A Novel IL-2 Mutein Selectively Expands Regulatory T Cells and Prolongs Skin Graft Survival
1Center for Transplantation Sciences, Massachusetts General Hospital, Charlestown, MA, 2Visterra, Inc., Waltham, MA
Meeting: 2022 American Transplant Congress
Abstract number: 584
Keywords: Graft survival, Immunosuppression, Interleukin-2 receptor, Tolerance
Topic: Basic Science » Basic Science » 10 - Treg/Other Regulatory Cell/Tolerance
Session Information
Session Name: Tregs and Tolerance
Session Type: Rapid Fire Oral Abstract
Date: Tuesday, June 7, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 6:10pm-6:20pm
Location: Hynes Room 304 / 306
*Purpose: Promoting immune regulation through expansion of regulatory T cell (Treg) may allow immunosuppression minimization and improve long-term graft outcomes. Low-dose IL-2 is known to expand Tregs but its short half-life and off-target expansion of NK and CD8 T cells limits its clinical applicability. Here, we show the effects of a novel mutein IL-2 (mIL-2) that has increased Treg selectivity and improved pharmacokinetics through conjugation with an antibody Fc portion.
*Methods: First, we treated mouse splenocytes in vitro with mIL-2, WT Fc-IL-2 or negative control and measured the levels of phosphorylated STAT5 (pSTAT5), a downstream effector of IL-2 receptor in various immune cells. Next, we studied in vivo effects of single-dose and sustained-dose (twice a week for 3 weeks) mIL-2 treatment in B6 mice. Splenocytes from these mice were evaluated for Treg functional markers and cytokine production by flow cytometry. Lastly, we tested mIL-2 in two minor mismatch skin transplant models: male to female B6 and OVA to B6; as well as rechallenged with allo or third-party grafts. Recipients were subcutaneously treated twice a week with 0.5 mg/kg of mIL-2 or control IgG.
*Results: mIL-2 increased levels of pSTAT5 selectively in Tregs in a wide dose range but not in NK or CD8 T cells. In vivo, single dose mIL-2 increased circulating Tregs up to 40% of CD4+ T cells by day 4 with an effect lasting for 7 days. Sustained mIL-2 treatment led to stable expansion of circulating Tregs at 40-50 % without expanding effector cells and a 5.3-fold rise in splenic Tregs (Fig.1A). Regarding functional suppressive markers, mIL-2 increased % of CTLA-4+, TGF-b+, and IL-10+ splenic Tregs at day 4 after single injection (Fig.1B). In male to female skin transplant model, mIL-2 led to a sustained Treg expansion without affecting NK cells (Fig.1C) or CD8 T cells (not shown). It also prolonged median graft survival (MGS) to >185 days vs 34.5 days (p=0.0004) in the control group (Fig.1D). Treatments were stopped, and recipients were challenged with a similar allo-skin or third-party skin (male B6 or OVA B6, respectively). Second male skin grafts survived long-term while third-party grafts rejected early, indicating antigen-specific tolerance (MGS >65 vs 17 days, respectively, p<0.001). Lastly, mIL-2 also prolonged graft survival in OVA to B6 recipient mice (MGS 13 vs >30 days, p=0.01).
*Conclusions: mIL-2 selectively expands Tregs, increases CTLA-4+ Tregs, and prolongs skin graft survival in mice.
To cite this abstract in AMA style:
Efe O, Borges TJ, Gassen RB, Morena L, Jurdi AAl, Lape IT, Bobcock GJ, Madsen JC, Riella LV. A Novel IL-2 Mutein Selectively Expands Regulatory T Cells and Prolongs Skin Graft Survival [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/a-novel-il-2-mutein-selectively-expands-regulatory-t-cells-and-prolongs-skin-graft-survival/. Accessed December 2, 2024.« Back to 2022 American Transplant Congress