B-lymphocyte homeostasis and BLyS-directed immunotherapy in transplantation

Abstract

Current strategies for immunotherapy after transplantation are primarily T-lymphocyte directed and effectively abrogate acute rejection. However, the reality of chronic allograft rejection attests to the fact that transplantation tolerance remains an elusive goal. Donor-specific antibodies are considered the primary cause of chronic rejection. When naive, alloreactive B-cells encounter alloantigen and are activated, a resilient "sensitized" state, characterized by the presence of high-affinity antibody, is established. Here, we will delineate findings that support transient B-lymphocyte depletion therapy at the time of transplantation to preempt sensitization by eliminating alloreactive specificities from the recipient B-cell pool (ie, "repertoire remodeling"). Recent advances in our understanding of B-lymphocyte homeostasis provide novel targets for immunomodulation in transplantation. Specifically, the tumor necrosis factor-related cytokine BLyS is the dominant survival factor for "tolerance-susceptible" transitional and "preimmune" mature follicular B-cells. The transitional phenotype is the intermediate through which all newly formed B-cells pass before maturing into the follicular subset, which is responsible for mounting an alloantigen-specific antibody response. Systemic BLyS levels dictate the stringency of negative selection during peripheral B-cell repertoire development. Thus, targeting BLyS will likely provide an opportunity for repertoire-directed therapy to eliminate alloreactive B-cell specificities in transplant recipients, a requirement for the achievement of humoral tolerance and prevention of chronic rejection. In this review, the fundamentals of preimmune B-cell selection, homeostasis, and activation will be described. Furthermore, new and current B-lymphocyte-directed therapy for antibody-mediated rejection and the highly sensitized state will be discussed. Overall, our objective is to propose a rational approach for induction of humoral transplantation tolerance by remodeling the primary B-cell repertoire of the allograft recipient.

Figure 1. Central and Peripheral B Cell Ontogeny and Antigen-Mediated Activation

Hematopoietic stem cells produce Pro-B cells, which upon successful rearrangement of their heavy chain loci undergo a proliferative burst (yellow arrow) to generate Pre-B cells. Upon successful rearrangement of their light chain immunoglobulin loci Pre-B cells become immature (17) B cells. Receptor-specificity based clonal deletion (gray, ruffled cells) commences at the IMM B cell stage in the bone marrow. This central selection occurs in an all-or-none fashion. IMM cells that survive this central tolerance checkpoint (~10%) hematogenously emigrate from the bone marrow to the periphery where they are identifiable as newly emerging/transitional (TR) B cells. TR B cells are subject to a peripheral tolerance checkpoint regulated by the cytokine, BLyS. Following passage through this checkpoint these cells become mature follicular (MA/FO) or marginal zone (MZ) B cells (BLyS-dependent survival, gray) capable of participating T cell independent (TI, purple) or T cell dependent (TD, orange) responses. MZ B cells can also mature directly from bone marrow IMM B cells (dotted green line) and are BLyS-dependent. Short-lived plasma cells are formed following TI responses. The TD response occurs within the confines of the germinal center and is the initiating source of DSA. The germinal center reaction produces somatically hypermutated (SHM), high affinity memory B cells and plasmablasts (PBs). The resulting memory and plasma cells may reside within the periphery or in tertiary lymphoid structures. Ultimately, long-lived plasma cells find robust pro-survival conditions (yellow) within the bone marrow. Abbreviations: HSCs hematopoietic stem cells, IMM immature B cells, TR transitional B cells, MA/FO mature follicular B cells, MZ marginal zone B cells, MA/REC mature recirculating B cells, MEM memory B cells, SLPC short-lived plasma cells, PB plasmablasts, LLPC long-lived plasma cells.

Figure 2. The BLyS Family of Receptors and Ligands

The cells listed along the bottom of the figure produce soluble BLyS and/or APRIL. The B cell receptors listed along the top bind either of the trimeric peptides of BLyS, APRIL, or both. BR3 is the primary receptor for BLyS and governs peripheral B cell tolerance and mature B cell life-span.

Figure 3. The BLyS Dependent Peripheral B Cell Tolerance Checkpoint

The level of soluble BLyS (green) dictates the stringency of peripheral B cell negative selection (orange) at the TR→FO checkpoint. In the presence of high soluble BLyS levels, B cell clones normally subject to deletion (red cells) are permitted to enter the FO B cell pool. On the other hand, under BLyS limited conditions a range of TR B cell clonotypes normally capable of maturing (blue cells) do not survive. Examples of BLyS levels regulating humoral tolerance in the clinical setting are cited to the right.