IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation
Antibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2...
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2025-07-01
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| author | Konstantinos Mengrelis Mario Wiletel Romy Steiner Anna M. Weijler Laurenz Wolner Valentina Stolz Milos Nikolic Daniel Simon Florian Frommlet Jonathan Sprent Hannes Stockinger Nina Pilat |
| author_facet | Konstantinos Mengrelis Mario Wiletel Romy Steiner Anna M. Weijler Laurenz Wolner Valentina Stolz Milos Nikolic Daniel Simon Florian Frommlet Jonathan Sprent Hannes Stockinger Nina Pilat |
| author_sort | Konstantinos Mengrelis |
| collection | DOAJ |
| description | Antibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2 cplx) leads to the selective expansion of regulatory T cells (Tregs) and the prolonged survival of MHC-mismatched skin allografts. Although the grafts were eventually rejected, mice failed to develop DSAs. Here, we investigated the impact of IL-2 cplx on the humoral response and germinal center (GC) reaction during allograft rejection. IL-2 cplx treatment prevents Bcl-6 upregulation, leading to suppressed development of GC T and B cells. The IL-2 cplx-induced impairment of GC development limits IgG allo-Ab production but allows for IgM synthesis. By employing a hapten–carrier system to investigate affinity maturation, we found that IL-2 cplx induces a distinct shift in specific Ab production favoring low-affinity IgM while simultaneously decreasing IgG responses. These findings illuminate the potential of IL-2 cplx therapy for inducing humoral tolerance, potentially paving the way for refining strategies aimed at preventing and treating ABMR. |
| format | Article |
| id | doaj-art-45669ae98b4f43d9b9dffb9bdc79578a |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-45669ae98b4f43d9b9dffb9bdc79578a2025-08-20T02:45:34ZengMDPI AGCells2073-44092025-07-011414108610.3390/cells14141086IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody FormationKonstantinos Mengrelis0Mario Wiletel1Romy Steiner2Anna M. Weijler3Laurenz Wolner4Valentina Stolz5Milos Nikolic6Daniel Simon7Florian Frommlet8Jonathan Sprent9Hannes Stockinger10Nina Pilat11Department of Cardiac and Thoracic Aortic Surgery, Medical University of Vienna, 1090 Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Cardiac and Thoracic Aortic Surgery, Medical University of Vienna, 1090 Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Vienna, AustriaCenter for Biomedical Research and Translational Surgery, Medical University of Vienna, 1090 Vienna, AustriaDivision of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, 1090 Vienna, AustriaCenter for Medical Statistics, Informatics and Intelligent Systems, Section for Medical Statistics, Medical University of Vienna, 1090 Vienna, AustriaGarvan Institute of Medical Research, Immunology Division, Sydney, NSW 2010, AustraliaCenter for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, Medical University of Vienna, Vienna 1090, AustriaDepartment of Cardiac and Thoracic Aortic Surgery, Medical University of Vienna, 1090 Vienna, AustriaAntibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2 cplx) leads to the selective expansion of regulatory T cells (Tregs) and the prolonged survival of MHC-mismatched skin allografts. Although the grafts were eventually rejected, mice failed to develop DSAs. Here, we investigated the impact of IL-2 cplx on the humoral response and germinal center (GC) reaction during allograft rejection. IL-2 cplx treatment prevents Bcl-6 upregulation, leading to suppressed development of GC T and B cells. The IL-2 cplx-induced impairment of GC development limits IgG allo-Ab production but allows for IgM synthesis. By employing a hapten–carrier system to investigate affinity maturation, we found that IL-2 cplx induces a distinct shift in specific Ab production favoring low-affinity IgM while simultaneously decreasing IgG responses. These findings illuminate the potential of IL-2 cplx therapy for inducing humoral tolerance, potentially paving the way for refining strategies aimed at preventing and treating ABMR.https://www.mdpi.com/2073-4409/14/14/1086transplantationregulatory T cellsgerminal centerdonor-specific antibodieshumoral tolerance |
| spellingShingle | Konstantinos Mengrelis Mario Wiletel Romy Steiner Anna M. Weijler Laurenz Wolner Valentina Stolz Milos Nikolic Daniel Simon Florian Frommlet Jonathan Sprent Hannes Stockinger Nina Pilat IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation Cells transplantation regulatory T cells germinal center donor-specific antibodies humoral tolerance |
| title | IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation |
| title_full | IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation |
| title_fullStr | IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation |
| title_full_unstemmed | IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation |
| title_short | IL-2 Complex Therapy Mitigates Humoral Rejection of Fully Mismatched Skin Allografts by Inhibiting IgG Alloantibody Formation |
| title_sort | il 2 complex therapy mitigates humoral rejection of fully mismatched skin allografts by inhibiting igg alloantibody formation |
| topic | transplantation regulatory T cells germinal center donor-specific antibodies humoral tolerance |
| url | https://www.mdpi.com/2073-4409/14/14/1086 |
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