Novel immunotherapeutic strategies to target alloantibody-producing B and plasma cells in transplantation.

PURPOSE OF REVIEW: There is an unmet need for immunotherapeutic agents that target humoral alloimmunity in solid organ transplantation. This includes sensitized patients with preformed donor-specific human leucocyte antigen antibodies and patients who develop de-novo donor-specific antibodies, both of which are associated with acute and chronic antibody-mediated rejection and allograft loss. RECENT FINDINGS: In this review, we discuss recent progress in the generation of B-cell and plasma cell-targeted therapeutics, with an emphasis on novel agents. To deplete or inhibit B cells, B-cell-specific mAbs have been developed, including CD20, CD22, CD19 and bi-specific antibodies that target two B-cell antigens. In addition, inhibition of B-cell-activating cytokines, such as B cell-activating factor, may also reduce allo-B-cell activation. Plasma cells remain a difficult therapeutic target, but inhibition of germinal centre responses via costimulatory blockade or IL21 neutralization, induction of plasma cell apoptosis using proteasome inhibitors or disruption of the plasma cell niche are potential avenues being explored. SUMMARY: The ultimate aim of these animal and human studies is to develop agents that efficiently target humoral effectors, whilst sparing B and plasma cells with a regulatory capacity to promote long-term allograft survival, but we remain some distance away from this goal.