Mediators of Inflammation

Review Article

Tolerance in Kidney Transplantation: What Is on the B Side?

Table 1

Summary of the recently used Breg induction methods in human in vitro.


	Stimulation	Characterization of induced Breg	Immunosuppressive effect (mechanism of action)	Reference

CD19 positive selection	CpG (10 ug/mL) + CD40L (1 ug/mL) for 24 hours	CD24^hiCD27⁺IL-10⁺	Inhibition of TNF-α production by antigen-specific CD4⁺ T cells and by monocytes Both CD24^hiCD27⁺ B cell and CD24^lowCD27⁻ B cell inhibit TNF-α production by CD4⁺ T cell equally (IL-10 independent pathway)	[15]

CD22 positive selection	CpG (0.5 μM) + BAFF (20 μM) + rHIL-4 (50 U/mL) for 24 hours	IL-10⁺IL-6⁺ Increased expression of TLR9	—	[61]

CD19 negative selection	Anti-IgA+IgG+IgM (6.5 μg/mL) + IL-21 (50 ng/mL) for 16 hours	CD38⁺CD1d⁺IgM⁺CD147⁺IL-10⁺CD25⁺ IDO⁺	Suppression of autologous CD4⁺ T cell proliferation (GzmB mediated)	[36]

CD19 negative selection	CpG (1 µM) + PPD for 48 hours	CD73⁻CD25⁺CD71⁺IL-10⁺ Enriched in: CD5⁺IgM⁺IgD⁻ IL-10⁺CD27⁺ have less CD27 MFI than IL-10⁻CD27⁺	Suppression of autologous PPD-stimulated CD4⁺ T cell proliferation (IL-10 mediated)	[14]

CD19 negative selection	Ultra-CD40L (5% solution) and 200 IU/mL of IL-4 for 5 days	Increased expression levels of CD39 Downregulated CD73	Suppression of autologous CD4⁺ and CD8⁺ T cell proliferation (likely to be partially mediated by ADO and 5′-AMP production by B cell)	[62]

CD19 positive selection	IL-2 (10 ng/mL) + IL-6 (10 ng/mL) + CpG 2006 (1 µg/mL) + IFN-α or IFN-β (1,000 U/mL) for 4 days	CD27^intCD38⁺ plasmablasts from naïve and immature B cells	—	[23]

PBMC or CD43 negative selection	LPS (10 µg/mL) + IL-4 (10 ng/mL) + rHIL-35 single-chain fusion protein (100 ng/mL) for 4 days	IL-10⁺	—	[35]

CD19 positive selection	Irradiated CDw32L expressing anti-CD40 mAb	CD11b⁻CD5⁻CD27⁻IgD⁺CD1d^hiIL-10⁺	Suppression of autologous T cell proliferation and IFN-γ production	[60]

CD19 negative selection	CpG (3 μg/mL) + anti-IgA + IgG + IgM (10 μg/mL) for 48 h	CD11c⁺IL-10⁺ Enriched in CD38⁺CD27⁻ GCs Depleted in CD38⁺CD27⁺ PCs	—	[16]

CD19 negative selection	CpG (10 μg/mL) + rHCD40L for 48 hours	CD5⁺CD27⁺CD138⁺CD38⁺IgD⁻GzmB⁺	Inhibition of proliferation of autologous CD4⁺CD25⁻ T cell (GzmB mediated)	[12]

CD19 negative selection	CpG (0.25 μM) for 4 days	—	Effects on CD4⁺ autologous T cell: Suppression of proliferation and differentiation into Th1 cell Reduction of TNF-α and IFN-γ production Induction of Foxp3⁺CD4⁺ T cell, Tr1 cell, and Th3 cell Upregulation of CTLA-4 (IL-10, TGF-β, IDO, and CTLA-4 mediated)	[37]

CD43 negative selection from tonsils	Adipose tissue derived MSC (ratio B cell : MSC 5 : 1) + anti-IgM (10 μg/mL) + IL-2 (10³ IU) + anti-CD40 agonistic mAb (5 μg/mL) for 10 days	CD19⁺CD27⁻CD38^hiCD24^hiIL10⁺	—	[63]

CD19 positive selection	CD40L (2 mg/mL) + IL-4 (200 IU/mL) for 4 days	CD24^hiCD38^hiCD25⁺CD39^hiCD73^hi	Decrease in CD69 expression and proliferation Increase of IL-6 secretion from autologous T effector CD4⁺(ADO-A2AR mechanism)	[64]

CD19 positive selection from cord blood	Irradiated CD40L transfected L cells + CpG and anti-BCR for 4 days	IL10⁺ found either in CD24^hiCD38^hi or CD24^intCD38^int	Suppression of proliferation of allogeneic CD4⁺ T cell Suppression of secretion of IFN-γ, TNF-α, and IL-2 by allogeneic CD4⁺ T cell	[65]

PBMC	50% conditioned media with APRIL for 3 days + CpG (10 μg/mL) for additional 24 hours	IL-10⁺	Decrease of IFN-γ and TNF-α production from autologous CD4⁺ T cell	[66]

PBMC: peripheral blood mononuclear cells; rH: recombinant human; PPD: purified protein derivative; ADO: adenosine; CTLA-4: Cytotoxic T-Lymphocyte Antigen 4; A2AR: A2A receptor. otherwise indicated, B cells were isolated from PBMC.