Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation

Matz, Mareen; Lehnert, Martin; Lorkowski, Christine; Fabritius, Katharina; Unterwalder, Nadine; Doueiri, Salim; Mashreghi, Mir‐Farzin; Neumayer, Hans‐H.; Budde, Klemens

doi:10.1111/j.1432-2277.2012.01537.x

Cited by 32 publications

(25 citation statements)

References 57 publications

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“…71 The fact that mTOR inhibitors are able to prevent the in vitro production of Ig with equal efficiency when human B cells are cultured with preactivated or not preactivated T cells further shows that mTOR inhibitors, in contrast with CNIs, have a direct effect on B cells. 65,72 This concept is also validated by the results of a recent study that compared the effects of CNI and mTOR inhibitors on B cells from healthy volunteers. Only sirolimus was able to inhibit the proliferation of B cells and their differentiation into plasma cells.…”

Section: Mtor Inhibitorssupporting

confidence: 51%

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Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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The negative effect of donor-specific antibodies on the success of solid transplant is now clearly established. However, the lack of effective treatment to prevent the development of antibody-mediated lesions deepens the need for clinicians to focus on primary prevention of de novo humoral allosensitization. Among the factors associated with the risk of developing de novo donor-specific antibodies, therapeutic immunosuppression is the most obvious parameter in which improvement is possible. Beyond compliance and the overall depth of immunosuppression, it is likely that the nature of the drugs is also crucial. Here, we provide an overview of the molecular effect of the various immunosuppressive drugs on B cell biology. Clinical data related to the effect of these drugs on de novo humoral allosensitization are also examined, providing a platform from which clinicians can optimize immunosuppression for prevention of de novo donor-specific antibody generation at the individual level.

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Section: Mtor Inhibitorssupporting

confidence: 51%

“…93 Similar findings have been reported in the T/B coculture model. 65,72 As expected, however, the drug has no effect on terminally differentiated plasma cells, 93 suggesting that it can only prevent (but not cure) AMR.…”

Section: Belataceptmentioning

confidence: 94%

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Thaunat

Koenig

Leibler³

et al. 2016

JASN

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“…A recurrent issue in such a study is the effect of immunosuppressive treatments. Different immunosuppressive drugs are potent inhibitors of human B lymphocyte function and activation . Nevertheless, none of our patients was under these particular drugs and the decreased expression of XBP1 in late differentiated B cells from tolerant recipients was not shared by HV, suggesting that the effect of treatment was not involved in this process.…”

Section: Discussionmentioning

confidence: 79%

Unique B Cell Differentiation Profile in Tolerant Kidney Transplant Patients

Chesneau

Pallier

Braza

et al. 2014

American Journal of Transplantation

125

133

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Operationally tolerant patients (TOL) display a higher number of blood B cells and transcriptional B cell signature. As they rarely develop an allo-immune response, they could display an abnormal B cell differentiation. We used an in vitro culture system to explore T-dependent differentiation of B cells into plasma cells. B cell phenotype, apoptosis, proliferation, cytokine, immunoglobulin production and markers of differentiation were followed in blood of these patients. Tolerant recipients show a higher frequency of CD20 þ CD24 hi CD38 hi transitional and CD20 þ CD38 lo CD24 lo na€ ıve B cells compared to patients with stable graft function, correlating with a decreased frequency of CD20 À CD38 þ CD138 þ differentiated plasma cells, suggestive of abnormal B cell differentiation. B cells from TOL proliferate normally but produce more IL-10. In addition, B cells from tolerant recipients exhibit a defective expression of factors of the end step of differentiation into plasma cells and show a higher propensity for cell death apoptosis compared to patients with stable graft function. This in vitro profile is consistent with down-regulation of B cell differentiation genes and anti-apoptotic B cell genes in these patients in vivo. These data suggest that a balance between B cells producing IL-10 and a deficiency in plasma cells may encourage an environment favorable to the tolerance maintenance.

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“…And there was 31- and 8.8-folds increased risk of developing all- and high-grades pneumonia when compared to controls. Additionally, the mTOR inhibitors were potent immunosuppressants and showed strong effects on the B-cell functions, CD80 and CD86 expression, proliferation, IgG/IgM and cytokine production in a dose-dependent manner [41], [42]. As a result, the use of mTOR inhibitors was associated with increased risk of infection due to immunosuppression.…”

Section: Resultsmentioning

confidence: 99%

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis

Huang

Yao

et al. 2013

PLoS ONE

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BackgroundTwo novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.MethodsWe searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.ResultsA total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3–2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21–8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.ConclusionWith the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.

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Effects of sotrastaurin, mycophenolic acid and everolimus on human B-lymphocyte function and activation

Cited by 32 publications

References 57 publications

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant

Unique B Cell Differentiation Profile in Tolerant Kidney Transplant Patients

Incidence and Risk of Treatment-Related Mortality with mTOR Inhibitors Everolimus and Temsirolimus in Cancer Patients: A Meta-Analysis

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