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-γ, macrophage inflammatory protein (MIP)-1β, transforming growth factor-β, and tumor necrosis factor-α. 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-1β, IL-10, interferon-γ, and tumor necrosis factor-α 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-1β (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-1β in co-cultures of B and NK cells. Levels of MIP-1β were higher in patients with a high affinity Fc-receptor compared to those with a lower affinity FcγRIIIa (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-1β. Rituximab-induced MIP-1β secretion depends on the combined presence of B cells and FcR-bearing cells, especially NK cells.