Prevention Of Renal Allograft Rejection Research Articles

The Effect of ASP2409, a Novel CD86-Selective Variant of CTLA4-Ig, on Renal Allograft Rejection in Nonhuman Primates.

Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients. To address these issues, a novel CTLA4-Ig variant, ASP2409, with improved CD86 binding selectivity and affinity relative to belatacept was created using DNA shuffling directed evolution methods. We evaluated the immunosuppressive effect of ASP2409 on in vitro alloimmune T cell responses, in vivo tetanus toxoid (TTx)-induced immunological responses and renal transplantation in cynomolgus monkeys. ASP2409 had 6.1-fold higher and 2.1-fold lower binding affinity to monkey CD86 and CD80 relative to belatacept, respectively. ASP2409 was 18-fold more potent in suppressing in vitro alloimmune T cell responses relative to belatacept. In a cynomolgus monkey TTx immunization model, ASP2409 inhibited anti-TTx immune responses at a 10-fold lower dose level than belatacept. In a cynomolgus monkey renal transplantation model, subcutaneous injection of 1 mg/kg ASP2409 prevented allograft rejection through complete CD86 and partial CD80 receptor occupancies and dramatically prolonged renal allograft survival in combination with tacrolimus or mycophenolate mofetil/methylprednisolone. These results support the potential of ASP2409 as an improved CTLA4-Ig for maintenance immunosuppression in organ transplantation.

Effects of ASKP1240 combined with tacrolimus or mycophenolate mofetil on renal allograft survival in Cynomolgus monkeys.

Blocking the CD40-CD154 signal pathway has previously shown promise as a strategy to prevent allograft rejection. In this study, the efficacy of a novel fully human anti-CD40 monoclonal antibody-ASKP1240, administered as a monotherapy or combination therapy (subtherapeutic dose of tacrolimus or mycophenolate mofetil), on the prevention of renal allograft rejection was evaluated in Cynomolgus monkeys. Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.5 or higher in the two-way mixed lymphocyte reaction monkey pairs. Animals were divided into 12 groups and observed for a maximum of 180 days. Histopathologic, hematology, and biochemistry analyses were conducted in all groups. Cytokine release (interleukin [IL]-2, IL-4, IL-5, IL-6, tumor necrosis factor, and interferon-γ) was investigated in several groups. ASKP1240 prolonged renal allograft survival in a dose-dependent manner in monotherapy. Low-dose (2 mg/kg) or high-dose (5 mg/kg) ASKP1240, in combination with mycophenolate mofetil (15 mg/kg) or tacrolimus (1 mg/kg), showed a significantly longer allograft survival time compared with monotherapy groups. No obvious side effects including drug-related thromboembolic complications were found. Cytokine release was not induced by ASKP1240 administration. The present study indicates that ASKP1240, alone or in combination with other immunosuppressive drugs, could be a promising antirejection agent in organ transplantation.

Treatment With a Spleen Tyrosine Kinase Inhibitor Reduced Inflammation and Protected Kidney Function in Experimental Renal Allograft Rejection.

Introduction: Spleen tyrosine kinase (SYK) mediates signalling of immune receptors. We have shown that fostamatinib, a SYK inhibitor, was effective in treatment of antibody mediated experimental glomerulonephritis (JASN. 21:231, 2010). We have now studied SYK inhibition for prevention of renal allograft rejection. Method: We studied the effect of fostamatinib (from Rigel Pharmaceuticals and AstraZeneca) in a rat (Brown Norway (BN) to Lewis (LEW)) model of renal allograft rejection. In experiment 1, the left kidney of a LEW rat was replaced by a left kidney from a BN rat. This is a severe model of rejection characterised by cortical infarction by day 7. Severity of rejection was analysed after 7 days. The percentage of the cortex of the allograft with infarction was assessed by a pathologist blinded to treatment group on to the following scale: 0=0, 0-10%=1, 11-25%=2, 26-50% =3, 51-75%=4, >75%=5. In experiment 2, bilateral nephrectomy was performed in the recipient LEW rat at the time of transplantation so that transplant kidney function could be assessed by creatinine clearance (CrCl); rats were culled on day 6 for assessment of cell infiltrates before graft infarction. Treatment was given by gavage twice daily. The results are median values analysed by non-parametric tests. Results: In experiment 1, control rats (vehicle or no treatment, n=10), showed severe allograft infarction, grade 5. In the fostamatinib treated rats, there was complete prevention of allograft infarction grade 0 and 0 in rats treated with 30 mg/kg (n=7) or 20 mg/kg (n=7) respectively twice daily (p<0.001). In experiment 2, treatment was started on day 2 when the rats recovered from surgery. Treatment with 30 mg/kg of fostamatinib twice daily from day 2-6 reduced severity of tubulointerstitial injury, grade 3, in the fostamatinib treated group (n=8) v grade 5, (p<0.005) in the vehicle treated group (n=7), reduced cortical infiltration by macrophages (1.7 v 10.5 au by image analysis, p<0.005) and CD8+ cells (1.7 v 7.4 au, p<0.05) and protected renal function compared with the vehicle treatment (CrCl 4.2 v 0.1 ml/min, p<0.005). Conclusion: Treatment with a SYK inhibitor reduces the severity of experimental renal allograft rejection and protects renal function. DISCLOSURE:Masuda, E.: Employee, Rigel Pharmaceuticals, Other, Rigel Pharmaceuticals, Stock option. Tam, F.: Grant/Research Support, AstraZeneca, Other, Rigel Pharmaceuticals, Consultancy.

Mycelia glycoproteins from Cordyceps sobolifera ameliorate cyclosporine-induced renal tubule dysfunction in rats

Ethnopharmacological relevanceCordyceps sorbolifera has been used in Traditional Chinese Medicine for improving the renal function. Cyclosporine A (CsA) is an important immunosuppressive agent in the prevention of renal allograft rejection, but long-term usage of CsA could lead to chronic nephrotoxicity and renal graft failure. The study was aimed to investigate whether the mycelia glycoproteins of Cordyceps sobolifera (CSP) exert prevention effects on CsA-induced nephrotoxicity. Materials and methodsSprague-Dawley (SD) rats were randomly assigned into four groups (n=6 per group): normal saline (control group), CSP group, CsA group, and CSP-CsA group (CsA combined treatment with CSP). Glomerular and tubular functions were assessed and histological studies were performed. ResultsCSP, prepared by hot water extraction, ethanol precipitation and membrane dialysis, was found to be composed of three glycoproteins with average molecular weights of 543, 31, and 6.3kDa, respectively. CsA impaired urea clearance and creatinine clearance were significantly improved by concomitant administration of CSP. TUNEL histochemical stain revealed that CSP significantly decreased CsA-induced apoptosis in renal tubular cells. The reducing effect of caspase-3 activation by CSP was suggested through the over-expression of the anti-apoptosis protein Bcl-2 in renal tubule cells. In assessment of CSP protection of renal tubule function, we found that CSP restored CsA induced magnesium wasting by increasing the magnesium reabsorption channels TRMP6 and TRMP7. ConclusionThe results suggested that CSP had a significant suppressive activity on CsA-induced apoptosis and protective activity against nephron loss possibly via its restoring activity by increasing the magnesium reabsorption channels TRMP6 and TRMP7 on CsA induced magnesium wasting.

Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells

Recent data suggest that donor-specific memory T cells (T(mem)) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4(+)/ 8(+) GFP(+) T(mem) before transplantation to achieve similar pre-transplant frequencies of donor-specific T(mem) as seen in many patients. T cell depletion alone induced long-term graft survival in naïve recipients but could not prevent acute rejection in T(mem)(+) rats, like in patients. Only if T cell depletion was combined with permanent CNI-treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in T(mem)(+) rats. Our model allows evaluation of novel therapies under clinically relevant conditions.

Relationship between mycophenolate mofetil side effects and mycophenolic acid plasma trough levels in renal transplant patients

There has been limited experience with routine therapeutic monitoring of mycophenolic acid (MPA; CAS 24280-93-1), which is the active metabolite of the new immunosuppressive prodrug mycophenolate mofetil (MMF; CAS 115007-34-6). MMF was introduced with recommendation for fixed oral dosing (1 g twice daily) in combination with cyclosporin A (CSA) and a glucocorticoid for the prevention of renal allograft rejection. In the course of routine CSA monitoring a MPA monitoring was performed in adult renal transplant patients receiving MMF in combination with CSA and methylprednisolone (MEP). For 30 consecutive patients with 234 plasma samples the relationship of MMF doses used and MPA plasma through levels estimated at steady state (C88 min) to clinical outcome was evaluated retrospectively. The MPA concentrations were determined with the enzyme-multiplied immunoassay technique (EMIT mycophenolic acid assay) on a Cobas Mira Plus analyzer. The within-run (n = 10) and between-run (n = 10) coefficients of variation were 3.6%, 3.5%, 3.1% and 3.6%, 5.1%, 6.7% analysing three MPA level plasma controls (1.25 mg/l, 7.5 mg/l, 12.5 mg/l), respectively. The data analysis of the MPA plasma trough levels resulted in a high variability between patients (0.3 to 3.4 mg/l) received the recommended fixed MMF dose (2 g/day). There was a higher incidence of adverse reactions with increasing MPA plasma trough levels (2.13 +/- 1.35 mg/l in 13 patients with side effects versus 1.53 +/- 0.67 mg/l in 17 patients without side effects; p < 0.001), regardless of reduction of MMF dose (1.77 +/- 0.3 g/day versus 1.89 +/- 0.2 g/day; NS), respectively. No acute rejection episodes occured under MMF administration in combination with CSA and MEP. The study shows that the to date recommended MMF dose resulted in individual, quite different MPA plasma trough levels, which were associated with incidence of side effects rather than the MMF doses. Therefore, monitoring of plasma MPA trough levels and individual dose adjustment could be helpful to reduce the incidence of adverse reactions and to increase the safety of MMF therapy.

Recent advances in immunosuppressive therapy for prevention of renal allograft rejection

Current immunosuppressive therapies are highly successful at regulating acute allograft rejection and inducing long-term transplanted kidney survival; however, currently available medications are associated with generalized immune suppression and drug toxicities, including nephrotoxicity. In recent years, advances in immunosuppression that target specific pathways involved in immune activation have been developed. In particular, promising medications are currently under evaluation that target ischemia-reperfusion injury as well as the cellular and humoral branches of the adaptive immune response. Targets of T-cell-mediated activation include antibodies and fusion proteins interfering with LFA-1/ICAM-1, CD2/LFA-3, CD40/CD154, and CD28/B7.1 and B7.2 interactions. Intracellular targets involved in T- and B-cell activation pathways are being evaluated, including protein kinase C inhibitors, Janus-associated kinase (JAK) inhibitors, and proteasome inhibitors. Several new medications demonstrate promise in inhibiting donor-directed humoral immunity by targeting B-cell-activating factor (BAFF) and complement activation pathways. The present review evaluates the recent clinical advances in immunosuppressive therapies for kidney transplantation. Publications regarding advances in immunosuppressive therapies over the past year were evaluated in the context of the specific immune pathways involved in allograft rejection.

Reduced C0 Concentrations and Increased Dose Requirements in Renal Allograft Recipients Converted to the Novel Once-Daily Tacrolimus Formulation

Recently, a once-daily prolonged release formulation of tacrolimus (TacOD) has been approved for the prevention of renal allograft rejection. Studies reported equivalent area under the concentration-time curve0-24 and predose trough (C0) concentrations when compared with the standard twice-daily tacrolimus (Tac) formulation. Hence, the package insert advices a 1:1 mg conversion. Here, we report our independent experience with conversion to TacOD according to the manufacturer's instructions. Retrospective single-center study evaluating the evolution of C0 concentrations and dose requirements after conversion to TacOD in 284 renal allograft recipients. Potential clinical, biochemical, and genetic determinants of changes in C0 concentrations and dose requirements after conversion were explored in univariate and multivariate analyses. After conversion, C0 concentrations decreased significantly (-1.36+/-2.51 microg/L or -12.66%+/-24.36%, P<0.0001). In 38.3% of patients, this decrease exceeded 20%. TacOD dose was increased in 52.5% of patients. Average dose requirements increased to 0.71+/-1.78 mg/day or 14.68%+/-28.87% (P<0.0001). In 28.0% of patients, dose requirements increased more than 20%. Dose changes were more profound in patients converted within 1 year after transplantation, and in this subgroup (n=78), higher creatinine and lower hemoglobin levels were associated with a larger increase in dose requirements in multivariate analysis (r=0.35, P<0.0001). Despite dose adjustments, average C0 concentrations remained 9.09%+/-28.85% lower after conversion (P<0.0001). Conversion from standard twice-daily tacrolimus formulation to TacOD on a 1:1 mg basis results in reduced Tac C0 concentrations and increased dose requirements. Thus, conversion is not as straightforward as suggested by the manufacturer, and converted patients should be monitored strictly until stable C0 concentrations are achieved.

Prevention of renal allograft rejection without immune suppression: a model to revisit

Spectacular success in preventing renal allograft rejection in rats was obtained over 40 yr ago using only the reactants of the response: donor-type antigen and homologous antiserum directed against donor-type antigen. Tolerance was antigen specific and sustained by persistent antigen of the graft. The model has never been tested rigorously in a large species, though the rationale for why the procedures should work applies across species including humans. Confirming the results in a large species would have profound impact on research for treating multiple immune mediated diseases, in addition to providing a way for treating some transplant recipients. This is a propitious time to confirm the applicability to larger species. If successful, only the lack of imagination limits the potential impact.

Systemisches Voclosporin bei Uveitis

To date cyclosporine is the only immunosuppressive drug approved for the treatment of uveitis in Germany. However, side effects often limit its use in daily practice. Voclosporin (Luveniq) represents a next generation calcineurin inhibitor which had shown efficacy in an animal model of experimental autoimmune uveitis as well as in clinical trials for the prevention of renal allograft rejection and for plaque psoriasis. The LUMINATE program included three prospective, randomized, double-masked, placebo-controlled multicenter trials which demonstrated the efficacy and tolerability of voclosporin 0.4 mg/kg b.i.d. in noninfectious intermediate and posterior uveitis and panuveitis. In Europe, the Marketing Approval Application (MAA) of voclosporin for the treatment of uveitis was submitted to the European Medicines Agency (EMA) in February 2010 and could be approved in March 2011.

A phase I study of the mTOR inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel (nab-P).

2534^ Background: Preclinical data suggest that mTOR inhibitors potentiate the efficacy of taxanes. Sirolimus (Rapamycin, R) is an FDA-approved mTORC1 inhibitor for prevention of renal allograft rejection. nab-P has greater efficacy and less toxicity than cremophor-based P. Primary aim is to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Secondary aims are to evaluate pharmacokinetics (PK) and biologic effect of R on Akt pathway in pre\/post therapy tumor samples. Methods: Cohorts (C) of 3-6 patients (pts) were enrolled and treated. Oral R doses were escalated; C1 (5 mg, n = 3), C2 (10 mg, n = 6), C3 (20 mg, n = 3), C4 (40 mg, n =6), C5 (60 mg, n=5) on day -7, 2, 9, 16 and nab-P 100 mg/m2 on day -14, 1, 8, 15 of 28-day cycle. Pre- and posttherapy biopsies were performed on 10 and 9 pts. Results: 23 pts (10 lung, 2 sarcoma, 3 ovarian, 3 breast, 3 endometrial, 1 melanoma, 1 head and neck) with median age of 61 (range 41-78) were treated. Median number of cycles is 3 (range 1-8). The following DLT occurred: a grade 3 DLT dyspnea/hypoxia (C2); ANC<1,500ul > 2 wk (C4); grade 4 pericardial effusion and grade 3 fatigue (C5). Other grade 3 non-hematologic toxicities included weight loss (C1); elevated AST/ALT (C4); hypertriglyceridemia, diarrhea, subcutaneous edema, deep vein thrombosis (C5). One grade 4 neutropenia occurred (C4). MTD is 40 mg. Best response is partial response in 6 pts (2 lung, 2 breast, 1 endometrial, 1 ovarian)[4/6 confirmed]; stable disease in 9 and progression in 7 pts. There were proportionate increases in AUC and Cmax with increasing dose of R (Cmax = 4,700, 3,810, 1,733, 10,036, 10,307, 43,256 ng/mL and AUCinf = 5,099, 5,310, 3,059, 8,460, 16,776 hr*ng/mL at R dose levels of 5, 10, 20, 40, 60 mg, respectively) and no evidence of drug accumulation at cycle 2. There were high correlations between baseline AKT pathway markers (mTOR, Akt, pAkt, S6K1 and pS6K1; Spearman's rho-0.406-0.867). This correlation was lost in post therapy samples. There was a trend for higher levels of mTOR to predict resistance to therapy (p 0.08). Conclusions: R in doses up to 40 mg can be safely combined with nab-P 100 mg/m2on day 1, 8, and 15 q 28 day with promising activity in solid tumors. Post-therapy change in marker expression suggests biologic effect of R. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Clinical utility of therapeutic drug monitoring of mycophenolic acid in transplantation medicine: Where are we? / Der klinische Nutzen des Therapeutischen Drug Monitoring von Mycophenolsäure in der Transplantationsmedizin: Wo stehen wir?

Abstract Mycophenolate mofetil (MMF, CellCept®, Roche Pharmaceuticals) received its first approval for the prevention of renal allograft rejection in 1995 and has now become the most frequently used antiproliferative agent in maintenance immunosuppressive therapy for kidney, pancreas, liver, and heart transplantation. In 2004, a second mycophenolate formulation – the enteric-coated mycophenolate sodium (EC-MPS, Myfortic®, Novartis Pharma) – was introduced. Whereas therapeutic drug monitoring (TDM) is well established for other immunosuppressants, the use of this tool for individualization and optimization of mycophenolate therapy remains a matter of debate during these years. This article focuses on the basic pharmacology of mycophenolic acid and current knowledge about the utility of monitoring mycophenolic acid concentrations. Different tools for performing TDM of mycophenolic acid, current recommendations for TDM of MMF in transplantation medicine, as well as analytical techniques available will be discussed.

Very early alloantigen-independent trafficking of lymphocytes during ischemic acute kidney injury

Lymphocytes play an important role during ischemia-reperfusion injury (IRI). Lai et al. have demonstrated, for the first time, an increase in kidney lymphocytes 1 hour after IRI, a newly identified kidney lymphocyte reservoir, and have confirmed the pathogenic role of lymphocytes by manipulating the sphingosine-1-phosphate (SIP)-sphingosine-1-phosphate type 1 (S1P1) receptor pathway.

Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma

Daclizumab (Zenapax) identifies the alpha subunit of the interleukin-2 (IL-2) receptor and blocks the interaction of this cytokine with its growth factor receptor. The scientific basis for the choice of the IL-2 receptor alpha subunit as a target for monoclonal antibody-mediated therapy of leukemia/lymphoma is that very few normal cells express IL-2R alpha, whereas the abnormal T cells in patients with an array of lymphoid malignancies express this receptor. In 1997, daclizumab was approved by the FDA for use in the prevention of renal allograft rejection. In addition, anti-Tac provided effective therapy for select patients with T-cell malignancies and an array of inflammatory autoimmune disorders. Finally, therapy with this antibody armed with (90)Y has led to clinical responses in the majority of patients with adult T-cell leukemia. These insights concerning the IL-2/IL-2 receptor system facilitated the development of effective daclizumab antibody therapy for select patients with leukemia/lymphoma.

Anti-Tac (daclizumab, Zenapax) in the Treatment of Leukemia, Autoimmune Diseases, and in the Prevention of Allograft Rejection: A 25-Year Personal Odyssey

Twenty-five years ago, we reported the production of the monoclonal antibody, anti-Tac that identifies the IL-2 receptor alpha subunit and blocks the interaction of IL-2 with this growth factor receptor. In 1997, daclizumab (Zenapax), the humanized form of this antibody, was approved by the FDA for use in the prevention of renal allograft rejection. In addition, we demonstrated that daclizumab is of value in the treatment of patients with noninfectious uveitis, multiple sclerosis, and the neurological disease human T-cell lymphotropic virus I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Others demonstrated therapeutic efficacy with daclizumab in patients with pure red cell aplasia, aplastic anemia, and psoriasis. Thus, translation of basic insights concerning the IL-2/IL-2 receptor system obtained using the monoclonal antibody daclizumab provided a useful strategy for the prevention of organ allograft rejection and the treatment of patients with select autoimmune diseases or T-cell leukemia/lymphoma.

FTY720 (fingolimod) in renal transplantation

FTY720 (Fingolimod) is a novel immunomodulator with a mode of action that is completely different from classical immunosuppressants. FTY is a structural and functional analogue of the natural serum lipid, sphingosine, and is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1P-R) modulators. This review discusses the recent findings on the mechanism of action, preclinical models and outlines the results of the ongoing clinical development program. FTY is highly effective in prolonging allograft survival in preclinical models of transplantation and in experimental models of autoimmune diseases. In clinical trials, this novel compound was investigated in de novo renal transplantation and in multiple sclerosis. Pharmacokinetics are characterized by a prolonged absorption phase, a large volume of distribution, and a long elimination half-life. FTY induces a rapid and transient decrease in lymphocyte counts, which supports the modulatory effects of the drug on lymphocyte sequestration. The most common adverse event was asymptomatic transient bradycardia, a pharmacodynamic effect modulated by atrial S1 P-R. FTY failed to show an improvement in efficacy for the prevention of renal allograft rejection in two large phase III studies. FTY treatment regimens were associated with impaired renal function and the development of macula edema. Consequently, the further development in renal transplantation was stopped. Because initial clinical studies strongly suggest that FTY is highly effective in multiple sclerosis FTY is now being explored in phase III studies for the treatment of demyelinating diseases, Ongoing studies in multiple sclerosis are eagerly awaited because they may provide novel therapeutic options for patients with autoimmune diseases.

Mycophenolate mofetil in organ transplantation: focus on metabolism, safety and tolerability

Mycophenolate mofetil (MMF) received its first approval for the prevention of renal allograft rejection in 1995 and has now become the most frequently used antiproliferative agent in maintenance immunosuppressive therapy for kidney, pancreas, liver and heart transplantation. In addition, its use for the treatment of autoimmune diseases steadily increases. This review focuses on the miscellaneous pharmacodynamic properties of the drug, its pharmacokinetics in healthy subjects, recipients of different organ transplants and combination therapy with other pharmaceuticals, as well as its safety profile. The immunosuppressive activity of MMF is thought to derive mainly from the potent and selective inhibition of purine synthesis in both T and B lymphocytes. In contrast to other immunosuppressants on the market, it is metabolised primarily by glucuronidation and lacks nephrotoxicity, cardiovascular toxicity or diabetogenic potential, thus making it a suitable candidate for combination regimens. The most important side effects under MMF include gastrointestinal disorders, of which the underlying mechanisms are not yet fully understood, but seem to be complex and related to both effects of mycophenolic acid and its acyl glucuronide, as well as to decreased -immunity due to general immunosuppression after transplantation.

Mycophenolate mofetil (CellCept): an alternative therapy for autoimmune inflammatory myopathy

Mycophenolate mofetil (MMF) is a new immunosuppressive agent currently being used for the prevention of renal allograft rejection. MMF is a specific inhibitor of lymphocytes and is well tolerated leading to its use in other autoimmune diseases. We have used MMF for the treatment of seven patients with inflammatory myopathy and are hereby reporting our results. All of our patients were females (age 17-65 yr). They were symptomatic upon presentation and met classification criteria for idiopathic inflammatory myopathy. Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein as well as creatine kinase were significantly elevated in all the patients, indicating active disease. Corticosteroids were concomitantly being administered (20-60 mg/day of prednisone). Initial therapy with conventional immunosuppressives was either ineffective or had significant adverse effects leading to their discontinuation. MMF was started in doses of 500 mg twice a day and titrated up to 1 g twice a day. Our patients have exhibited an impressive serological response to therapy with MMF and six patients had a marked improvement in their weakness. One patient had incomplete improvement in her weakness and has required additional therapies. MMF has been well tolerated during the treatment period (12-36 months). A striking clinical and laboratory response of active myositis in six out of seven patients in this series illustrates that MMF can be effectively used in management of autoimmune inflammatory myopathy and may be a suitable alternative to the conventional immunosuppressive agents.

Preliminary safety and efficacy of daclizumab in the treatment of patients with moderate to severe chronic persistent asthma

Rationale Daclizumab (Zenapax®), a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25, Tac), is approved for prevention of renal allograft rejection and is under evaluation for treatment of patients with asthma and autoimmune diseases. Daclizumab inhibits Th1 and Th2 cytokine secretion and acts synergistically with dexamethasone in vitro (JACI, 2002, 109(1): S27). In this phase II trial, we studied the safety and efficacy of daclizumab in patients with moderate to severe chronic asthma. Methods Non-smoking asthmatics age 18-70 with baseline FEV1 50-80% predicted despite use of ≥1200 μg daily inhaled triamcinolone (TAA) or equivalent were enrolled in a randomized, multi-center, double-blind, placebo-controlled, parallel trial. Patients with demonstrated requirement for inhaled corticosteroids during run-in were randomized (3:1 active: placebo) to daclizumab (loading dose of 2 mg/kg i.v. followed by 1 mg/kg i.v. every 2 weeks) or placebo added to stable dose TAA. Starting at week 12, patients underwent 25% reduction of TAA every two weeks while continuing study drug. The primary efficacy endpoint was the change in FEV1 from baseline at week 12. Results Baseline characteristics of the 116 randomized patients included: (mean ± SD) age 42.6 ± 12.5 years, disease duration 22.9 ± 13.5 years, FEV1 (% predicted) pre-bronchodilator 68.8 ± 8.7 and post-bronchodilator 80.3 ± 10.8. Eight patients have reported serious adverse events, of which 3 patients had events assessed as related to (blinded) study drug. Conclusions Preliminary safety and efficacy will be assessed following completion of study follow up visits. Unblinded analysis will be presented.

Antibodies in the prevention of renal allograft rejection

Antibodies in the prevention of renal allograft rejection