Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues, ameliorating GVHD post-HSCT Available to Purchase

• TL1A-Ig+IL-2LD pre-HSCT induces Treg expansion persisting early post-HSCT diminishing GVHD, improving outcomes and maintaining GVL.

• TL1A-Ig+IL-2LD pre-treatment increases the frequency of tissue resident, functionally active Tregs in GVHD target tissues.

The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the TNF superfamily receptor TNFRSF25 and the high affinity IL-2 receptor with a TL1A-Ig fusion protein and low dose IL-2, respectively was used to pre-treat recipient mice prior to allogeneic-HSCT (aHSCT). Pre-treatment induced Treg expansion persisting 1-2 weeks post-HSCT leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in the frequency of stable and active Tregs creating a suppressive tissue environment in the colon, liver and eye. Importantly, pre-treatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria outgrowth and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, it was found that the increased tissue Treg frequency included resident CD69+CD103+FoxP3+ hepatic Tregs. In contrast to infusion of donor Treg cells, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient prior to the receipt of donor allo-reactive T cells and successful perseveration of GVL responses. We posit strategies that circumvent the need of producing large numbers of Tregs ex-vivo through manipulating this recipient compartment in vivo, can provide translational approaches to improve aHSCT outcomes.