The Role of Long-Lived Plasma Cells in Antibody-Mediated Rejection of Kidney Transplantation: An Update

Abstract

Background: Antibody-mediated rejection (ABMR) following kidney transplant is closely associated with poor prognosis of the recipients. Long-lived plasma cells (LLPCs) produce alloantibodies as long as life time and play a crucial role in ABMR.

Summary: LLPCs generate from germinal centers and reside in survival niches in the bone marrow as well as the inflamed tissues. They are the main and long-term source of the antibodies. LLPCs mediate ABMR via the generation of preformed antibodies in sensitized patients and de novo antibodies after transplantation. They have been acknowledged as the leading causes of ABMR; however, LLPCs are insensitive to traditional immunosuppressive therapy that removes B cells. Strategies targeting LLPCs, such as antithymocyte globulin, proteasome inhibitors as well as monoclonal antibodies, are promising methods to persistently and thoroughly clear the entire PC pool.

Key message: LLPCs play an important role in ABMR by producing alloantibodies continually, and targeting LLPCs might be a novel and effective approach against ABMR.

Keywords: Antibody-mediated rejection; Immunology; Immunosuppression; Kidney transplantation; Long-lived plasma cells.

Fig. 1

Triggers and routes of B-cell development. Immature B cells derived from LSCs leave the bone marrow and differentiate into mature B1 and B2 cells, then plasma cells are developed via TI and (or) TD mechanisms. The former one is non-BCR or T-cell dependent. However, the TD pathway requires the assistance from activated CD4+ Th cells. First, following an extra-follicular response the SLPCs are generated. Next, some of the SLPCs reenter the B-cell follicle receiving the help of Th cell, forming a GC, and then migrate to the bone marrow becoming LLPCs. LSC, lymphoid stem cells; LLPC, long-lived plasma cell; TI, T cell-independent; TD, T cell-dependent; GC, germinal center; Th, T helper; SLPC; short-lived plasma cell.

Fig. 2

The mechanisms involved in SLPCs to LLPCs. There are primarily 4 mechanisms contributing to LLPCs generation; they are (1) survival niches, that highly regulated by chemokines and adhesion molecules, including CXCRs and CC-chemokine receptors; (2) survival factors, such as IFN-γ and IL-17A; (3) autophagy processes, and the deficiency of autophagy will impair B cell's ability to generate LLPCs; (4) surface molecules modulation, for instance, the suppression of CD19 expression. SLPC; short-lived plasma cell; LLPC, long-lived plasma cell.

Fig. 3

Current and potential therapeutic drugs targeting plasma cells. Current therapeutic approaches mainly target B cells to inhibit the generation of SLPCs, such as CD20 monoclonal antibody. Frequently, the LLPCs are refractory to conventional immunosuppressive drugs, but second generation of PIs, Mas, and microRNAs targeting the survival of LLPCs are promising remedies to deplete LLPCs. ATG, antithymocyte globulin; LLPC, long-lived plasma cell; MA, monoclonal antibodies; PI, proteasome inhibitor.

Fig. 4

Summary of the current and potential treatments against ABMR by targeting LLPC and its survival niches. ATGs may trigger complement-mediated LLPC lysis. PIs induce apoptosis of LLPCs owing to the accumulation of unfolded proteins. CD38 is highly expressed in B-cell ontogeny in both the early and late stages of maturation. CD38 blockade is possible to suppress LLPCs' generation; however, more studies are in demand. Interaction of B-cell maturation antigen with BAFF and APRIL is essential for LLPCS survival; therefore, depleting these proteins may result in LLPCs apoptosis. CXCL12 is vital for LLPCs migration and survival. Blockade of CXCL12 contributes to LLPCs depletion. As miRNA is also crucial for LLPCs survival, silencing some miRNAs (e.g., miRNA-155, miRNA-17-92) may be a promising approach. PI, proteasome inhibitor; BCMA, B-cell maturation antigen; BAFF, B-cell activating factor; ATG, antithymocyte globulin; LLPC, long-lived plasma cell.