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Masafumi Takahashi

Publications and source records attributed to Masafumi Takahashi.

At least 19 recordsLinked to original sources
PubMed2006

M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1-CXCR4 system.

OBJECTIVE: Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF [500 microg/(kg x day)] or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation. CONCLUSIONS: These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.

Animals↗
PubMed2006

Use of sphingosine-1-phosphate 1 receptor agonist, KRP-203, in combination with a subtherapeutic dose of cyclosporine A for rat renal transplantation.

BACKGROUND: We demonstrate the long-term effectiveness of KRP-203 treatment in combination with a subtherapeutic dose of cyclosporine A (CsA) on rat renal allografts. METHODS: We tested the effect of KRP-203 in combination with CsA using a rat skin allograft model. The Pharmacokinetic interaction between CsA and KRP-203 was evaluated. The selectivity of KRP-203 for sphingosine-1-phosphate (S1P)1 and S1P3 receptors were investigated in vitro. Heart rate alteration following bolus injection of phosphorylated KRP-203 (KRP-203-P) or FTY720 (FTY720-P) was also monitored in rats. Finally, the long-term effectiveness of KRP-203 in conjunction with a low dose of CsA was investigated in a rat renal transplantation model. RESULTS: Administration of KRP-203 with CsA prolonged skin allograft survival. KRP-203 and CsA had no effect on the pharmacokinetics of the other. While FTY720-P activated both S1P1 and S1P3 receptors, KRP-203-P selectively activated S1P1, but not the S1P3 receptor (EC50:>1000 nM). Compared to FTY720-P, a tenfold higher dose of KRP-203-P was necessary to induce transient bradycardia. With a low dose of CsA (1 mg/kg/day), KRP-203 (0.3 mg/kg/day) significantly prolonged renal allograft survival (P<0.05, survival time: 9.8 days (CsA) vs. >27.4 days (CsA+KRP)). Although a higher dose of CsA (3 mg/kg/day) alone kept recipients alive, this caused severe renal graft dysfunction. Use of KRP-203 (3 mg/kg/day) in conjunction with CsA markedly improved graft function (P<0.05, creatinine clearance: 0.41+/-0.25 ml/min [CsA] vs. 1.15+/-0.16 ml/min [CsA+KRP]). CONCLUSIONS: The selectivity of KRP-203 for S1P1 reduces the risk of bradycardia, and the combination therapy of KRP-203 with CsA represents a safe and effective strategy for use in renal transplantation.

Animals↗
PubMed2006

Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.

Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI.

Animals↗
PubMed2006

Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

Animals↗
PubMed2006

Change from cyclosporine to combination therapy of mycophenolic acid with the new sphingosine-1-phosphate receptor agonist, KRP-203, prevents host nephrotoxicity and transplant vasculopathy in rats.

BACKGROUND: Replacement of calcineurin inhibitor (CI) with anti-metabolic agents in transplant patients with CI-induced nephrotoxicity is performed clinically and improves renal function, but increases the risk of rejection. We investigated whether the change from cyclosporine (CsA) to a limited dose of mycophenolic acid (MPA) together with a new sphingosine-1-phosphate (S1P) receptor agonist, KRP-203, is sufficient to prevent both transplant vasculopathy and CsA-induced nephrotoxicity. METHODS: Orthotopic aortic transplantation was conducted in a high-responder rat combination of Dark Agouti (DA; major histocompatibility complex [MHC] haplotype RT-1a) to Lewis (RT-1(l)). After CsA administration (15 mg/kg/day) for 2 weeks, the recipients were divided into the following treatment groups for 6 weeks: MPA (10 mg/kg); KRP-203 (KRP; 1 mg/kg); and MPA + KRP. Serum creatinine (Cr), arteriolar hyalinosis and expression of transforming growth factor (TGF)-beta1 in the recipient kidney were examined as parameters indicating nephrotoxicity. Intimal hyperplasia was assessed by vascular occlusion, and graft-infiltrated cells were semi-quantitatively evaluated histologically and then characterized immunohistochemically. RESULTS: Continuous CsA treatment attenuated intimal hyperplasia and cell infiltration (2.9 +/- 0.3% and 0.4 +/- 0.1; p < 0.01 vs vehicle), but increased Cr and hyalinosis (0.43 +/- 0.03 mg/dl and 57.2 +/- 0.4%; p < 0.01) with upregulated TGF-beta1. Replacement of CsA by MPA or KRP treatment alone improved nephrotoxicity, but worsened intimal hyperplasia and cell infiltration. Conversion to MPA + KRP treatment prevented nephrotoxicity (Cr, 0.32 +/- 0.02 mg/dl; hyalinosis, 5.6 +/- 1.3%; p < 0.01 vs CsA) and markedly suppressed intimal hyperplasia and cell infiltration (3.6 +/- 1.2% and 1.0 +/- 0.3; p = not significant vs CsA), with reduced T-cell infiltrates in the graft. CONCLUSIONS: Changing from CsA to a combined therapy of MMF with S1P agonist is a promising strategy in clinical transplantation to overcome CI-induced nephrotoxicity and chronic rejection.

Animals↗
PubMed2006

Sphingosine-1-phosphate receptor agonists suppress concanavalin A-induced hepatic injury in mice.

T cell-mediated immune responses play a critical role in a variety of liver injuries including autoimmune hepatitis. Injection of concanavalin A (Con A) into mice mimics the histological and pathological phenotype of T cell-mediated hepatitis. Recent advances in host immune control of organ transplantation include the development of sphingosine-1-phosphate (S1P) receptor agonists such as FTY720, which alter lymphocyte homing but do not suppress host general immunity. Herein we examined the effect of the new S1P receptor agonist KRP-203 on the Con A-induced liver damage model. In normal liver lymphocytes of BALB/c mice, both FTY720 and KRP203 promoted lymphocyte sequestering from the liver to secondary lymph nodes and significantly reduced the number of liver lymphocytes (p<0.05). Based on this observation, KRP203 was employed in the Con A-induced hepatitis model. KRP203 markedly reduced the number of CD4(+) lymphocytes that infiltrate Con A-treated liver (p<0.05) and successfully reduced serum transaminase elevation (p=0.017), therefore protecting mice from Con A-induced liver injury. Interestingly this homing modulation less occurs in natural hepatic T cell homing through the chemokine receptor, CXCR4. Therefore, S1P receptor agonists preferentially target CXCR4(+)CD4(+) peripheral blood T lymphocytes and suppress the occurrence of Con A-induced hepatitis, suggesting their therapeutic usefulness against T cell-mediated hepatic injury.

Animals↗
PubMed2006

Development of liver regenerative therapy using glycoside-modified bone marrow cells.

Several recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency at which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase efficiently. We tried to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor and desialylated BMCs. Desialylated BMCs were produced with treatment of neuraminidase. Desialylated BMCs that expressed green fluorescent protein (GFP) were injected into Long Evans Cinnamon (LEC) rats, a human Wilson's disease model, intravenously. At 3 and 5 months after transplantation, GFP-expressing hepatocyte nodules appeared in the liver of these BMC-transplanted LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated by the direct accumulation of BMCs and that this strategy is new BMC therapy for liver regeneration.

Animals↗
PubMed2006

Collagen synthesis is required for ascorbic acid-enhanced differentiation of mouse embryonic stem cells into cardiomyocytes.

Ascorbic acid has been reported to promote the differentiation of embryonic stem (ES) cells into cardiomyocytes; however, the specific functions of ascorbic acid have not been defined. A stable form of ascorbic acid, namely, l-ascorbic acid 2-phosphate (A2-P), significantly enhanced cardiac differentiation; this was assessed by spontaneous beating of cardiomyocytes and expression of cardiac-specific markers obtained from mouse ES cells. This effect of ascorbic acid was observed only when A2-P was present during the early phase of differentiation. Treatment with two types of collagen synthesis inhibitors, l-2-azetidine carboxylic acid and cis-4-hydroxy-d-proline, significantly inhibited the A2-P-enhanced cardiac differentiation, whereas treatment with the antioxidant N-acetyl cysteine showed no effect. These findings demonstrated that ascorbic acid enhances differentiation of ES cells into cardiomyocytes through collagen synthesis and suggest its potential in the modification of cardiac differentiation of ES cells.

Animals↗
PubMed2006

Granulocyte colony-stimulating factor (G-CSF) accelerates reendothelialization and reduces neointimal formation after vascular injury in mice.

OBJECTIVE: Neointimal formation following percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since reendothelialization is one of the determinant factors for the development of neointimal formation, we examined the effects of granulocyte colony-stimulating factor (G-CSF) on reendothelialization and neointimal formation after vascular injury in mice. METHODS AND RESULTS: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. G-CSF pretreatment significantly accelerated reendothelialization and decreased neointimal formation following vascular injury; however, this inhibitory effect of G-CSF was diminished when G-CSF was started following the injury. Flow cytometry analysis revealed that G-CSF treatment increased the number of endothelial progenitor cells (EPCs: CD34+/Flk-1+) in the peripheral circulation. Vascular injury was also produced in 2 types of mice whose bone marrow was replaced with that of enhanced green fluorescent protein- and Tie2/LacZ-transgenic mice. In the reendothelialized artery of these mice, few bone marrow-derived EPCs were detected. Furthermore, G-CSF treatment reduced the serum level of interleukin (IL)-6. CONCLUSION: G-CSF treatment accelerated reendothelialization and decreased neointimal formation following vascular injury, although there was little contribution of bone marrow-derived EPCs to the reendothelialization of the artery. These results suggest that G-CSF pretreatment has a therapeutic potential for prevention of restenosis following PCI.

Angioplasty, Balloon, Coronary↗
PubMed2006

Efficacy of mycophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model.

BACKGROUND: To explore a more effective and less toxic immunosuppressive strategy in organ transplantation, we recently developed the novel sphingosine-1-phosphate receptor agonist KRP-203. This study examined the efficacy of KRP-203 combined with mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil, in rat heart allografts. METHODS: Heterotopic heart transplantation was performed in a rat combination of DA (MHC haplotype: RT1(a)) to Lewis (RT1). The recipients were divided into 12 groups (n = 5-7): Syngeneic (Lewis to Lewis), Vehicle, KRP-203 (0.3 and 1 mg/kg), MPA (10 and 20 mg/kg), 10 mg/kg MPA with KRP-203 (0.03, 0.3, 1, and 3 mg/kg), and 20 mg/kg MPA with KRP-203 (0.3 and 1 mg/kg). MPA, KRP-203, and vehicle were given orally. RESULTS: The mean days of survival were 5.8 (vehicle), 7 and 7.9 (0.3 and 1 mg/kg KRP-203, respectively), 12.7 and >54.4 (10 and 20 mg/kg MPA), >39.6 and >30.5 (10 mg/kg MPA with 1 and 3 mg/kg KRP-203), >100 and >87.8 (20 mg/kg MPA with 0.3 and 1 mg/kg KRP-203). Histologic and immunohistochemical analysis revealed that diffuse mononuclear cell infiltration (macrophages and T cells), hemorrhage, myocardial necrosis and fibrosis, and expression of endothelin-1, transforming growth factor-beta1, monocyte chemoattractant protein-1, interleukin-8, and E-selectin were markedly diminished in the allografts treated with MPA combined with KRP-203. Pharmacokinetic experiments indicated no interaction between MPA and KRP-203, and both combination regimens were well tolerated. CONCLUSIONS: Combination therapy of MPA with KRP-203 has a therapeutic potential as a novel immunosuppressant strategy in clinical transplantation.

Animals↗
PubMed2006

A histone deacetylase inhibitor enhances recombinant adeno-associated virus-mediated gene expression in tumor cells.

The transduction of cancer cells using recombinant adeno-associated virus (rAAV) occurs with low efficiency, which limits its utility in cancer gene therapy. We have previously sought to enhance rAAV-mediated transduction of cancer cells by applying DNA-damaging stresses. In this study, we examined the effects of the histone deacetylase inhibitor FR901228 on tumor transduction mediated by rAAV types 2 and 5. FR901228 treatment significantly improved the expression of the transgene in four cancer cell lines. The cell surface levels of alpha v integrin, FGF-R1, and PDGF-R were modestly enhanced by the presence of FR901228. These results suggest that the superior transduction induced by the HDAC inhibitor was due to an enhancement of transgene expression rather than increased viral entry. Furthermore, we characterized the association of the acetylated histone H3 in the episomal AAV vector genome by using the chromatin immunoprecipitation assay. The results suggest that the superior transduction may be related to the proposed histone-associated chromatin form of the rAAV concatemer in transduced cells. In the analysis with subcutaneous tumor models, strong enhancement of the transgene expression as well as therapeutic effect was confirmed in vivo. The use of this HDAC inhibitor may enhance the utility of rAAV-mediated transduction strategies for cancer gene therapy.

Animals↗
PubMed2006

Therapeutic potential of endothelial progenitor cells for cardiovascular diseases.

In the past decade, researchers have defined committed stem or progenitor cells from various tissues, including bone marrow, peripheral blood, brain, liver and reproductive organs, in both adult animals and humans. Recently, endothelial progenitor cells (EPCs) were isolated from peripheral blood mononuclear cells and were shown to be incorporated into foci of neovascularization. This finding that circulating EPCs may home into sites of neovascularization and differentiate into mature endothelial cells in situ is consistent with the concept of 'vasculogenesis' and suggests that vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization. Furthermore, experimental and clinical studies on ischemic cardiovascular diseases suggest a therapeutic potential for EPC transplantation. In this review, we summarize the biological features of EPCs and discuss their therapeutic potential for the treatment of cardiovascular diseases.

Adult↗
PubMed2005

Changes in cardiac lipid metabolism during sepsis: the essential role of very low-density lipoprotein receptors.

OBJECTIVE: Sepsis accompanies myocardial dysfunction and dynamic alterations of cardiac metabolism. We have recently demonstrated that the very low-density lipoprotein receptor (VLDL-R), which is abundantly expressed in the heart, plays a key role in energy metabolism of the fasting heart. However, little is known about the function and regulation of the VLDL-R during sepsis. In the present study, we explored lipid accumulation and VLDL-R expression in the lipopolysaccharide (LPS)-stimulated heart in vivo and regulation of VLDL-R expression in vitro. METHODS AND RESULTS: Electron microscopy and immunohistochemistry demonstrated that LPS significantly decreased both lipid accumulation and VLDL-R expression in the hearts of fasting mice. Treatment with LPS also downregulated VLDL-R in rat neonatal cardiac myocytes, and this downregulation was completely reversed by interleukin (IL)-1beta receptor antagonist. IL-1beta downregulated the expression of VLDL-R in a time- and dose-dependent manner and markedly reduced the uptake of DiI-labeled beta-VLDL but not DiI-labeled low-density lipoprotein (LDL). Use of specific pharmacologic inhibitors and short interference RNA revealed that Hsp90 was required for IL-1beta to downregulate VLDL-R expression. CONCLUSIONS: These findings suggest that IL-1beta is a principle mediator of changes in cardiac lipid and energy metabolism during sepsis through the downregulation of myocardial VLDL-R expression.

Animals↗
PubMed2005

Cre/loxP-mediated CTLA4IgG gene transfer induces clinically relevant immunosuppression via on-off gene recombination in vivo.

OBJECTIVE: Transfer of the CTLA4IgG gene induces long-term and high levels of CTLA4IgG expression, which can result in generalized immunosuppression. In this study, we utilized Cre/loxP-mediated on-off switch recombination to eliminate transgene expression of CTLA4IgG following acceptance of murine cardiac allografts. METHODS: Fully MHC-mismatched hearts from BALB/c donor mice were transplanted into C3H/He recipient mice. Adenovirus-containing CTLA4IgG flanked between two loxP sites was administered via a recipient tail vein immediately after transplantation. Cre-recombinase gene was subsequently transferred at day 30 posttransplantation. RESULTS: Long-term allograft survival was observed in recipients that received the CTLA4IgG gene. Cre-mediated recombination reduced CTLA4IgG gene expression without any adverse effect on the graft survival. Secondary skin grafts of donor type and of third party were promptly rejected in the recipients that accepted cardiac allografts. In addition, the B cell response against ovalbumin was suppressed during high levels of serum CTLA4IgG, but recovered after Cre-mediated inactivation of CTLA4IgG gene. CONCLUSION: CTLA4IgG gene transfer promoted long-term survival of murine cardiac allografts; however, this was not sufficient to induce tolerance. Cre/loxP-mediated on-off switch recombination was useful to inactivate the CTLA4IgG gene so that recipients' immune responses against neoantigens were restored without an influence on the allograft survival. This system may open novel strategies to orchestrate clinically relevant immunosuppression.

Abatacept↗
PubMed2005

Gene transfer to the rat kidney in vivo and ex vivo using an adenovirus vector: factors influencing transgene expression.

BACKGROUND: The characteristics of adenovirus-mediated gene transfer into the kidney are not well examined. We studied the effects of contact time and temperature on adenovirus-mediated transgene expression in rat kidneys, using catheter-based in vivo gene transfer and a rat renal transplant model ex vivo. METHODS: An adenovirus vector containing the luciferase (Ad-Luc) or beta-galactosidase (Ad-LacZ) gene was introduced in vivo into the kidney via a renal artery catheter. Various contact times and temperatures were evaluated. Ex vivo, the renal graft was injected with Ad-Luc through the renal artery, chilled for 60 min and then transplanted. Luciferase expression was evaluated periodically by a non-invasive bioimaging system or histology. Cells expressing the LacZ gene were identified by immunoelectron microscopy. RESULTS: In in vivo gene transfer, successful transgene expression was achieved; however, its efficiency was independent of contact time or temperature. In ex vivo gene transfer, transgene expression in the renal graft peaked early and gradually decreased. Strong gene expression was observed in the recipients' livers. LacZ expression was detected in fibroblasts, parietal epithelial cells of Bowman's capsule, mesangial cells, podocytes and tubular cells. CONCLUSIONS: This study generated new information about in vivo and ex vivo gene transfer into the kidney, which would be useful for renal gene therapy.

Adenoviridae↗
PubMed2005

Development of new inbred transgenic strains of rats with LacZ or GFP.

The ideal goal of regeneration medicine is to restore form and function to damaged tissues. While stem cell transplantation is considered a promising therapeutic approach, knowing the fate of transplanted cells using appropriate markers is essential. We developed new inbred transgenic rat strains with lacZ and GFP based on the transgenic (Tg) animal technique in rats. These Tg animals expressed most of their marker genes ubiquitously, compared to previous Tg rats. Immunological antigenicity against marker proteins was evaluated using conventional skin grafting, and results suggested lacZ-Tg-derived skin was much less immunogenic than that of GFP-Tg. However, GFP-positive cells from parental transgenic rats were still potential candidates for the study of cellular fate in immune privilege sites, such as the brain. Taking advantage of less immunogenic lacZ, we also examined the role of bone marrow-derived cells (BMDCs) in skin wound healing using an in vivo biological imaging system. Although transplantation of BMDCs enhanced wound healing at the injection site, BMDCs were detected only for a short time, suggesting a transient contribution of autologous BMDC-transplantation in wound healing. Our Tg-rat system may provide great benefits for the elucidation of the cellular process of regenerative medicine, including cell and tissue transplantation.

Animals↗
PubMed2005

KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.

BACKGROUND: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. METHODS AND RESULTS: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. CONCLUSIONS: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.

Animals↗