Introduction: We previously reported that inhibition of IL-6/IL-6R interactions by an anti-IL6R monoclonal (mMR16-1) attenuates anti-HLA-A2 responses in a mouse model of sensitization. The current study investigated the effect of mMR16-1 on T-cells in this model.
Methods: C57BL/ mice were allosensitized by skin grafts from HLA-A2.1+ mice and then divided into two treatment groups. Isotype controls were intraperitoneally injected with a mouse IgG2a (10mg/kg/day) while IL-6R blockade animals were treated with anti-IL6R mAb (mMR16-1, 30mg/kg/day). Animals were sacrificed at Day 1, 2, 3, and 7 post-transplantation (Ptx) to provide splenic lymphocytes for FACS analysis of T-cell subsets during the development of sensitization.
Results: All allo-sensitized mice had increases in total T-cell populations compared to naÏve animals (33±2.24% in isotype control vs. 20.8 ±0.13% in naive, p=0.016 and 35.67±4.13% in mMr16-1 treated vs. 20.8 ±0.13 in naive, p=0.017). However, no difference was observed in total T-cells between isotype control and mMR16-1-treated animals. Also, no difference existed between the treated and control groups with regard to relative populations of CD4 or CD8 T-cells. As expected, mMR16-1- treated animals had a decrease in membrane-bound IL-6R (mIL-6R) expression by splenocytes as compared to isotype control animals (15% VS.1.95% at Day 1-2; 32% vs. 6.3% at Day 7 Ptx). Especially, mIL-6R expression by CD4+ T-helper cells was significantly suppressed by mMR16-1 as compared to the control (p=0.022 at Day 1-2 and p=0.011 at Day 7). There was also a notably decrease in IL-6R signal transducer subunit gp130 (CD130) expression in the treated animals at Days 1-2 Ptx (30.45 ±2.84% vs. 18.39 ± 4.1%, p=0.03). In addition, a decrease in the subset of CD44+CD62L+CD8 effector/memory T cells (52.33+5.3% vs. 70.35+3.8%, p=0.027) was observed in mMR16-1-treated animals. There was no significant difference found in regulatory T cells (CD4+CD25+Foxp3+) between isotype control and mMR16-1 groups.
Conclusions: Detectable mIL-6R expression by CD4 T-cells was significantly minimized by mMR16-1 treatment, which possibly attenuates the T cell responsiveness through classic IL-6 signaling. Functional assays looking at the impacts of IL-6R antibody on Th1, Th2, Th17 and Treg responses (cytokine production and clonal expansion) would further define the T-cell suppression mechanisms exerted by IL-6R blockade.
To cite this abstract in AMA style:Kim I, Wu G, Chai N, Jordan S, Klein A. Evidence That Anti-Interleukin-6 Receptor Treatment Modulates Splenic T-Cell Subsets during Development of Allosensitization [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/evidence-that-anti-interleukin-6-receptor-treatment-modulates-splenic-t-cell-subsets-during-development-of-allosensitization/. Accessed May 9, 2021.
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