The persistent elimination of B cells responding to blood group A carbohydrates by synthetic group A carbohydrates and B-1 cell differentiation blockade: novel concept in preventing antibody-mediated rejection in ABO-incompatible transplantation

Abstract

We demonstrated a novel strategy for specific and persistent inhibition of antibody (Ab) production against blood group A or B carbohydrate determinants necessary for successful ABO-incompatible transplantation. Similar to human blood group O or B individuals, mice have naturally occurring Abs against human blood group A carbohydrates in their sera. B cells with receptors for A carbohydrates in mice belonging to the CD5+CD11b+B-1a subset have phenotypic properties similar to those of human B cells. These cells could be temporarily eliminated by injecting synthetic A carbohydrates (GalNAcα1–3, Fucα1–2Gal) conjugated to bovine serum albumin (A-BSA) and anti-BSA Abs. In mice that received the injection of A-BSA/anti-BSA Abs, the serum levels of anti-A IgM were reduced, but immunization with human A erythrocytes resulted in increased serum levels of anti-A Abs. When combined with cyclosporin A (CsA) treatment, which blocks B-1a cell differentiation, and treatment with A-BSA/anti-BSA Abs, the serum levels of anti-A Abs were persistently undetectable in the mice even after the immunization. B cells with receptors for A carbohydrates were markedly reduced in these mice. These results are consistent with the hypotheses that treatment with A-BSA/anti-BSA Abs temporarily depletes B cells responding to A determinants, and CsA treatment prevents the replenishment of these cells.

Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation

“…The Tacrolimus/MMF combination is likely to have a continuous suppressive effect on B cell lineage that is capable of producing antiblood type antibodies . Irei, et al .…”

ABO, alemtuzumab and allogeneic transplantation

“…In mice, circulating A-antigen/antibody complexes lead to a specific deletion of B splenocytes secreting anti-A. 19 Indirect evidence for a similar process in humans can be observed in a humanized NOD/SCID/γc null mouse model. Resnik et al 3 Ozkurt et al 4 Blin et al 5 Kimura et al 6 Seebach et al 7 Stussi et al 8 Mielcarek et al A neglected area of study is the role of blood group genetics on transplant outcomes, which may account for some of the differences between published studies.…”

Blockade of invariant TCR-CD1d interaction specifically inhibits antibody production against blood group A carbohydrates

“…13,14 Extensive anti-A IgM and IgG production occurred when the mice were immunized with human group A-RBCs. To determine whether or not anti-A Ab responses were T-cell dependent, we immunized Balb/c nude mice and B6 C2D mice, both of which lack CD4 1 T cells, using human group A-RBCs 2 times per week.…”

“…13,14 The serum antigroup A Ab levels in the mice significantly increased through activation of these B-1a cells, which bear receptors for A determinants following their immunization with human group A red blood cells (RBCs). Further, we used a similar technique and demonstrated that sIgM 1 CD11b 1 CD5 -B-1b cells with receptors for Gala1-3Galb1-4GlcNAc (Gal) epitopes, which are major xenogeneic Ags, were present in a1,3-galactosyltransferasedeficient (GalT…”