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)-α 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-1β, IL-10, and TNF-α 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≤ 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.