IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

• Published in: Nature communications 2024-06, Vol.15 (1), p.4309-16
• Main Authors: Muckenhuber, Moritz, Mengrelis, Konstantinos, Weijler, Anna Marianne, Steiner, Romy, Kainz, Verena, Buresch, Marlena, Regele, Heinz, Derdak, Sophia, Kubetz, Anna, Wekerle, Thomas
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 14; 14/19; 38; 38/91; 631/250/1854/2812; 631/250/2520; 64/60; Abatacept - pharmacology; Abatacept - therapeutic use; Allografts; Allografts - immunology; Animals; Antilymphocyte Serum - pharmacology; Antilymphocyte Serum - therapeutic use; CTLA-4 protein; Cytokines; Depletion; Effector cells; Globulins; Graft rejection; Graft Rejection - immunology; Graft Rejection - prevention & control; Graft Survival - drug effects; Graft Survival - immunology; Heart transplantation; Heart Transplantation - adverse effects; Humanities and Social Sciences; Immunoglobulins; Immunoregulation; Immunosuppressive Agents - pharmacology; Inflammation; Interleukin 6; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Rejection; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Thymocytes; Transplantation; Transplants; Transplants & implants
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48574-w

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation. The use of CTLA4-Ig fusion proteins in transplantation remains limited due to co-stimulation blockade-resistant rejection (CBRR). In this study, the authors demonstrate that IL-6 blockade reduces CBRR in murine cardiac transplants in the context of T cell-depleting induction regimens and CTLA4-Ig treatment.