Rapamycin for Immunosuppression in Organ Allografting

Calne, R. Y.; Lim, Susan M. L.; Samaan, A.; Collier, Dean S.; Pollard, S.; White, D J; Thiru, S

doi:10.1016/s0140-6736(89)90417-0

Cited by 334 publications

(153 citation statements)

References 5 publications

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“…Either CyA (5 mg/kg/day) or saline was administered into the recipient rats for 4 wk. Consistent with previous reports (1,(35)(36)(37), administration of CyA paradoxically promoted transplant arteriosclerosis in this rat model (Table I). Preinfection of the graft endothelium with AdenoFasL significantly inhibited the neointima formation at 4 wk.…”

Section: Endothelial Fasl Inhibits Transplant Arteriosclerosissupporting

confidence: 93%

“…4C), nor did it reveal detectable differences in the cellular composition of the graft (data not shown), suggesting that the lesions within the grafted vessels stabilize by 4 wk. Numerous reports suggest that administration of CyA or FK506 alters the pathogenesis of transplant-associated arteriosclerosis in heart (1,(35)(36)(37), kidney (38), and liver (39). Thus, we examined whether endothelial FasL overexpression could inhibit vasculopathy in the immunosuppressed allografts.…”

Section: Endothelial Fasl Inhibits Transplant Arteriosclerosismentioning

confidence: 99%

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Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia

Sata

Luo

Walsh

2001

The Journal of Immunology

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Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of transplant recipients. Chronic graft vasculopathy is believed to result from recipient inflammatory responses, and it is characterized by early mononuclear cell infiltration of the transplanted vessel. Here we show that endothelial cells can be genetically modified to overexpress functional, cell-surface Fas ligand (FasL) by adenovirus-mediated gene transfer without undergoing self-destruction. In a rodent model of transplant graft vasculopathy, endothelial overexpression of FasL attenuated T cell and macrophage infiltration at 1 wk posttransplantation. These vessels also displayed reduced neointima formation at one and 2 mo posttransplantation. These results indicate that inhibition of the early inflammatory response to allografted vessels by endothelial cell-specific overexpression of FasL may have utility in the treatment of transplant arteriosclerosis.

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Section: Endothelial Fasl Inhibits Transplant Arteriosclerosissupporting

confidence: 93%

Section: Endothelial Fasl Inhibits Transplant Arteriosclerosismentioning

confidence: 99%

Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia

Sata

Luo

Walsh

2001

The Journal of Immunology

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“…In sirolimus-treated rats (3 mg/kg), mean survival of heart allografts was prolonged to 24 Ϯ 7.9 days versus 7 Ϯ 0.35 days in untreated controls. These findings later were confirmed, 5 and further studies of rat heart allograft recipients showed not only strong synergism with cyclosporine A, 47 but also with tacrolimus, which was in contrast to previous in vitro studies. In a model to study reversal of ongoing acute rejection, the combination of low-dose tacrolimus and sirolimus showed significantly longer graft survival than for each immunosuppressive agent alone (P Ͻ .05).…”

Section: Preclinical Animal Studiessupporting

confidence: 50%

mTOR inhibitors: An overview

Neuhaus

Klupp

Langrehr

2001

Liver Transplantation

179

142

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“…Rapamycin is well tolerated in humans. 7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma.…”

Section: Introductionmentioning

confidence: 99%

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Teachey

Obzut

Cooperman

et al. 2006

Blood

157

128

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Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheralblood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy. IntroductionWhile children with precursor B-cell acute lymphoblastic leukemia (ALL) are often cured, children with relapsed ALL and adults with ALL usually succumb to their disease with current therapy. Even with aggressive therapy, these patient groups have 5-year diseasefree survival rates of only 28% to 39%. 1 Thus, the development of novel therapeutic agents is crucial.One potential class of novel therapeutics is mTOR inhibitors (MTIs). MTIs are a class of signal transduction inhibitors with anticancer activity that were initially developed as immunosuppressive agents. [2][3][4][5] Rapamycin, a macrocyclic lactone produced by Streptomyces hydroscopicus, 6 was the first MTI to be used in a clinical setting. Rapamycin is well tolerated in humans. 7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, 12-15 but preclinical studies have not previously been performed in primary human ALL.Preclinical testing of chemotherapeutic agents often involves using transformed tumor lines and transgenic mouse models. While these are valuable tools, they may not be representative of human disease. More clinically relevant data may be obtained from systems using primary human ALL cells. Two of these systems, bone marrow stroma-supported culture 16 and xenografting human ALL in nonobese diabetic/severe combined immunodeficient (NOD/ SCID) mice, have recently been developed. 17 Both of these systems allow for direct testing...

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Rapamycin for Immunosuppression in Organ Allografting

Cited by 334 publications

References 5 publications

Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia

Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia

mTOR inhibitors: An overview

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

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