The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and has important roles in the activation of effector T cells and the function and proliferation of regulatory T cells. In this Review, we discuss our current understanding of the mTOR pathway and the consequences of mTOR inhibition, both in DCs and T cells, including new data on the regulation of forkhead box P3 expression.

/pdf/immunoregulatory-functions-of-mtor-inhibition-4tquguj4do.pdf

Immunoregulatory functions of mTOR inhibition

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.

/pdf/murine-models-of-systemic-lupus-erythematosus-2yz4mrsgfq.pdf

Murine Models of Systemic Lupus Erythematosus

The therapeutic, clinical and economic success of Continuous Ambulatory Peritoneal Dialysis (CAPD) has spawned an entirely new industry. Peritoneal dialysis is now offered in most chronic dialysis programs throughout the world [1]. In many countries where dialysis in performed, a substantial minority and in many cases a majority of patients undergo chronic support of their end stage renal disease with this modality (Fig. 1). Many national and international symposia are dedicated to the research projects associated with this broad, expanding therapeutic system [2–6]. Technological and product developments have created a new industry to manufacture and distribute the materials required to safely deliver CAPD. In the past decade, a new society, (International Society for Peritoneal Dialysis), dedicated to the study of peritoneal dialysis has been organized and a new international journal, (Peritoneal Dialysis International), has been developed for the dissemination of scientific information.

Continuous ambulatory peritoneal dialysis

Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the care of patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases. The activity of various metabolic pathways can influence the function and differentiation of T cells. T cell metabolism is dysfunctional in systemic lupus erythematosus (SLE) and targeting metabolic pathways in SLE could be a promising therapeutic avenue.

T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy.

Background Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice. Methods Six-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies. Results Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES. Conclusions We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.

/pdf/rapamycin-attenuates-the-severity-of-established-nephritis-4pgoblnye1.pdf

Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice.

Rapamycin is a potent immunosuppressive drug currently used mainly for rejection prophylaxis in renal transplantation The aim of this study was to determine the effect of rapamycin treatment on the development of nephritis in lupus-prone New Zealand Black/White F1 (NZB/W F1) mice Twelve-week-old female NZB/W F1 mice were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 20 weeks The severity of nephritis was assessed by clinical and biochemical parameters, renal histology, immunohistochemistry and gene expression studies Rapamycin treatment markedly reduced proteinuria, improved renal function, decreased serum anti-double stranded DNA antibody levels and diminished splenomegaly Kidney sections from saline-treated mice showed marked mesangial proliferation, tubular dilation with protein cast deposition and interstitial inflammatory cell infiltration Rapamycin-treated mice had near normal renal histology, with marked reduction in glomerular immune deposition and the infiltration by T cells, B cells and macrophages Rapamycin treatment was associated with down-regulation of intra-renal expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein We conclude that rapamycin is highly effective in preventing the development of nephritis in NZB/W F1 mice The beneficial effects of rapamycin are mediated through inhibition of lymphoproliferation and reduced MCP-1 expression

Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice.

The aim of this study was to determine the effect of rapamycin on renal ischemia-reperfusion injury (IRI) in mice. Renal IRI was induced in male BALB/c mice by clamping both renal pedicles for 45 min. The mice were treated with either vehicle or rapamycin (2 mg/kg/day) by oral gavage, starting 1 day before the IRI and continued daily till killing. The mice were killed on days 1, 3 and 7 after the operation. The severity of the renal IRI was assessed by serum creatinine levels and renal histology. Proliferation of renal tubular cells was quantified by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). One day after the IRI, the serum creatinine levels of rapamycin-treated mice were significantly higher than those of the vehicle-treated mice. Kidney sections from rapamycin-treated mice showed more marked tubular damage and significantly lower number of PCNA-positive cells. The number of PCNA-positive cells in the rapamycin-treated mice remained significantly lower on day 3 after the IRI. By day 7 after the IRI, the serum creatinine levels, renal histology and positive PCNA staining in the kidney sections became similar between the two treatment groups. We conclude that in this murine model of renal IRI, rapamycin treatment aggravates renal IRI during the first 3 days after the insult. This effect might be mediated, at least partly, through inhibition of renal tubular cell proliferation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-2277.2006.00361.x

Effect of rapamycin on renal ischemia-reperfusion injury in mice.

Background: Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive g

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Introduction Peritoneal dialysis (PD) is recognized as an effective treatment for patients with end-stage renal failure. Conventional PD solutions are unphysiological, as they contain bio-incompatible concentrations of glucose to provide the osmotic drive (Popovich et al. 1978) Thus, with increasing duration on PD, the peritoneum undergoes progressive structural and functional deterioration. Diabetiform alterations of the peritoneum, for example, the reduplication of the basement membrane, and increased matrix accumulation and deposition within the submesothelium are commonly observed in PD patients. These changes are mediated in part through activation of PKC and induction of TGF-β1 (Ha et al. 2001). Emodin (3-methyl-1,6,8 trihydroxyanthraquinone) has previously been demonstrated to reduce cell proliferation and fibronectin synthesis in cultured mesangial cells (Kuo et al. 2001; Yao et al. 1994). How emodin modulates glucose-induced fibronectin synthesis in human peritoneal mesothelial cells (HPMCs) has not been elucidated and thus constitutes the aim of this study.



Materials and methods  Confluent growth-arrested HPMCs were cultured under physiological (5 mm) or elevated (30 mm) d-glucose concentrations in the presence or absence of emodin (20 µg/ml) for periods up to 72 h. PKC-α activation in HPMCs cultured under control and experimental conditions was determined by Western blot analysis of cytosolic and cell membrane extracts. Synthesis of fibronectin and TGF-β1 was investigated by a combination of ELISAs, immunohistochemistry and Western blot analysis. Mannitol was used as the hexose control.



Results  Exposure of HPMCs to 30 mm d-glucose resulted in the activation of PKC-α commencing 12 h after stimulation, as demonstrated by the translocation of PKC-α from the cytosol to the cell membrane. Maximum induction of PKC-α was observed 48 h after stimulation and increased 1.4-fold and 3.7-fold in the cytosolic and membrane fractions, respectively, compared to 5 mm d-glucose. Activation of PKC-α was accompanied by the induction of TGF-β1 secretion in a time-dependent manner (3.72 ± 0.29 and 4.30 ± 0.50 pg/µg cellular protein at 24 h and 48 h, respectively, for 30 mm d-glucose compared to 2.13 ± 0.23 and 2.65 ± 0.32 pg/µg cellular protein at 24 h and 48 h, respectively, for 5 mm d-glucose, P < 0.001 at both time points) and increased fibronectin synthesis. Whilst emodin had no effect on constitutive PKC-α, TGF-β1 or fibronectin synthesis, emodin abrogated elevated glucose stimulation of PKC-α, and decreased TGF-β1 secretion and fibronectin synthesis to basal levels.



Discussion  Our findings demonstrate that emodin can ameliorate the undesirable effects of concentrated glucose on HPMCs through the suppression of PKC-α activation. This study suggests that emodin may have therapeutic potential in the prevention or treatment of glucose-induced structural and functional abnormalities in the peritoneal membrane.

Emodin ameliorates glucose‐induced fibronectin synthesis in human peritoneal mesothelial cells by inhibiting PKC‐α activation

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