Essential role for B cells in transplantation tolerance

Abstract

T lymphocytes are the primary targets of immunotherapy in clinical transplantation. However, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Therefore, the achievement of transplantation tolerance will likely require induction of both T and B cell tolerance to alloantigens. Moreover, human and animal investigations have shown that subsets of B cells, Transitional and Regulatory, are inherently tolerogenic. Developing therapeutic strategies that exploit these populations may be key to achieving transplantation tolerance. In this review we describe the current evidence for the essential role of B cells in transplant tolerance and discuss emerging B cell directed strategies to achieve allograft tolerance.

Fig. 1

B cell development and selection checkpoints. (a) Immature B cells have successfully rearranged their heavy and light chain immunoglobulin genes. During the BCR checkpoint, immature B cells that are engaged by high avidity antigens are induced to die, while those who do not, transit to the periphery and become transitional cells. The continued survival of transitional B cells in the periphery is dictated by the availability of BLyS and relative BCR tonic signaling. In instances when excess BLyS available it has been shown that the frequency of autoreactive cells entering the peripheral pool is increased. (b) The frequency of developing B cell survival is depicted here as development progresses across the BCR and peripheral selection checkpoint.

Fig. 2

Novel approaches to directed plasma cell therapy. As the survival factors required for plasma cell (PC) persistence become known, new and more targeted approaches to elimination of alloantibody secreting cells will become available. Atacicept binds both BLyS and APRIL. PCs are known to rely heavily on APRIL production and there sequestration has been shown to reduce PCs. Mepoluzimab binds IL-5, which is known to be a critical eosinophil survival factor. Eosinophils are known to be one of the major sources of APRIL for PCs and could be a novel target for desensitization. The 26S proteasome inhibitor Bortezomib has been shown to reduce alloantibody and is somewhat selective for PCs. Rank-L has been shown to be a marker of long-lived plasma cells, and its blockade with Denosumab could be an additional target for desensitization.