Cytokine Release After Treatment With Rituximab in Renal Transplant Recipients

BACKGROUND: Treatment with rituximab may be accompanied by a systemic cytokine release. We studied the effects of a single dose of rituximab on cytokine levels in transplant patients and examined the underlying mechanism. METHODS: Twenty renal transplant recipients (10 rituximab-treated, 10 placebo-treated) were recruited from a randomized clinical trial. Rituximab or placebo was infused during surgery, and blood samples were taken before, during, and after surgery and analyzed for interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12, IL-17, interferon-gamma, macrophage inflammatory protein (MIP)-1beta, transforming growth factor-beta, and tumor necrosis factor-alpha. in vitro, healthy donor peripheral blood mononuclear cells, purified B cells, monocytes, natural killer (NK) cells, or combinations thereof were incubated with rituximab, rituximab-F(ab')2, or medium and MIP-1beta, IL-10, interferon-gamma, and tumor necrosis factor-alpha levels were measured in the supernatant. RESULTS: Rituximab-treated patients had higher serum levels of IL-10 (101 +/- 35 pg/mL vs 41 +/- 9 pg/mL; P < 0.01) and MIP-1beta (950 +/- 418 pg/mL vs 125 +/- 32 pg/mL; P < 0.001) compared to placebo-treated patients at 2 hours after start of infusion. There was no difference in the level of other cytokines. In vitro, the addition of rituximab, but not rituximab-F(ab')2 fragments, only led to significantly increased levels of MIP-1beta in co-cultures of B and NK cells. Levels of MIP-1beta were higher in patients with a high affinity Fc-receptor compared to those with a lower affinity FcgammaRIIIa (1356 +/- 184 pg/mL vs 679 +/- 273 pg/mL; P < 0.01). CONCLUSIONS: In addition to B-cell depletion, rituximab can modulate the immune response by inducing cytokine secretion, especially IL-10 and MIP-1beta. Rituximab-induced MIP-1beta secretion depends on the combined presence of B cells and FcR-bearing cells, especially NK cells.