Tipping the balance toward transplantation tolerance: in vivo therapy using a mutated IL-2
Geoffrey Camirand, Fadi G. Lakkis
Geoffrey Camirand, Fadi G. Lakkis
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Commentary

Tipping the balance toward transplantation tolerance: in vivo therapy using a mutated IL-2

Abstract

Immune tolerance to allogenic transplanted tissues remains elusive, and therapeutics promoting CD4+FOXP3+ Tregs are required to achieve this ultimate goal. In this issue of the JCI, Efe and colleagues engineered an Fc domain fused to a human mutein IL-2 (mIL-2–Fc) bearing mutations that confer preferential binding to the high-affinity IL-2 receptor expressed on Tregs. In vivo mIL-2–Fc therapy effectively heightened mouse, monkey, and human Treg numbers, promoted tolerance to minor antigen mismatched skin grafts in mice, and synergized with immunosuppressive drugs used in the clinic. These findings warrant clinical trials that assess the efficacy of mIL-2–Fc in transplantation.

Authors

Geoffrey Camirand, Fadi G. Lakkis

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Figure 1

mIL-2–Fc with trimeric IL-2R specificity induces tolerance in low effector T cell contexts.

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mIL-2–Fc with trimeric IL-2R specificity induces tolerance in low effect...
The high-affinity trimeric IL-2R is expressed on Tregs and on recently activated effector T cells among others. mIL-2–Fc with specificity for the trimeric IL-2R, but not the dimeric IL-2R expressed on memory T cells and NK cells, expands Tregs in vivo and induces immunological tolerance to minor antigen-mismatched skin grafts in which low effector T cell levels are present at the time of treatment. In contrast, immunological tolerance with mIL-2–Fc treatment cannot be achieved against major antigen-mismatched skin grafts in which elevated effector T cell levels are present at the time of treatment, despite expansion of Tregs.