B-cell tolerance in transplantation: is repertoire remodeling the answer?

Abstract

T lymphocytes are the primary targets of immunotherapy in clinical transplantation; however, B lymphocytes and their secreted alloantibodies are also highly detrimental to the allograft. Therefore, the achievement of sustained organ transplant survival will likely require the induction of B-lymphocyte tolerance. During development, acquisition of B-cell tolerance to self-antigens relies on clonal deletion in the early stages of B-cell compartment ontogeny. We contend that this mechanism should be recapitulated in the setting of alloantigens and organ transplantation to eliminate the alloreactive B-cell subset from the recipient. Clinically feasible targets of B-cell-directed immunotherapy, such as CD20 and B-lymphocyte stimulator (BLyS), should drive upcoming clinical trials aimed at remodeling the recipient B-cell repertoire.

Figure 1. The naive pre-immune B-cell subsets with cell surface markers and B-lymphocyte stimulator family cytokine receptors

BCR: B-cell receptor; BR3: B-lymphocyte stimulator receptor 3; TACI: Transmembrane activator 1 and calcium-signaling modulator and cyclophilin ligand-interactor.

Figure 2. 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 B cells. The continued survival of transitional B cells in the periphery is dictated by the availability of B-lymphocyte stimulator (BLyS) and relative BCR tonic signaling. (B) The frequency of developing B-cell survival is depicted here as ontogeny progresses across the BCR and peripheral selection checkpoints. At the BCR checkpoint (red line), only 10% of the immature B cells survive, while at the peripheral B-cell selection checkpoint (green line), approximately 30% of the remaining B cells become mature follicular B cells. BCR: B-cell receptor; BR3: B-lymphocyte stimulator receptor 3; TACI: Transmembrane activator 1 and calcium-signaling modulator and cyclophilin ligand-interactor.

Figure 3. B-lymphocyte stimulator family of cytokines and ligands

(A) Cells producing BLyS and/or APRIL. (B) Relative binding affinities for each receptor–ligand combination are very similar. However, it is important to note that the primary BLyS receptor responsible for regulating pre-immune B-cell homeostasis is BR3. APRIL: A proliferation-inducing ligand; BAFF: B-cell-activating factor; BCMA: B-cell maturation antigen; BLyS: B-lymphocyte stimulator; BR3: B-lymphocyte stimulator receptor 3; TACI: Transmembrane activator 1 and calcium-signaling modulator and cyclophilin ligand-interactor.

Figure 4. Inter-/intra-cellular mechanisms of B-lymphocyte stimulator neutralization and anti-CD20 treatment

(A) BLyS–BR3 binding and tonic BCR signaling promotes B-cell survival, while anti-BLyS treatment favors apoptotic signals. (B) Anti-CD20 (e.g., rituximab) causes B-cell death via three separate mechanisms. (C) Prosurvival signals are upregulated in the setting of downstream cross-talk after BCR crosslinking and BLyS–BR3 binding. ADCC: Antibody-depedent cell-mediated cytotoxicity; BCR: B-cell receptor; BLys: B-lymphocyte stimulator; BR3: B-lymphocyte stimulator receptor 3; CDC: Complement-dependent cytotoxicity; MAC: Membrane-attack complex.

Figure 5. Mainstay immunosuppression versus repertoire remodeling in solid organ transplantation

(A) After standard immunotherapy, the alloreactive B-cell subset persists, producing donor-specific antibodies, and ultimately causing chronic allograft (B) In the B-cell rejection. repertoire remodeling scenario, the alloreactive B-cell subset of the pre-immune B-cell repertoire is eliminated after B-cell depletion therapy. Induction T-cell depletion therapy is also given. Following transplantation, the B-cell repertoire undergoes reconstitution in the presence of alloantigens permitting clonal deletion of the alloreactive subset under B-lymphocyte stimulator-limiting conditions. In the absence of donor-specific B cells, allograft survival may improve.

Figure 6. B-lymphocyte stimulator levels (red) determine peripheral B-cell selection stringency and the number of B cells (blue)

(A) After rituximab induction therapy, B cells are depleted and BLyS levels rise, risking the development of alloreactive B cells upon reconstitution. (B) A similar scenario occurs with anti-BLyS induction. (C) Maintenance anti-BLyS following B-cell depletion creates BLyS-limiting conditions that minimize the risk of developing alloreactive B cells and antibody-mediated rejection.

Figure 7. Antigen-experienced B-cell subsets with cell surface markers and B-lymphocyte stimulator family cytokine receptors

BCMA: B-cell maturation antigen; BLyS: B-lymphocyte stimulator; BR3: B-lymphocyte stimulator receptor 3; GC: Germinal center; TACI: Transmembrane activator 1 and calcium-signaling modulator and cyclophilin ligand-interactor.