Mycophenolate mofetil inhibits lymphocyte binding and the upregulation of adhesion molecules in acute rejection of rat kidney allografts

doi:10.1016/S0966-3274(96)80039-6

Transplant Immunology

Volume 4, Issue 1, March 1996, Pages 64-67

https://doi.org/10.1016/S0966-3274(96)80039-6 Get rights and content

Abstract

Mycophenolate mofetil (MMF) interacts with purine metabolism and possibly with the expression of adhesion molecules. In the present study, we analysed the expression of these molecules in transplanted kidney allografts treated with RS LBNF1 kidneys were orthotopically transplanted into Lewis rats and either treated with RS (20 mg/kg/day) or vehicle. Rats were harvested 3, 5 and 7 days following transplantation. For binding studies, fresh-frozen sections of transplanted kidneys were incubated with lymph node lymphocytes (LNL) derived from transplanted rats. Additionally, immunohistology was performed with various monoclonal antibodies. In general, MMF resulted in better preservation of graft structure by 7 days. Cellular infiltration and tubular atrophy were less pronounced. At day 3, macrophages were diminished in MMF-treated animals to a high extent, while the number of T cells was almost identical to that of controls. In addition, the number of cells positive for MHC class II and LFA-1 was reduced in the MMF-treated animals. These findings correlated with the binding results. Three days following engraftment, LNL bound to MMF-treated kidneys to a lesser extent compared to controls. In conclusion, MMF resulted in a markedly reduced leucocytic infiltrate, presumably based on a reduced expression of lymphocytic adhesion molecules and an interaction with macrophages

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Cited by (65)

Mycophenolate mofetil promotes down-regulation of expanded B cells and production of TNF-α in an experimental murine model of colitis
2008, Cytokine
In this study, we used a murine intestinal inflammation model that mimics immunologic characteristics of human Crohn’s disease (CD) to investigate the anti-inflammatory effects of mycophenolate mofetil (MMF) on intestinal injury and tissue inflammation. When these colitic mice were pretreated with MMF, we observed a significant decrease in mortality rates and body weight loss as well as an improvement in both wasting and histopathologic signs of colonic inflammation, relative to untreated colitic mice. To determine the mechanisms of action of MMF, we compared various immunological characteristics of the untreated and MMF-pretreated colitic mice. MMF-pretreated colitic mice showed an 18% decrease in the proportion of CD19⁺ B cells compared with untreated colitic mice 3 days. As a result, MMF pretreatment increases proportion of apoptotic T and B cells, especially CD19⁺ B cells. Also, down-regulation of Th1 cytokines (TNF-α, IFN-γ) and augmentation of CD4⁺CD45RB^low regulatory T (Treg) cells were observed in MMF-pretreated colitic mice compared with untreated colitic mice. Furthermore, mycophenolic acid (MPA) reduced TNF-α-stimulated NF-κB activation in HT-29 colon epithelial cells. Also, MMF-pretreated colitic mice significantly reduced expression of MD-1 compared with untreated colitic mice on B cells and dendritic cells (DCs). These studies show that MMF pretreatment can improve experimental colitis by down-regulation of expanded B cells population through apoptosis and augmentation of Treg cells. Through these mechanisms, MMF might also be an effective agent for the treatment of other diseases characterized by mucosal inflammation.
Chronic allograft nephropathy: The mechanisms and strategies
2007, Hong Kong Journal of Nephrology
Chronic allograft nephropathy (CAN) is the main cause of long-term renal allograft loss. It is an active but slowly progressive injury mainly caused by alloreactivity to the graft, and further deteriorated by non-immunologic nonspecific factors. After an overview of the pathologic characteristics of CAN based on the Banff Working Classification, the underlying mechanisms and therapies are explored in this review, with an emphasis on novel theories and new findings. With regard to the mechanisms, indirect antigen presentation, ICOS-B7h costimulatory pathways, the roles of immune cells, humoral immunity, epithelial–mesenchymal transition and fibrogenesis are paid more attention than non-immunologic factors including calcineurin inhibitor (CNI) nephrotoxicity, ischemia/reperfusion, senescence and other various factors. With regard to therapeutic strategy, we line up the clinical and experimental proceedings based on the mechanisms. Sufficient immunosuppression, CNI sparing, rapamycin conversion, and administration of mycophenolate mofetil have been applied clinically and are discussed. New experimental therapies on deletion of humoral factors, blockade of costimulation pathway, intervention of fibrogenesis, blockade of signal transduction pathway, protection of endothelium and tissues, and induction of accommodation are introduced together with other nonspecific treatments. [Hong Kong J Nephrol 2007;9(2):58–69]
Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats
2006, Biochemical and Biophysical Research Communications
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.
Efficacy of mycophenolic acid combined with KRP-203, a novel immunomodulator, in a rat heart transplantation model
2006, Journal of Heart and Lung Transplantation
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.
Heterotopic heart transplantation was performed in a rat combination of DA (MHC haplotype: RT1^a) to Lewis (RT1^l). 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.
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-β1, 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.
Combination therapy of MPA with KRP-203 has a therapeutic potential as a novel immunosuppressant strategy in clinical transplantation.
The effect of anti-inflammatory properties of mycophenolate mofetil on the development of lung reperfusion injury
2005, Journal of Heart and Lung Transplantation
Lung ischemia–reperfusion injury (LIRI) is associated with an increased incidence of both primary graft failure and obliterative bronchiolitis. The immunosuppressant mycophenolate mofetil (MMF) has recently been shown to attenuate inflammatory injury in acute ischemia–reperfusion models via a mechanism that is presently unclear. These experiments studied the effects of MMF in a warm, in situ LIRI model, focusing on transcriptional regulation of pro-inflammatory mediators.
Left lungs of rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 10 mg/kg of intravenous MMF at 2 hours before ischemia. Left lung injury was quantitated by myeloperoxidase (MPO) content, permeability indices and bronchoalveolar lavage (BAL) inflammatory cell counts. Lungs were analyzed by electrophoretic mobility shift assay (EMSA) for transcription factor transactivation and by enzyme-linked immunoassay for BAL chemokine protein content.
MMF significantly reduced lung vascular permeability indices, MPO content and alveolar leukocyte counts at 4 hours of reperfusion. There was significant attenuation of activator protein 1 (AP-1) and early growth response 1 (EGR-1) transactivation, whereas nuclear factor–κB (NF-κB) was unaffected. Reductions in bronchoalveolar lavage monocyte chemoattractant protein 1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) protein content were found at 4 hours of reperfusion.
MMF limits lung ischemia–reperfusion-induced increases in vascular permeability and inflammatory cell sequestration in lung parenchyma and alveolar spaces. The protection is mediated at the transcriptional level via an attenuation of early EGR-1 and AP-1 transactivation, which was found to be associated with reduced late MCP-1 and CINC protein secretion. The use of MMF in concert with an agent that affects NF-κB activation may provide even further protection against lung reperfusion injury as multiple inflammatory pathways are inhibited.
Mycophenolate mofetil prevents the development of experimental autoimmune myocarditis
2005, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
MMF inhibits purine synthesis in activated lymphocytes, with subsequent inhibition of selective lymphocyte proliferation. As well as inhibiting lymphocyte proliferation, MMF inhibits pro-inflammatory cytokine production [8,9], adhesion molecule expression [10,11], and antibody production [12], suggesting that it has anti-inflammatory properties. In fact, we have recently demonstrated that MMF prevents glomerular macrophage infiltration and crescent formation in a rat model of glomerulonephritis [13].
Experimental autoimmune myocarditis (EAM) is characterized by the appearance of multinucleated giant cells. EAM leads to severe myocardial damage and is a useful model of human giant cell myocarditis. We investigated whether mycophenolate mofetil (MMF), which is a potent immunosuppressant, prevents the development of myocarditis in a rat EAM model, and focused on the role of osteopontin (OPN) in the pathogenesis of this disorder. Adult Lewis rats were immunized with porcine cardiac myosin to establish EAM. The early MMF treatment completely prevented the development of EAM, and the late MMF treatment was also effective even against established EAM. Echocardiogram demonstrated that left ventricular function was also improved by the treatment with MMF. Real-time RT-PCR analysis showed that both early and late MMF treatments significantly inhibited myocarditis-induced OPN mRNA expression in the heart. Immunohistochemistry revealed that OPN expression was prominent in the myocardium on day 14, whereas expression was observed in the infiltrated macrophages on day 21. Mycophenolic acid (MPA) did inhibit agonist-induced OPN expression in cultured cardiomyocytes. These results show the therapeutic potential of MMF for autoimmune myocarditis and provide new insights into the pathogenesis of this disease.

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Mycophenolate mofetil inhibits lymphocyte binding and the upregulation of adhesion molecules in acute rejection of rat kidney allografts

Abstract

Adhesion molecules and transplantation

Ann Surg

The role of leukocyte adhesion molecules in acute transplant rejection

Curr Opin Nephrol Hypertens

Immunosuppressive effects of the morpholinoethyl ester of MMF (RS-61443) in rat and nonhuman primate recipients of heart allografts

Transplant Proc

Placebo-controlled study of mycophenolat mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection

Lancet

The inhibition of nucleic acid synthesis by MMF

Biochem J

RS-61443: a new immunosuppressive agent

Transplant Proc