Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion

Abstract

Activation of TNFR2 with a novel agonist expands T reg cells in vivo and protects allo-HCT recipients from acute GvHD while sparing antilymphoma and antiinfectious properties of transplanted donor T cells.

Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis

“…The TNFRII agonist mainly induced expansion of both CD4+ and CD8+ Treg subpopulations, whereas at the single‐cell level, the suppressive potential was not altered. This is consistent with a recent report on TNFRII‐selective expansion of CD4+ Treg cells . Importantly, TNFRII agonist–mediated expansion of Treg cells is not restricted to mouse immune cells, as similar effects were observed for both CD4+ and CD8+ human Treg cells, indicating the translational potential of TNFRII‐induced Treg cell expansion.…”

“…For use in nonhumanized mice, we genetically engineered a mouse TNFRII–specific variant of EHD2‐scTNF R2 (EHD2‐sc‐mTNF R2 ). EHD2‐sc‐mTNF R2 is composed of a covalently stabilized TNFRII‐selective (D221N/A223R) single‐chain mouse TNF (sc‐mTNF R2 ; amino acids 91–235) fused to the EH domain–containing protein 2 (EHD2) dimerization domain derived from the heavy‐chain domain C H 2 of IgE , constituting a disulfide‐bonded dimer that is, with respect to TNFRII interaction sites, a hexavalent molecule (Figure A).…”

IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection

“…Liver pathology in Treg depleted mice correlated with an enhanced CD8 + T cell response but not with virus load. Similar to previous studies, no significant difference of virus titers was observed between Treg depleted and non-depleted mice or mice in which Treg cells were selectively expanded to avoid graft-versus-host disease [16, 39]. We have shown that CD8 + T cells readily accumulate in liver of CMV infected mice and are heavily activated, and that a significant proportion of them express granzyme B and IFNγ.…”

Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

“…Novel targets include kinase inhibitors that block the protein serine/threonine kinase ROCK1 111 , Aurora kinase A 112 , MEK 113 , and others (Supplemental appendix and Figure 3B). Strategies being investigated to improve Treg efficacy by in vivo Treg expansion in mouse models include TNFRSF25 (DR3) stimulation using a fusion protein to ligate the receptor 114 , agonistic DR3 antibody 115 and agonistic TNFR2 antibody 116 .…”