We examined the effect of APRIL/BLyS blockade on B cell lineages & donor specific antibody (DSA) in preclinical rodent model as a novel desensitization strategy. Limited success in desensitization protocols require new ideas to transplant patients with high cPRA. APRIL and BLyS are critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody production.

Lewis rats were sensitized by i.v. injection of 0.5 ml heparinized Brown Norway (BN) blood. 21 days after sensitization, rats were treated with 250 mg of TACI-Ig administered 3x/week for 21 days. B cell subset analysis by flow cytometry and flow cross match (FXM) were performed to assess the effect of APRIL/BLyS inhibition. The three groups are baseline, transfusion (Tn) and transfusion with 21d TACI Ig (Tn + TACI Ig).

In animals that were sensitized and treated with TACI-Ig, we observed a significant reduction in Marginal Zone B cells in the spleen (p<0.01) , bone marrow (BM, p<0.002), lymph nodes (LN, p<0.003) and PBMC (p<0.003), as well as significant reductions in Transitional cells in BM (p<0.002), LN (p<0.003) and PBMC (p<0.003). We also observed a significant reduction in Plasma Cells in both spleen (p<0.005) and BM (p<0.04). All sensitized animals had significantly elevated DSA for all isotypes. However, the only isotype that was reduced by TACI-Ig treatment was IgG2a (p<0.004).

In Lewis rats, TACI Ig was able to reduce many B cell subsets, including plasma cells. Only IgG2a isotype DSA were reduced by the TACI Ig treatment. The TACI used in the construct for the drug was optimized for mouse sequence, not rat sequence. Even though the mouse and rat proteins are related, evidently there are sufficient differences to result in reduced effect on DSA desensitization.

CITATION INFORMATION: Wilson N., Verhoven B., Boldt B., Bath N., Ding X., Redfield III R. TACI-Ig as a Desensitization Agent in a Rat Model of Antibody Mediated Rejection Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress