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

Figures & data

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 rejection. (B) In the B-cell 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.

Table 1. Summary of B-cell tolerance-promoting strategies/agents.

Target	B-cell tolerance strategy/agent	Mechanism of action	Ref.
Pre-immune alloreactive B cells	Infant transplantation	Persistent presence of alloantigen; tolerance-prone immature B cells	[36,37]
CD152	Alemtuzumab	Depletes T-cells, B cells, NK cells and dendritic cells	[32–35,119–121,127–129]
CD20	Rituximab	Depletes B cells via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or apotosis	[18,116–119,158,162,163,167,169–171,181,182–185,187,191]
BLyS	Anti-BLyS	BLyS antagonist, depletes peripheral B cells via loss of intracellular prosurvival pathways such as NF-κB, Pim2 kinase, Akt/mTOR, antiapoptotic Bcl-2 proteins and protein kinase C-δ	[42,43,63,71,76–80,82,83,85,87,88,91,95,105–107,109,110,112,113,116,118,120–123,142,146]
APRIL, BLyS	Atacicept	APRIL and BLyS antagonist, depletes peripheral B cells and plasma cells	[89,90,143,193,195–199], Refs for BLyS
CD40, CD154	Anti-CD40, anti-CD154	Blocks T–B-cell costimulation response	[26,38,43,51,136,154,155]

APRIL: A proliferation-inducing ligand; BLyS: B-lymphocyte stimulator (i.e., BAFF, B-cell-activating factor of TNF); mTOR: Mammalian target of rapamycin; NK: Natural killer.

Table 2. Potential agents for treating antibody-mediated rejection and/or the presensitized patient.

Therapeutic agent	NK cells	Dendritic cells	T-cells	B cells
				Pro/pre	Immature	Transitional	Follicular	Marginal zone	Memory	Plasma cells
Rituximab	-	-	-	±	+	+	+	±	±	-
Anti-BLyS	-	-	-	-	-	±	+	+	-	-
Atacicept	-	-	-	-	-	±	+	+	±	±
Alemtuzumab	±	±	+	+	+	+	+	+	+	±
Anti-CD22	-	-	-	±	+	+	+	±	±	-
Bortezomib	±	±	±	±	±	±	±	±	±	+

The relative efficacy for neutralizing different-cell types is denoted as +: Effective; -: Not effective; ±: Intermediate.

BLyS: B-lymphocyte stimulator; NK: Natural killer.