B Tebbe

University of Duisburg-Essen, Essen, North Rhine-Westphalia, Germany

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Publications (4)8.6 Total impact

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    ABSTRACT: Background: Immunosuppressive therapy with mammalian target of rapamycin inhibitors (mTORi) requires maintenance of an effective inhibition of the alloimmune response, whereas reducing drug-related nephrotoxicity. Therapeutic monitoring is based on mTORi trough levels, which do not necessarily reflect biologic effects on the PI3K-Akt-mTOR pathway and hence may often result in under-immunosuppression or over-immunosuppression. Methods: Phosphorylation of p70S6 kinase was studied by phosphoflow cytometry and by Western blot in both peripheral blood monocyte cells and CD3+ T cells of renal transplant recipients (RTX) receiving tacrolimus (n=34) or cyclosporine A (CsA) (n=24) or an mTORi (n=26). 16 healthy age-matched volunteers served as a control group. To clarify whether p70S6K activity is varying among CD4(+) T-cell subsets, cell sorted CD4(+)CD25(hi) regulatory T cells (Tregs) and CD4(+)CD25- T cells were analyzed for p70S6K phosphorylation. Results: Simultaneous analysis of p70S6K phosphorylation by phosphoflow cytometry and Western blot showed high correlation in peripheral blood mononuclear cells of renal transplant patients (r=0.91, P<0.001). Mammalian target of rapamycin inhibition was associated with marked reduction of p70S6K phosphorylation compared to healthy volunteers or RTX patients receiving calcineurin inhibitors (all P<0.001) but did not correlate with mTORi trough levels. Interleukin-2 production in mitogen-stimulated CD3(+) T cells correlated with the degree of p70S6K phosphorylation in everolimus-treated patients. p70S6K phosphorylation in CD4+CD25(hi) Tregs was significantly lower compared to CD4(+)CD25- T cells (n=3). In mTORi treated RTX recipients, p70S6K phosphorylation was selectively reduced in CD4(+)CD25- T cells leaving CD4(+)CD25(hi) Tregs unimpaired. Conclusion: Phosphoflow cytometric quantification of p70S6K phosphorylation may play an adjunct role to pharmacodynamically guide an individualized mTORi therapy. It may have potential to be used in purity testing of Treg suspensions generated for adoptive tolerogenic therapies.
    Transplantation 08/2014; 99(1). DOI:10.1097/TP.0000000000000273 · 3.83 Impact Factor
  • B. Tebbe · B. Wilde ·
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    ABSTRACT: Die Entwicklung der Kalzineurininhibitoren (CNI) hat die moderne Transplantationsmedizin möglich gemacht. Trotz der Effektivität zur Inhibition von Abstoßungsreaktionen sind diese Medikamente weit vom idealen Immunsupressivum entfernt. Der Blutspiegel muss häufig kontrolliert werden, ebenso stellt die Nephrotoxizität ein großes Hindernis bei der weiteren Verbesserung der Langzeitergebnisse nach Nierentransplantation dar [7]. Alternative Wirkstoffe, die ebenso effektiv die Immunreaktion unterdrücken, sind Gegenstand intensiver Forschung. In den letzten Jahren sind spezifische Wirkstoffe verstärkt in den Fokus gerückt, die für die T-Zellaktivierung essenzielle Signalkaskaden hemmen. Im Folgenden soll insbesondere auf Kinaseinhibitoren eingegangen werden, die bereits in klinischen Studien bei Patienten nach Nierentransplantation evaluiert wurden.T-ZellaktivierungEin zentraler Schritt in der Induktion einer suffizienten Immunantwort ist die T-Zellaktivierung (Abb. 1). Über die Inhibition d ...
    Der Nephrologe 01/2014; 10(1):53-55. DOI:10.1007/s11560-014-0918-5
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    ABSTRACT: Peripheral immunoregulation depends on T regulatory cell trafficking into the allograft to modulate the local alloresponse. Little is known about the relevance of trafficking receptors for Tregs after solid organ transplantation in humans. In this study, expression of the peripheral chemokine receptors CXCR3 and CCR5 on CD4⁺ FOXP3⁺ Treg cells was analysed and correlated with allograft function in renal transplant recipients. Flow cytometry analysis of peripheral blood mononuclear cells of 54 renal transplant recipients receiving a calcineurin inhibitor-based immunosuppression was performed for CD4, CD25, FOXP3, CXCR3 and CCR5 within the first 18 months post-transplantation. Correlation analysis of chemokine receptor expression and glomerular filtration rate as calculated by MDRD (eGFR) was performed. Expression of the peripheral homing receptors CXCR3 (r = 0.44, P < 0.05) and CCR5 (r = 0.45, P < 0.05) on FOXP3⁺ Tregs correlated with renal allograft function (eGFR) in patients receiving tacrolimus (n = 28), but not cyclosporine A (CsA) (n = 26). CsA but not tacrolimus reduced surface expression of CXCR3 on FOXP3⁺ Tregs in renal transplant recipients as correlated to trough levels (r = -0.42, P < 0.05). In contrast to CD4⁺ CXCR3⁺ CD25(lo) T cells, flow-sorted CD4⁺ CXCR3⁺ CD25(hi) Tregs isolated from healthy individuals did not produce IFNγ or IL-17 ex vivo and expressed high levels of GARP mRNA both at baseline as well as after TCR activation indicating functional regulatory activity. Expression of the peripheral trafficking receptors CXCR3 and CCR5 on FOXP3⁺ Tregs is associated with renal allograft function. These results suggest that Treg trafficking may also depend on the interaction of CXCR3 or CCR5 and their respective ligands.
    Scandinavian Journal of Immunology 06/2012; 76(3):320-8. DOI:10.1111/j.1365-3083.2012.02732.x · 1.74 Impact Factor
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    A Hoerning · S Köhler · C Jun · J Lu · J Fu · B Tebbe · S Dolff · T Feldkamp · A Kribben · P F Hoyer · O Witzke ·
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    ABSTRACT: The peripheral chemokine receptors chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) have been reported to be associated with allograft rejection. The impact of the expression of immunosuppressive drugs on peripherally circulating CD4(+) T cell subsets after renal transplantation is unknown. Expression of CXCR3 and CCR5 was investigated by flow cytometry in 20 renal allograft recipients participating in a prospective, randomized trial (NCT00514514). Initial immunosuppression consisted of basiliximab, cyclosporin A (CsA), mycophenolate sodium and corticosteroids. After 3 months, patients were treated either with CsA, mycophenolate sodium (MPA) plus corticosteroids (n = 6), CsA and everolimus plus corticosteroids (n =8) or CsA-free (CsA(free)) receiving everolimus, MPA and corticosteroids (n = 6). After initial reduction of CD4(+) forkhead box protein 3 (FoxP3)(+) and CD4(+) CD25(hi) FoxP3(+) regulatory T cells (T(regs)) (P < 0.05; P < 0.01), 3-month post-transplant percentages of T(regs) were reconstituted in CsA(free) and CsA(lo) arms compared to CsA(reg) 12 months post transplant. Expression of CCR5 and CXCR3 on CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells 12 months post transplant was increased in CsA(free) versus CsA(reg). Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) cells between 3 and 12 months correlated negatively with the glomerular filtration rate (GFR) slope/year [modification of diet in renal disease (MDRD); r = -0.59, P < 0.01]. CsA, but not everolimus, inhibits both T(reg) development and expression of CXCR3 and CCR5 on CD4(+) T cell subsets. Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) T cells is associated with early loss in allograft function.
    Clinical & Experimental Immunology 05/2012; 168(2):251-9. DOI:10.1111/j.1365-2249.2012.04571.x · 3.04 Impact Factor