Treatment of antibody-mediated rejection (AMR) in renal transplant (Tx) patients (pts) is still challenging and long-term outcomes remain poor. Because plasma cells (PCs) are crucial for donor specific HLA antibody (DSA) formation, targeting this cell population with proteasome inhibitor bortezomib (BZ) is quiet reasonable. Thus, combination with the B-cell depletion agent rituximab displays a synergistic approach to affect both precursor and mature DSA producing PCs.

The aim of this study was to investigate the efficacy of a combined AMR therapy including rituximab and BZ on peripheral blood B-cells and PCs in a prospective manner over 6 months. Influence on protective vaccination titers was reviewed in this context.

AMR therapy was introduced in 9 Tx pts (men: 6; mean age: 42y) with graft dysfunction, DSA and biopsy proven AMR according to BANFF classification. Therapy included steroid pulse, Plasmapheresis (6x), 1 cycle of BZ (1.3 mg/m2 per body surface; day 1, 4, 8, 11), 500mg rituximab and IVIG (1.5g/kg bodyweight). PBMC were analyzed by flow cytometry for anti-CD3, -19, -20, -27, -38, -4, -25 and FOXP3 at baseline (BL), months (M) 1, 3 and 6. Serum IgG titers specific for mumps, measles and rubella (MMR) were measured by ELISA.

1M after treatment CD19dimCD27highCD20neg PCs count were significantly lower compared to BL (mean: 0.21±0.1/¯o;l vs. 1.3±0.3/¯o;l; p=0.002) respectively. Treatment effects on PCs were evident at 3M (0.09±0.03/¯o;l) and 6M (0.23±0.07/¯o;l). Similarly, we observed a significant depletion of CD19B-cells 1M after therapy (BL: 531±145/¯o;l vs. 2.3±0.6/¯o;l at M1; p<0.001). Even after 6M, CD19B-cells did not recover (M6: 4.0±1.1/¯o;l; p<0.001 vs. BL). Frequencies of regulatory T-cells were not affected significantly due to therapy. All pts had protective antibodies against MMR that were not significantly changed due to therapy (Mumps: BL=2541 vs M6=2530 IU/ml).

The present study observed a profound and sustained reduction of peripheral PCs and B-cells after 1 cycle of BZ and rituximab in pts with AMR. Interestingly, beside PC reduction in the periphery, protective MMR titers were not affected. Thus, the effect of BZ on tissue-based long lived PCs may be limited. Longer follow-up is necessary to thoroughly investigate the re-population of distinct B-cell and PC cell subsets. This may help to better understand the effects of AMR therapy.

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