The B-cell depleting antibody rituximab is widely used for the treatment of B-cell malignancies and autoimmune disorders. In organ transplantation, it is especially applied to reduce the level of alloantibodies. Substantial evidence indicates that the mechanism of action of rituximab is not confined to reducing antibody production, but also involves other functions of B cells, such as antigen presentation and cytokine production. Rituximab may thereby also affect T-cell activation and differentiation. In a randomized double-blind placebo-controlled study for the prevention of rejection after renal transplantation, we studied the effects of rituximab in combination with standard immunosuppressive therapy on the peripheral T- and B-cell population. Renal transplant patients received immunosuppression consisting of tacrolimus, mycophenolate mofetil, prednisolone, and a single dose of 375 mg/m² rituximab or placebo during transplant surgery. In 20 patients (10 rituximab, 10 placebo) without any rejection or CMV infection, we analyzed the PBMCs by multicolor flow cytometry before transplantation, and at 3, 6, 12, and 24 months after transplantation. A single dose of rituximab resulted in a long lasting B-cell depletion. At 24 months after treatment, the CD19⁺ B-cell counts were still below 20 cells/¯o;l in 88% of the rituximab treated patients, while the median value was 127 (range 50-380) in the placebo group. Interestingly, at 12 months the percentage of CD24⁺⁺CD38⁺⁺ transitional B cells was significantly higher in rituximab-treated patients compared to the placebo group. The expression of Th1- (CXCR3, IFNΓ, TNFΑ), Th2- (CCR4, IL-4), Th17- (CCR6, RORΓt, IL-17), and Treg-associated (CD25, FOXP3) markers in the peripheral T-cell population as well as the numbers of naÏve and memory T cells were not influenced by rituximab treatment. Also, in iliac lymph nodes obtained during surgery from renal transplant patient who had received rituximab 4 weeks earlier in preparation for an ABO-incompatible transplantation, we found no change in the phenotype of T cells as compared to lymph nodes from control patients. In conclusion, although a single dose of rituximab results in a long lasting B-cell depletion in peripheral blood, this is not accompanied by changes in the T-cell compartment.

van den Hoogen, M.: Grant/Research Support, Roche. Hilbrands, L.: Grant/Research Support, Roche.

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