ASP0028 in combination with suboptimal-dose of tacrolimus in Cynomolgus monkey renal transplantation model.

FTY720, a S1P-receptor modulator, has shown to be effective in several transplant and autoimmune disease models, via modulating lymphocyte homing into secondary lymphoid organs (SLOs), and thereby reducing these cells in peripheral blood. ASP0028, a newly developed S1P/S1P-selective agonist, presented comparable efficacy to FTY720 and wider safety margins than FTY720. In this study, we assessed the efficacy and safety of ASP0028 co-administered with suboptimal-dose of tacrolimus in the Cynomolgus monkey renal transplantation model.

ASP2409, A Next-Generation CTLA4-Ig, Versus Belatacept in Renal Allograft Survival in Cynomolgus Monkeys.

Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T-lymphocyte associated protein 4-immunoglobulin possessing 14-fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys.

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

Background: 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.

Methods: Heterotopic kidney transplants were performed in ABO-compatible, stimulation index 2.

Pharmacokinetics and pharmacodynamics of ASKP1240, a fully human anti-CD40 antibody, in normal and renal transplanted Cynomolgus monkeys.

Background: The purpose of this study was to evaluate the serum concentration of ASKP1240 (pharmacokinetics [PK]) and the CD40 occupancy of ASKP1240 (pharmacodynamics [PD]) in normal and renal transplanted Cynomolgus monkeys to clarify the PK/PD relationship.

Methods: In a 70-day study, two ASKP1240 doses (2 and 5 mg/kg) were evaluated in normal and transplanted monkeys. Full doses were administered during the induction phase, and half doses were administered during the maintenance phase.

Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates.

Objective: Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage.

Cartilage regeneration by selected chondrogenic clonal mesenchymal stem cells in the collagenase-induced monkey osteoarthritis model.

Osteoarthritis (OA) is the most common form of arthritis, in which cartilage is irreversibly degraded, causing severe pain and disability. Current therapeutic strategies cannot repair damaged cartilage. We evaluated the repair potential of selected chondrogenic clonal MSCs (sC-MSCs) by delivering them into the injured cartilage site in a collagenase-induced OA model in Cynomolgus monkeys.

Adoptive transfer of CD4+CD25+ regulatory cells combined with low-dose sirolimus and anti-thymocyte globulin delays acute rejection of renal allografts in Cynomolgus monkeys.

Although donor alloantigen specific Treg cells play an important role in transplant tolerance, therapeutic applications are limited by their low frequency. In this study, isolated Tregs from Cynomolgus monkeys were efficiently expanded by a co-culture system, and maintained suppressive function on the proliferation of CD4(+) effector cells in vitro. Adoptive transfer of expanded donor alloantigen specific Tregs without any immunosuppressants could prolong survival of MHC-mismatched allografts in Cynomolgus monkeys.

Surgical complications in kidney transplantation in nonhuman primates.

Surgical complications are important causes of graft loss in the nonhuman primate kidney transplantation model. We reviewed the incidence and intervention methods in 182 kidney transplantations performed in our lab recently 2 years in Cynomolgus monkeys. There were six renal artery thromboses (3.

Conversion from calcineurin inhibitors to sirolimus in kidney transplant recipients: a retrospective cohort study.

Background: Replacing a calcineurin inhibitor (CNI) with sirolimus (SRL) may preserve kidney graft function. However, at the present time, only short follow-up after conversion is available. The aim of this study was to assess whether conversion from a CNI-based to an SRL-based maintenance regimen was safe and effective.

Acute rejection in low-toxicity regimens: clinical impact and risk factors in the Symphony study.

The Symphony study assessed whether mycophenolate mofetil (MMF)-based regimens containing reduced doses of adjunct immunosuppressants could reduce toxicity while maintaining efficacy. Here, we examined the impact of acute rejection and associated risk factors. The incidence of biopsy-proven acute rejection in the low-dose tacrolimus group was approximately half that of the standard-dose cyclosporine and low-dose cyclosporine groups, and a third of that in the low-dose sirolimus group.

Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation.

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up.

Combined therapy of CD4(+)CD25(+) regulatory T cells with low-dose sirolimus, but not calcineurin inhibitors, preserves suppressive function of regulatory T cells and prolongs allograft survival in mice.

Our previous study proved that sirolimus is a potent immunosuppressant which induces long-term allograft survival depends on persistence of alloantigens. CD4(+)CD25(+) regulatory T (Treg) cells are potent suppressors in transplantation. Our objectives focus on whether combined-therapy of Tregs with immunosuppressants could prolong allograft survival in mice.

Dysfunction of IL-10-producing type 1 regulatory T cells and CD4(+)CD25(+) regulatory T cells in a mimic model of human multiple sclerosis in Cynomolgus monkeys.

CD4(+)CD25(+) Treg and IL-10(+) Tr1 cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Dysfunction of Tregs appears to be a critical factor in the pathogenesis of autoimmune diseases. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of CNS, where CD4(+) T cells result in nervous tissue damage.

The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study.

Background: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results.

Methods: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL).

Cryopreservation of vascularized ovary: an evaluation of histology and function in rats.

Cryopreservation of organs has been investigated to sustain the reproductive function of patients undergoing sterilizing chemotherapy and radiotherapy or reproductive surgery. A modified protocol for whole organ cryopreservation was described and the outcome of cryopreservative ovaries was evaluated, and apoptosis of cryopreservative cells stored for different time period and the viability of cryopreserved cells stored at different temperature was examined in rats. Lewis rat ovarian grafts were perfused for 30 min at 0.

Reduced exposure to calcineurin inhibitors in renal transplantation.

Background: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens.

Methods: We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus.

Effect of Baohuoside-1 aglycone and tacrolimus monotherapy and combination therapy on prevention of acute heart allograft rejection in the rat.

Baohuoside-1 (B-1), a recently introduced novel immunosuppressant that was proved to be potent in inhibition of T and B cell proliferation and B-1, also prevents cardiac allograft rejection in rodents. The present study further proved that monotherapy of B-1's analogue B-1 aglycone effectively prolongs cardiac allograft survival and combination therapy of B-1 aglycone with tacrolimus (FK506) produces synergistic effect in prevention acute cardiac allograft rejection in the rat. .

Effect of a novel inducible nitric oxide synthase inhibitor, FR260330, in prevention of renal ischemia/reperfusion injury in vervet monkeys.

Cytotoxic nitric oxide (NO) is produced during ischemia/reperfusion (I/R) injury by the expression of inducible NO synthase (iNOS). Therefore, continuous iNOS inhibition might prevent early graft dysfunction. FR260330, a potent and selective inhibitor of iNOS activity, impedes the dimmerization of iNOS monomer.

Renal cell carcinoma in kidney allografts: a case series from a single center.

In kidney transplant recipients, renal cell carcinoma (RCC) occurs either in the native kidney or, less frequently, in the grafted kidney. Here, we report a series of rare cases involving 5 patients from a single center who developed RCC in their grafts. The diagnosis was made serendipitously by ultrasound.

Baohuoside-1 inhibits activated T cell proliferation at G(1)-S phase transition.

Background: The effect of baohuoside-1 (B1), a novel flavonoid, on cell proliferation and the cell cycle was evaluated in this study.

Methods: The antiproliferative properties of B1 were evaluated by proliferation assay. Western blotting and flow cytometric analysis were employed to investigate the expression of cyclins and cyclin-dependent kinase proteins.

Effect of a novel inducible nitric oxide synthase inhibitor in prevention of rat chronic aortic rejections.

Background: Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization.

Immunological evaluation of combination therapy with tacrolimus and sirolimus on long-term allograft survival in nonhuman primates.

Unlabelled: We reported that a 60-day course of combination therapy with tacrolimus and sirolimus induced long-term survival of renal allograft after withdrawal of immunosuppressants in Vervet monkeys. In the present study, the mechanism of drug-induced allograft survival was evaluated via Th1/Th2 cytokines, apoptosis and MLC activity in primates.

Materials And Methods: Cytokines were evaluated by ELISA.

Baohuoside-1, a novel immunosuppressive molecule, inhibits lymphocyte activation in vitro and in vivo.

Background: We evaluated the in vitro and in vivo immunosuppressive effects of baohuoside-1 (B1), a novel flavonoid isolated from Epimedium davidii.

Methods: Proliferation assay was used to determine the antiproliferative properties on T-cell and B-cell proliferation. Flow cytometry analysis was applied to detect changes of phenotypes on activated cells.

Total cholesterol correlates with cyclosporine C2 levels in kidney transplant recipients under maintenance immunosuppression.

The aim of this study was to assess the relationship between cyclosporine (CyA) trough level (C0) and 2-hour postdose (C2) and total cholesterol (TC) in kidney transplant (KT) recipients on Neoral maintenance immunosuppression. In KT recipients who had more than 5 years of follow-up, stable graft function, and stable Neoral dose, we measured C2 and C0 blood levels, serum creatinine, mean total cholesterol (TC) over the last 5 years, prednisone dose, use of beta-blockers and thiazides. Correlations between C0 and C2 levels and TC were performed with the Pearson coefficient.

Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal.

Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n = 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group).