Perioperative IL-6 Blockade Promotes Intra-Graft Regulation and Prevents Costimulation-Blockade Resistant Rejection

M. Muckenhuber¹, K. Mengrelis¹, A. M. Weijler¹, V. Kainz¹, R. Steiner¹, H. Regele², T. Wekerle¹

¹Dept. of General Surgery, Div. of Transplantation, Medical University of Vienna, Vienna, Austria, ²Dept. of Pathology, Medical University of Vienna, Vienna, Austria

Meeting: 2022 American Transplant Congress

Abstract number: 486

Keywords: Co-stimulation, Graft-infiltrating lymphocytes, Heart/lung transplantation

Topic: Basic Science » Basic Science » 09 - Signaling and Co-Stimulation

Session Information

Session Name: Antigen Presentation and Costimulation

Session Type: Rapid Fire Oral Abstract

Date: Tuesday, June 7, 2022

Session Time: 3:30pm-5:00pm

Presentation Time: 4:20pm-4:30pm

Location: Hynes Room 309

*Purpose: Our group has recently shown that CTLA4-Ig monotherapy leads to limited murine heart allograft survival associated with decreased Treg frequencies and early acute T-cell mediated rejections. Herein we investigated whether the perioperative blockade of interleukin-6 (IL-6) in combination with ATG overcomes costimulation-blockade resistant rejection.

*Methods: C57BL/6 mice were grafted with a fully mismatched balb/c cardiac allograft under ATG induction (6mg/kg) and CTLA4-Ig maintenance (10mg/kg, day 0, 4, 14, 28, 56, 84) with or without additional perioperative IL-6 blockade (anti-IL-6 mAB; 600µg day -1, 300µg day 3 and 6). Peripheral blood, spleen and graft-infiltrating leukocytes were analyzed using flow cytometry. Heart allograft survival was followed via palpation for 100 days. Histological assessment and serum DSA analysis were performed at the time of rejection or end of follow-up.

*Results: CTLA4-Ig monotherapy prolonged graft survival, but nearly all grafts were rejected by day 45 (MST=36 days). Additional ATG induction extended the median survival time to 80 days. Combined induction therapy with ATG and anti-IL6 under CTLA4-Ig led to long-term (100 days) graft survival in all recipients (ATG+αIL6+CTLA4-Ig: 8/8 vs. ATG+CTLA4-Ig: 4/9; p=0.015) [Fig. 1A]. Perioperative blockade of IL-6 significantly increased Treg frequencies in peripheral blood (day 8, Freq. within CD4; ATG+αIL6+CTLA4-Ig: 12.81 +/- 3.40 % vs. ATG + CTLA4-Ig: 6.98 +/- 1.44 %; p=0.002) and within the cardiac allograft itself (day 14, Freq. within graft infiltrating leukocytes; ATG+αIL6+CTLA4-Ig: 0.75 +/- 0.44 % vs. ATG + CTLA4-Ig: 0.23 +/- 0.16 %; p=0.035) early upon transplantation. Transplants from recipients treated with IL-6 blockade harvested on day 14 showed markedly reduced lymphocyte infiltration in histology and a favorable CD8:Treg ratio [Fig. 1B]. This shift towards Tregs within the graft remained detectable in grafts at the end of the follow up 100 days post transplant [Fig. 1B]. In addition, the short-term IL-6 blockade prevented CD8 memory T-cell formation and reduced DSA development.

*Conclusions: A short-term perioperative blockade of interleukin-6 promotes intra-graft regulation and thereby prevents rejection under costimulation blockade in a murine cardiac transplantation model.

To cite this abstract in AMA style:

Muckenhuber M, Mengrelis K, Weijler AM, Kainz V, Steiner R, Regele H, Wekerle T. Perioperative IL-6 Blockade Promotes Intra-Graft Regulation and Prevents Costimulation-Blockade Resistant Rejection [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/perioperative-il-6-blockade-promotes-intra-graft-regulation-and-prevents-costimulation-blockade-resistant-rejection/. Accessed November 23, 2024.

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