Sirolimus Interferes with the Innate Response to Bacterial Products in Human Whole Blood by Attenuation of IL‐10 Production

Jørgensen, Per; Wang, J. E.; Almlöf, M.; Solberg, Rigmor; Okkenhaug, Cecilie; Scholz, Tim; Thiemermann, Christoph; Foster, Simon J.; Aasen, Ansgar O.

doi:10.1046/j.1365-3083.2001.00862.x

Cited by 37 publications

(25 citation statements)

References 54 publications

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“…The combination of immunosuppressive drugs required for preventing rejection of allogeneic hepatocytes in our studies was similar to that required previously in solid organ allografts, 21 despite the differences in immune responses elicited by solid organ or cell allografts. 22 Although most current immunosuppressive drugs do not specifically target cell subsets regulating the adoptive immune system, 23,24 we found that pharmacological regulation of the innate immune system benefited transplanted cell engraftment. It is noteworthy that the major fraction of transplanted hepatocytes is cleared intravascularly even before cells enter the liver parenchyma.…”

Section: Discussionmentioning

confidence: 80%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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Successful grafting of tissues or cells from mismatched donors requires systemic immunosuppression.It is yet to be determined whether immunosuppressive manipulations perturb transplanted cell engraftment or proliferation. We used syngeneic and allogeneic cell transplantation assays based on F344 recipient rats lacking dipeptidyl peptidase IV enzyme activity to identify transplanted hepatocytes. Immunosuppressive drugs used were tacrolimus (a calcineurin inhibitor) and its synergistic partners, rapamycin (a regulator of the mammalian target of rapamycin [mTOR]) and mycophenolate mofetil (an inosine monophosphate dehydrogenase inhibitor). First, suitable drug doses capable of inducing longterm survival of allografted hepatocytes were identified. In pharmacologically effective doses, rapamycin enhanced cell engraftment by downregulating hepatic expression of selected inflammatory cytokines but profoundly impaired proliferation of transplanted cells, which was necessary for liver repopulation. In contrast, tacrolimus and/or mycophenolate mofetil perturbed neither transplanted cell engraftment nor their proliferation. Therefore, mTOR-dependent extracellular and intracellular mechanisms affected liver replacement with transplanted cells. In conclusion, insights into the biological effects of specific drugs on transplanted cells are critical in identifying suitable immunosuppressive strategies for cell therapy. (HEPATOLOGY 2006;44:410-419.)

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Section: Discussionmentioning

confidence: 80%

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Joseph

Gupta

2006

Hepatology

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“…7B, 7C). Furthermore, in mDCs and monocytes short-term inhibition of mTOR clearly enhances various inflammatory molecules and processes needed for an effective inflammatory and immune response, such as NF-kB, IL-12, CD86, IL-1b, or Ag presentation, whereas it inhibits classical anti-inflammatory molecules like IL-10, PD-L1, or STAT3 (33,34,67) (Fig. 8).…”

Section: Discussionmentioning

confidence: 99%

A Versatile Role of Mammalian Target of Rapamycin in Human Dendritic Cell Function and Differentiation

Haidinger¹,

Poglitsch²,

Geyeregger

et al. 2010

The Journal of Immunology

202

226

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The mammalian target of rapamycin (mTOR) regulates cell growth and survival and exists as rapamycin-sensitive mTOR complex (mTORC) 1 and as rapamycin-insensitive mTORC2. Although mTOR is a well-known regulator of diverse immune cells, its detailed role in human dendritic cell (DC) function and differentiation is only incompletely understood. In this study, we demonstrate divergent roles of mTOR during activation and differentiation of myeloid DCs (mDCs) and monocyte-derived DCs (moDCs). Inhibition of mTORC1 in mDCs activated with TLR-dependent or -independent stimuli increased proinflammatory cytokines and NF-κB, whereas IL-10 and STAT3 were blocked. Rapamycin regulated the costimulatory/surface molecules CD86, programmed death ligand-1, and CD25 on mDCs and significantly increased the T cell allostimulatory potential of mDCs. In contrast, rapamycin suppressed immunostimulatory molecules and the allostimulatory potential of LPS-stimulated moDCs by an inability to augment NF-κB signaling. In differentiating moDCs, the PI3K/Akt-dependent mTOR pathway was constitutively activated by GM-CSF to induce DC differentiation in an mTORC1-dependent manner. Inhibition of mTORC1 or mTORC1/2 during moDC differentiation decreased moDC survival and markedly hampered its immunostimulatory phenotype. Analyzing the fate of DCs in vivo, we found that kidney transplant patients treated with rapamycin displayed an increased immunostimulatory potential of mDCs compared with patients treated with calcineurin inhibitors. Furthermore, rapamycin did not interfere with mDC differentiation in these patients. Collectively, mTOR exerts divergent immunoregulatory functions during DC activation and differentiation depending on the DC type that lead to opposing T cell responses, which might be of clinical importance in transplantation, cancer, and also for novel vaccination strategies.

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“…The rate of overall bacterial infection was significantly higher in everolimus-treated transplant patients than in azathioprine-treated patients (6). Rapamycin has potent antimigratory and antiproliferative effects and is associated with a dysregulation of the innate immune response, including a decrease in interleukin-10 gene transcription (12). Thaunat et al reported two cases of pulmonary infection caused by Mycobacterium xenopi during sirolimus therapy (19).…”

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confidence: 99%

Intrarenal Abscesses Due to Ureaplasma urealyticum in a Transplanted Kidney

Eilers¹,

Moter

Bollmann

et al. 2007

J Clin Microbiol

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A young woman developed multiple abscesses in her transplanted kidney. Amplification of the 16S rRNA gene with subsequent sequencing revealed Ureaplasma urealyticum as the infectious agent. Microbiological diagnosis and sensitivity testing led to therapy with levofloxacin, resulting in rapid recovery of the patient. CASE REPORTA 19-year-old young woman presented with abdominal pain, dysuria, macrohematuria, loss of weight (5 kg during the previous 6 weeks), and general fatigue. She had a history of juvenile nephronophthisis (diagnosed at the age of 9 years), leading to kidney transplantation at the age of 11. Transplant function was excellent, and primary immunosuppression therapy included tacrolimus and prednisolone. The patient was diagnosed with a posttransplant lymphoproliferative disease 6 years later. Histology showed a B-cell lymphoma, and immunosuppression therapy was reduced and switched to sirolimus (5 mg/kg/day) and prednisolone (5 mg/day). The patient also received four doses of rituximab (600 mg each). The posttransplant lymphoproliferative disease regressed rapidly, and the patient had no further evidence of recurrence during 2 years of follow-up. One month prior to presentation, a unilateral ovariectomy was performed because of a bleeding ovarian cyst. The patient had never experienced urinary tract infections.Laboratory investigations showed an elevated serum creatinine level (1.63 mg/dl; previous baseline, 0.8 mg/dl), a slightly elevated C-reactive protein (CRP) level (2.1 mg/dl), and massive leucocyturia (1,000 white blood cells [WBC]/l). The differential WBC analysis showed a shift to the left (rods, 11%; segmented neutrophils, 63%; lymphocytes, 34%; eosinophils, 2%; basophils, 1%), but the total WBC count was not elevated (9.15/nl); the hemoglobin level was 9.0 mg/dl. Immunosuppression therapy at this time consisted of sirolimus (trough level, 17 ng/ml; highly elevated) and prednisolone (5 mg/day).The ultrasound of the kidney transplant showed multiple abscesses (maximal diameter, 0.5 cm) which were diffusely distributed throughout the whole kidney (Fig. 1).With the diagnosis of transplant pyelonephritis with intrarenal bacterial abscess formations, the patient was treated with ampicillin (120 mg/kg/day) and ceftazidime (90 mg/kg/day) for 3 weeks. However, the patient did not respond to this therapy and developed persistent hyperthermia up to 40°C with little response to antipyretics. The CRP level rose to 10 mg/dl, and the intrarenal abscess formations showed an increase in volume up to Ø of 2 cm, while the serum creatinine increased to 2.9 mg/dl; urine output was sufficient at all times. After 10 days of treatment, the general condition of the young woman had not improved, and antibiotic therapy was supplemented with imipenem/cilastin (40 mg/kg/day).Repeated cultures of blood and urine remained sterile with conventional culture methods. Puncture of three abscesses resulted in purulent material. On microbiological examination, cultures for aerobic and anaerobic bacteria, fungi, and mycobacte...

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Sirolimus Interferes with the Innate Response to Bacterial Products in Human Whole Blood by Attenuation of IL‐10 Production

Cited by 37 publications

References 54 publications

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

A Versatile Role of Mammalian Target of Rapamycin in Human Dendritic Cell Function and Differentiation

Intrarenal Abscesses Due to Ureaplasma urealyticum in a Transplanted Kidney

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