Abstract
The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD), includes long-term pharmacological immune suppression, by which unwanted toxic side effects may accompany. Targeted allo-regulatory immunotherapies may serve to replace pan-immunosuppression. Investigations to manipulate regulatory cell populations to orchestrate transplant immune regulation are of value. Previous studies involving in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with the targeting of the IL-2 high-affinity receptor, CD25, with IL-2, resulted in transient but marked (~>30%) Treg expansion in donor mice spleen and lymph node that allowed for sufficient cell numbers for adoptive transfer to recipient mice, mediating suppressive activity with measurable effect. To further delineate the novel in vivo Treg expansion using TL1A-Ig in combination with low-dose IL-2 (IL-2LD) and its impact on the regulation of GVHD, these studies are analyzing alterations of recipient GVHD target organs at the cellular and microbiome level before and early post-transplant. TL1A-Ig+IL-2LD pretreatment induced a Treg expansion, persisting early post-aHSCT, leading to diminished GVHD and improved transplant outcomes. The expansion was accompanied by increased frequency of stable and functionally active Tregs, as evidenced by in vitro assays using cells from primary GVHD target tissues. In contrast to the infusion of donor Treg cells, the strategy developed here resulted in immunosuppressive target tissue environments in the recipient before receiving donor alloreactive T cells and successful preservation of GVL responses. Results of this study should allow for the harnessing of better adaptive cellular immunotherapy designed to manipulate regulatory cellular compartments of the recipient for GVHD, circumventing the need to produce large numbers of ex vivo manipulated Tregs and providing translational approaches to improve aHSCT outcomes.