BACKGROUND: It has been suggested that increased monocyte responses might play a role in chronic allograft rejection. METHODS: We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED). RESULTS: Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]. CONCLUSION: Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.
BACKGROUND: It has been suggested that increased monocyte responses might play a role in chronic allograft rejection. METHODS: We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED). RESULTS: Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]. CONCLUSION:Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.
Authors: Benjamin J Kopecky; Christian Frye; Yuriko Terada; Keki R Balsara; Daniel Kreisel; Kory J Lavine Journal: Am J Transplant Date: 2020-01-29 Impact factor: 8.086
Authors: Hsi-Min Hsiao; Ramiro Fernandez; Satona Tanaka; Wenjun Li; Jessica H Spahn; Stephen Chiu; Mahzad Akbarpour; Daniel Ruiz-Perez; Qiang Wu; Cem Turam; Davide Scozzi; Tsuyoshi Takahashi; Hannah P Luehmann; Varun Puri; G R Scott Budinger; Alexander S Krupnick; Alexander V Misharin; Kory J Lavine; Yongjian Liu; Andrew E Gelman; Ankit Bharat; Daniel Kreisel Journal: J Clin Invest Date: 2018-05-21 Impact factor: 14.808
Authors: Darinka Todorova Petrova; Frank Christian Schultze; Gunnar Brandhorst; Klaus-Dieter Luchs; Christof Lenz; Henning Urlaub; Diana Rubel; Oliver Gross; Philip D Walson; Michael Oellerich Journal: Proteome Sci Date: 2014-12-10 Impact factor: 2.480
Authors: Nynke M Kannegieter; Dennis A Hesselink; Marjolein Dieterich; Rens Kraaijeveld; Ajda T Rowshani; Pieter J M Leenen; Carla C Baan Journal: PLoS One Date: 2017-01-25 Impact factor: 3.240
Authors: Thierry P P van den Bosch; Nynke M Kannegieter; Dennis A Hesselink; Carla C Baan; Ajda T Rowshani Journal: Front Immunol Date: 2017-02-16 Impact factor: 7.561