and 3 years, respectively ( P < 0.05). Nephrotoxicity was seen in 20% of the FK506 group and 14.3 % of the CyA group. Hypercholesterolemia was less frequent in the FK506 group than the CyA group. The FK506-based regimen described here is a protocol with the potential to reduce its adverse effects. The whole blood concentration of FK506 should be monitored and blood levels maintained in the range of 5–10 ng/ml after 90 postoperative days for optimal efficacy and minimal toxicity.     

Synergistic effect of donor-specific blood transfusion and a short course of deoxyspergualin in rat kidney transplantation

Deoxyspergualin (DSG), an analogue of spergualin produced by B. laterosporus, has a strong immunosuppressive effect in various transplantation models. We have investigated the mechanism of donor-specific prolongation of survival time in rat kidney grafting by donor-specific blood transfusion (DST) and a short course of DSG. Lewis (LEW) kidney allografts were transplanted into fully allogeneic BN rats. Fresh, whole LEW blood 1.0 ml, was injected i.v. into BN rats 2 days prior to transplantation. Then, DSG, 6 mg/kg per day, was administered by i.m. injection on days 0, 1, and 2 after transplantation. The recipients were divided into five groups: group 1 (n=6) no treatment: group 2 (n=6) DST only; group 3 (n=7) DSG only; group 4 (n=7) DST and DSG; and group 5 (n=6), third party (ACI rats) blood transfusion and DSG. Lymphocytes (cervical lymph nodes) and serum were harvested from BN recipients on day 7 postgrafting. For suppressor cell assays, lymphocytes from BN recipients in each group were added as a third cell to the mixed lymphocyte reaction (MLC) between nontransplanted BN lymphocytes (responder) and LEW or other third party (PVGC, ACI, WKA rats) lymphocytes (stimulator). Antidonor lymphocytotoxic antibody (ADLA) was checked by microcytotoxicity assays. Median survival times (MST) for each group were: group 1, 10 days; group 1, 10 days; group 3, 13 days; group 4, 75 days; and group 5, 13 days. Remarkable prolongation of MST was only noted in group 4. In the suppressor cell assay, group 4 showed significant suppression (40%; P<0.05); the other groups did not show any suppression. This suppressive activity in group 4 was effective only during the MLC between BN and LEW, not during the MLC of third party-BN combinations. Thus, suppressor cells from DST/DSG-treated BN recipients appear to be donor-specific. In the microcytotoxicity assay, the only group that showed any ADLA was group 2, which was not treated with DSG. These results clearly show that both induction of donor-specific suppressor cells and inhibition of ADLA production are associated with the remarkable donor-specific prolongation of kidney allograft survival in DST/DSG-treated recipients.     

Bombesin can rescue the enteric ganglia from FK506 neurotoxicity on small bowel transplantation

Background/Purpose

FK506 has been reported to have neurotoxic effects. The aim of this study was to investigate whether FK506 causes neurotoxic effects on the transplanted graft enteric ganglia (TGEG) and whether bombesin (BBS) can prevent such atrophy.

Methods

Thirty rats heterotopically underwent small bowel transplantation and were divided into 5 groups as follows: group A, syngraft (SYN) alone; group B, SYN with FK506; group C, SYN with FK506 and BBS; group D allograft with FK506; group E, allograft with FK506 and BBS. From postoperative days 14 to 28, either BBS or normal saline was administered continuously. All recipients except for group A received FK506 daily. The ganglionic count was obtained by counting the number of protein gene product 9.5 immunohistochemically stained ganglia in the cross sections of each graft.

Results

The number of TGEG in groups A, B, and C was 69.7 ± 6.0, 51.5 ± 7.7, and 84.8 ± 10.2 ganglia per cross section, respectively. There was a significant difference between each group (P < .001). The number of TGEG in groups D and E was 44.6 ± 7.5 and 65.1 ± 9.5 ganglia per cross section, respectively. There was a significant difference between the 2 groups (P < .001).

Conclusions

FK506 causes severe neurotoxicity in transplanted grafts, and BBS protects graft enteric ganglia against the neurotoxic effects of FK506.     

FK778, a novel immunosuppressive agent, reduces early adhesion molecule up-regulation and prolongs cardiac allograft survival.

The adhesion molecules, P-selectin, ICAM-1, and VCAM-1 are important mediators of T-cell adhesion and T-cell co-stimulation. We investigated the effect of the malononitrilamide FK778 on cardiac allograft survival, acute allograft rejection, and adhesion molecule up-regulation in a heterotopic, cardiac transplantation model. Rats received low- or high-dose FK778 or no treatment. Grafts were harvested on the fifth postoperative day for histologic examinations. To assess allograft survival, recipients were treated for a maximum of 10 days and grafts were harvested after cessation of the contractile activity. FK778 low dose showed a mild but significant decrease in mononuclear infiltration but failed to markedly reduce histologic rejection, adhesion molecule up-regulation, or to prolong allograft survival. However, high-dose FK778 treatment significantly reduced early up-regulation of P-selectin, ICAM-1, and VCAM-1, abolished infiltration, reduced histologic rejection and resulted in prolonged cardiac allograft survival. Therefore, FK778 is a novel, highly desirable immunosuppressive drug for transplantation medicine.     

FK506 conversion for intractable rejection of the liver allograft

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were conerted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 moth) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P=0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastroitestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5–1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.     

Co-administration of ketoconazole and tacrolimus therapy: a transplanted rat model

Background/aim The aim of this work is to study the effect of addition of ketoconazole to experimental kidney transplanted rat treated with tacrolimus and precludes the percentage of tacrolimus dose reduction. Material and methods The material of this work included 60 male Sprague Dawely rats subjected to renal allotransplantation. They were equally divided into five groups: Group I: served as control group, Group II: received FK506 3.2 mg/kg/bw, Group III: received FK506 2 mg/kg/bw, Group IV: received FK506 1 mg/kg/bw, Group V: received FK506 1 mg/kg/bw plus ketoconazole 20 mg/kg/day. FK506 trough level and laboratory investigations were determined at 0, 3, 7, 10, 14, and 27 days post-transplantation. Results In all groups loss of body weight was observed at day 27 after treatment compared to that before transplantation. Serum creatinine significantly increased at day 27 compared to the basal level in groups treated with 1.0 mg and 3.2 mg FK506 (1.80 ± 0.50 vs. 0.39 ± 0.06 P = 0.001) and (1.03 ± 0.26 vs. 0.50 ± 0.07 P = 0.001) respectively. While for 2.0 mg or 1.0 mg plus keto groups, no significant differences in serum creatinine levels over time (0.56 ± 0.22 vs. 0.44 ± 0.10 P = 0.106) and (0.55 ± 0.30 vs. 0.42 ± 0.08 P = 0.160) were observed. Conclusion Concomitant administration of ketoconazole and FK506 is safe and results in increase blood trough level concentration of FK506 with 50% dose reduction in transplanted rat model.     

Acute effects of different immunosuppressive drugs on pancreatic,islet, renal,and arterial hepatic blood flow in anesthetized rats

The effects of four different immunosuppressive drugs on organ blood flow were investigated. Sprague-Dawley rats were injected intravenously with 0.2 ml of either 15-deoxyspergualin (DSG; 5 mg/kg body weight), RS 61443 (80 mg/kg body weight), FK 506 (0.5 mg/kg body weight), cyclosporin A (9.5 mg/kg body weight), or the vehicles used. At 15 or 60 min after injection of the drugs, the blood perfusion of the whole pancreas, the pancreatic islets, and the kidneys, as well as the arterial blood flow to the liver, were measured in anesthetized animals using a microsphere technique. Fifteen minutes after administration, both FK506 and DSG decreased the fraction of whole pancreatic blood flow diverted through the islets. FK 506 and cyclosporin A reduced renal blood flow, but only 60 min after injection of the drug. None of the drugs influenced hepatic blood flow. RS 61443 did not affect the blood flow of the organ systems investigated. These differences in the effects of the drugs tested on blood flow might have some important implications on their efficacy and side effects. Thus, in view of its lack of influence on organ blood flow, RS 61443 seems to be preferable, at least when compared with cyclosporin A and FK 506 in the context of organ transplantation.