Protopic
Role of T cells in development of chronic pancreatitis in male Wistar Bonn/Kobori rats: effects of tacrolimus.

Yamada T, Hashimoto T, Sogawa M, Kobayashi S, Kaneda K, Nakamura S, Kuno A, Sano H, Ando T, Kobayashi S, Aoki S, Nakazawa T, Ohara H, Nomura T, Joh T, Itoh M.

First Department of Internal Medicine, Nagoya City University Medical School, Nagoya 467-8601, Japan. yamtmaki med.nagoya-cu.ac.jp

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg x kg(-1) x day(-1) but not 0.025 mg x kg(-1) x day(-1) of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11705744&dopt=Abstract tacrolimus Protopic



Protopic
Influence of hepatocyte growth factor, epidermal growth factor, and mycophenolic acid on endothelin-1 synthesis in human endothelial cells.

Haug C, Schmid-Kotsas A, Linder T, Bachem MG, Gruenert A, Rozdzinski E.

Institute of Clinical Chemistry, University Hospital, Ulm, Germany. cornelia.haug medizin.uni-ulm.de

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictive peptide which plays an important pathophysiological role in ischaemic renal failure and drug-induced renal injury such as cyclosporin A (CsA)- and tacrolimus-associated nephrotoxicity. In contrast, hepatocyte growth factor (HGF) and epidermal growth factor (EGF) seem to accelerate renal regeneration after ischaemic and drug-induced renal injury. This study aimed to investigate the influence of HGF and EGF on ET-1 synthesis in cultured human umbilical vein endothelial cells (HUVEC) and renal artery endothelial cells (RAEC). In addition, we have investigated whether mycophenolic acid (MPA), a new immunosuppressive drug, which in contrast to CsA and tacrolimus lacks nephrotoxic side effects, modulates ET-1 synthesis in endothelial cells. METHODS: ET-1 release was measured with a specific enzyme-linked immunosorbent assay. ET-1 mRNA expression was investigated by reverse transcription polymerase chain reaction. RESULTS: HGF and EGF (0.001-10 nM) exerted a significant concentration-dependent inhibitory effect on ET-1 release by HUVEC and RAEC (minimum 56.1+/-4.3% of control, n=6, mean+/-SE). The suppressive effect of HGF and EGF on ET-1 synthesis was dose-dependently antagonized by the tyrosine kinase inhibitors tyrphostin AG1478, lavendustin A and methyl 2,5-dihydroxycinnamate. Incubation of HUVEC and RAEC with MPA (2.5, 10, 25, and 50 microg/ml) for 3-5 h induced a significant reduction of ET-1 mRNA expression. After 48 h incubation with MPA (1-50 microg/ml) a significant decrease of ET-1 release and DNA content per culture well was observed, whereas ET-1 release referred to the DNA content in the corresponding culture well did not differ significantly from controls. CONCLUSIONS: The present findings demonstrate that HGF and EGF reduce ET-1 synthesis in endothelial cells via their receptor tyrosine kinase activity and suggest that the renoprotective effects of HGF and EGF might be linked to their inhibitory action on ET-1 synthesis. This study also provides evidence that, in contrast to CsA and tacrolimus, MPA does not stimulate ET-1 synthesis. This might explain the clinical observation that renal function often improves when CsA or tacrolimus is replaced by mycophenolate mofetil.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11733621&dopt=Abstract tacrolimus Protopic



Protopic
Tacrolimus in the treatment of severe chronic idiopathic urticaria: an open-label prospective study.

Kessel A, Bamberger E, Toubi E.

Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel. aharon.kessel b-zion.org.il <aharon.kessel b-zion.org.il>

We report the result of a pilot study of low-dose tacrolimus for the treatment of patients with severe chronic idiopathic urticaria (CIU). Nineteen patients with severe CIU were treated with tacrolimus for 12 weeks. Two patients dropped out after 1 week of treatment because of side effects. Following 3 months of treatment, 12 of 17 patients (70.5%) had a clinical response to tacrolimus. In 9 patients, the urticaria had been improved significantly (urticarial score 0-1), enabling them to discontinue antihistamines and, in the case of two patients, corticosteroids. The remaining 3 patients had moderate improvement (urticarial score 2). Three months after the discontinuation of tacrolimus, 3 of 10 responders had a complete resolution of their urticaria (urticarial score 0), 3 had mild deterioration (urticarial score 1-2) controllable by antihistamines alone, and 4 patients had a full relapse (urticarial score 3). Our preliminary results suggest tacrolimus as a treatment option for patients with severe CIU.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15627098&dopt=Abstract tacrolimus Protopic



Protopic
Indications, results, and complications of tacrolimus conversion in pediatric renal transplantation.

Flynn JT, Bunchman TE, Sherbotie JR.

Division of Pediatric Nephrology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA. jflynn montefiore.org

It is the practice of many pediatric renal transplant programs to 'convert' children taking cyclosporin A (CsA) to tacrolimus, although the indications for, outcome, and complications of this practice remain obscure. To better understand these aspects of tacrolimus 'conversion', a fax survey was sent to 119 North American pediatric renal transplant centers. Analyzable responses were received from 52 centers (44%), and included data from approximately 1,815 pediatric renal transplants performed between 1991 and 98. Strong indications for tacrolimus conversion were: antibody-resistant rejection, CsA-resistant rejection, and CsA intolerance (strong indication in 72%, 65%, and 52% of centers, respectively). Steroid-resistant rejection and cosmetic side-effects were considered strong indications less often. Initial anti-rejection therapy was usually increased corticosteroid dose (47/52 centers). Antibody therapy was most commonly used for steroid-resistant rejection (44 centers). For steroid- and antibody-resistant rejection, tacrolimus conversion was most common (33 centers). Tacrolimus conversion for antibody-resistant rejection led to improvement of serum creatinine (SCr) in 27% of patients, stabilization of SCr in 46%, worsening of SCr in 11%, and graft loss in 16%. Reported complications after tacrolimus conversion included hyperglycemia, hyperkalemia, lymphoproliferative disorder, infection, and neurologic problems. We conclude that the major indication for tacrolimus conversion in pediatric transplant programs appears to be rejection. Outcome after tacrolimus conversion appears good, with the majority of patients experiencing stable or improved allograft function. These data provide direction for further study, including timing of tacrolimus conversion and interaction with other therapies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11737770&dopt=Abstract tacrolimus Protopic



Protopic
Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats.

Sakamoto Y, Makuuchi-M, Harihara Y, Imamura H, Sato H.

Department of Surgery, Graduate School of Medicine, University of Tokyo, Japan. sakamoto-2su h.u-tokyo.ac.jp

The neurotoxicity associated with tacrolimus is one of the major limitations for its administration after organ transplantation. This study investigated the correlation between neurotoxicity and the intracerebral concentration of tacrolimus. Rats were given one of three doses of tacrolimus (5, 10, and 20 mg/kg/d) orally twice a day for 2 weeks and neurotoxic events were observed. The rats were sacrificed on either day 7 or 14. The trough values of the whole blood and the corresponding intracerebral concentrations were then measured. None of the rats receiving dosage of 5 mg/kg/d showed any neurotoxic symptoms throughout the two-week test period. In rats receiving a dosage of 10 mg/kg/d, however, all seven surviving rats presented tremors or seizures during the second week. In rats receiving a dosage of 20 mg/kg/d, 40% of the rats presented tremors or seizures during the first week. The threshold concentration of tacrolimus in the brain resulting in neurotoxic events was therefore estimated as approximately 700 ng/g. At concentrations over this threshold value, the intensity of the neurological event increases with the concentrations of tacrolimus in the brain. Using a linear correlation between the whole blood and intracerebral concentrations (r=0.967) of tacrolimus, the pharmacological threshold for the whole blood trough level was estimated as approximately 20 ng/ml, which falls into the same value reported for the incidental threshold of neurotoxicity in renal transplant recipients [Bottiger et al., Br. J. Clin. Pharmacol., 48, 445--448 (1999)]. Therefore, it is suggested that the rat is a good animal model to quantitatively evaluate the risk of neurotoxicity associated with tacrolimus in human, and that frequent measurement of whole blood tacrolimus concentrations is important for predicting and preventing neurotoxic events.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10963314&dopt=Abstract tacrolimus Protopic



Protopic
Comparative long-term evaluation of tacrolimus and cyclosporine in pediatric liver transplantation.

Jain A, Mazariegos G, Kashyap R, Green M, Gronsky C, Starzl TE, Fung J, Reyes J.

Thomas E. Starzl Transplantation Institute, Children's Hospital, University of Pittsburgh, PA 15213, USA.

BACKGROUND: In this report, we compare the long-term outcome of pediatric liver transplantation (LTx) patients maintained with tacrolimus-based and with cyclosporine (CsA)-based immunosuppressive therapy. We examine long-term patient and graft survival, the incidence of rejection, and immunosuppression-related complications. METHOD: There were 233 consecutive primary LTx in children (ages <18 years) performed between October 1989 and December 1994 with tacrolimus-based immunosuppressive therapy (Group I). These were compared with 120 consecutive primary LTx performed with CsA-based immunosuppressive therapy between January 1988 and October 1989(Group II). Children in both groups were followed until July 1999. Mean follow-up was 91.41+/-17.7 months (range 55.6-117.8) for Group I, and 128+/-6.1 months (range 116.7-138.6) for Group II. RESULTS: At 9 years of follow-up, actuarial patient and graft survival were significantly improved (patient survival 85.41% in Group I vs. 63.8% in Group II, P=0.0001; graft survival Group I 78.9% vs. 60.8% Group II, P=0.0003) and the rate of re -transplantation was significantly lower among patients in Group I (12% in Group I vs. 22.5% in Group II P=0.01). Children in Group I also experienced a significantly reduced incidence of acute rejection (0.97 per patient Group I vs. 1.5 per patient Group II P=0.002) and significantly less steroid resistant acute rejection episodes (3.1% in Group I vs. 8.6% in Group II P=0.0001). The mean steroid dose was significantly lower in Group I compared with Group II at all time points (P=0.0001) after LTx. Freedom from steroid was also significantly higher in Group I compared with Group II at all time points after LTx (ranging from 78% to 84% in Group I and 9% to 32% in Group II during a 1- to 7-year posttransplant period P=0.0001). The rate of hypertension was significantly lower in Group I than Group II (P=0.0001), and the severity of hypertension (need for more than one anti-hypertensive medication) was also significantly lower in Group I than Group II (P=0.0001). Although the rate of posttransplant lymphoproliferative disorder (PTLD) was not significantly different (13.7% Group I vs.8.3% Group II, P=0.13), the survival after PTLD was significantly better for Group I at 81.2% than for Group II at 50% after 5 years (P=0.034). Conclusion. The results suggest that tacrolimus-based therapy provides significant long-term benefit to pediatric LTx patients, evidenced by significantly improved patient and graft survival, reduced rate of rejection, and hypertension with lower steroid doses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10972220&dopt=Abstract tacrolimus Protopic



Protopic
Mechanism of the combination immunosuppressive effects of rapamycin with either cyclosporine or tacrolimus.

Khanna AK.

The Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee 53226, USA.

BACKGROUND: The combination of rapamycin with Cyclosporine has demonstrated beneficial effects in organ transplantation; however, the mechanism of this combination immunosuppression is not fully understood. The mechanism of action of cyclosporine and tacrolimus has been explained on the basis of their inhibition of interleukin-2 (IL-2), and induction of transforming growth factor-beta (TGF-beta). In this study, we explored the effects of rapamycin in combination with either tacrolimus or cyclosporine on lymphocyte proliferation, and expression of interleulin-2 (IL-2) and TGF-beta METHODS: Peripheral blood mononuclear cells/lymphocytes were isolated from buffy coats obtained from blood center, and activated with phytohemagglutinin (PHA) in the presence or absence of rapamycin, cyclo sporine, and tacrolimus alone or in various combinations. The activation was quantified by 3H-thymidine uptake assay and using reverse transcriptase assisted polymerase chain reaction and ELISA, we studied the TGF-beta and IL-2 mRNA and protein expression, respectively. RESULTS: In this study, we report that rapamycin in combination with either tacrolimus or cyclosporine significantly inhibited the lymphocyte proliferation, IL-2 expression, and induced TGF-beta, compared with these drugs alone. The levels of TGF-beta and IL-2 correlated positively and negatively, respectively, with inhibition of lymphocyte proliferation. CONCLUSIONS: These novel findings provide the mechanism as well as the rationale to use these drugs in combination at subclinical dosages in organ transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10972232&dopt=Abstract tacrolimus Protopic