Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients.
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].


CONCLUSIONS
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.
Weimer
Rolf
R
Department of Internal Medicine, University of Giessen, Giessen, Germany. rolf.weimer@innere.med.uni-giessen.de
Mytilineos
Joannis
J
Feustel
Andreas
A
Preiss
Astrid
A
Daniel
Volker
V
Grimm
Helmut
H
Wiesel
Manfred
M
Opelz
Gerhard
G
D000328:Adult; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D016030:Kidney Transplantation / Q000276:immunology* / Q000502:physiology; D008213:Lymphocyte Activation; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D018121:Receptors, Cytokine / Q000235:genetics*; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D016207:Cytokines; D018121:Receptors, Cytokine; D009173:Mycophenolic Acid