IL-21 receptor antagonist ATR-107: pioneer in decreasing humoral immunity in an allogeneic setting

K. de Leur, F.J.M.F. Dor, M. Dieterich, J.N.M Ijzermans, M.G.H. Betjes, R.W. Hendriks, C.C. Baan

Chair(s): dr. Hennie G. Otten, medisch immunoloog, UMC Utrecht & dr. Laura B. Bungener, medisch immunoloog, UMC Groningen

Thursday 10 march 2016

9:00 - 9:10h at Zaal 1 & 2

Categories: Parallelsessie (basaal)

Parallel session: Parallelsessie VII - Basaal immunologie

Background and aims:
Antibody-mediated rejection is an immunological restriction contributing to high rates of allograft dysfunction. The extent of this humoral immune response is often underestimated. It does not only result in the formation of circulating donor-specific antibodies (DSAs), but also involves interaction between CD4+CXCR5+ T follicular helper (Tfh) cells and CD19+CD27+ memory B cells, leading to immunoglobulin-producing plasmablasts. Within this process, IL-21 acts as primary cytokine. Here, we investigated the effect(s) of the IL-21R antagonist ATR-107 on IL-21/IL-21R controlled phosphorylation of STAT3, and on Tfh-mediated B cell help upon allogeneic stimulation.

Phospho-flow cytometry was used to determine the phosphorylation level of IL-21 stimulated peripheral CD4+ and CD8+ T cells in pre-transplant blood of kidney transplant patients. Mixed lymphocyte reactions (MLRs) were performed with FACS sorted CD4+CXCR5+ Tfh cells and CD19+CD27+ memory B cells stimulated with alloantigen. B cell differentiation and immunoglobulin class switching were analysed by flow cytometry. Both approaches were performed in the presence or absence of ATR-107 (10ug/ml).

ATR-107 inhibited the phosphorylation of STAT3 in a dose-dependent manner in both CD4+ and CD8+ T cells. After MLR, a significant CD27+CD38+ plasmablast population was detected (14.28±3.78%), which was significantly reduced in the presence of ATR-107 (3.14±0.64%, p<0.01). Inhibition of plasmablast differentiation was associated with impaired immunoglobulin class switching measured by decreased proportions of membrane bound IgG on memory B cells (from 13.12±5.07% to 2.23±1.05%, p<0.05).

In conclusion, interrupting the interaction between Tfh and memory B cells via the IL-21/IL-21R pathway may be a promising and novel approach to reduce B cell-mediated alloreactivity in organ transplantation.