Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival

Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody‐mediated ag...

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Published in:	American journal of transplantation Vol. 22; no. 4; pp. 1101 - 1114
Main Authors:	Marfil‐Garza, Braulio A., Pawlick, Rena L., Szeto, Jake, Kroger, Charles, Tahiliani, Vikas, Hefler, Joshua, Dadheech, Nidheesh, Seavey, Mathew M., Wolf, Jeffrey, Jasuja, Rahul R., James Shapiro, A. M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Limited 01-04-2022
Subjects:	Allografts Animals Antibodies basic (laboratory) research / science Blood glucose costimulation molecule specific Diabetes mellitus endocrinology / diabetology experimental Flow cytometry Graft rejection Graft Rejection - etiology Graft Survival immune regulation Immunoglobulin G Immunohistochemistry Immunological tolerance Immunoregulation immunosuppressant ‐ fusion proteins and monoclonal antibodies Immunosuppression immunosuppression / immune modulation Infiltration Islet cells islet transplantation Islets of Langerhans Transplantation Lymphocytes T Male Metastases Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred CBA Monoclonal antibodies Necrosis Pancreas transplants Pancreatic islet transplantation rejection Streptozocin T cell mediated (TCMR) T-Lymphocytes, Regulatory tolerance translational research / science Transplants & implants Tumor necrosis factor Tumor necrosis factor-TNF immunosuppression / immune modulation basic (laboratory) research / science translational research / science endocrinology / diabetology T cell mediated (TCMR) costimulation molecule specific experimental islet transplantation immune regulation immunosuppressant - fusion proteins and monoclonal antibodies rejection tolerance
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Summary:	Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody‐mediated agonistic stimulation of the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) pathway and its potential to prolong graft survival in a mouse model of islet allotransplantation. C57BL/6 male mice were treated with a single dose of TNFRSF25 agonistic antibodies (4C12 or mPTX‐35) or IgG control. Diabetes was induced using streptozotocin. Four days later, flow cytometry was completed to corroborate Treg expansion, and 500 islets (CBA/J male mice) were transplanted. Glycemia was assessed thrice weekly until rejection/endpoint. Early intra‐graft Treg infiltration was assessed 36 h posttransplant. TNFRSF25 antibodies enabled pronounced Treg expansion and treated mice had significantly prolonged graft survival compared with controls (p < .001). Additionally, the degree of Treg expansion significantly correlated with graft survival (p < .001). Immunohistochemistry demonstrated marked Treg infiltration in long‐term surviving grafts; intra‐graft Treg infiltration occurred early posttransplant. In conclusion, a single dose of TNFRSF25 antibodies enabled in vivo Treg expansion, which promotes prolonged graft survival. TNFRSF25‐mediated in vivo Treg expansion could contribute to achieving lasting immunological tolerance in organ transplantation. In a preclinical islet transplantation model, antibody‐mediated agonistic stimulation of the Tumor Necrosis Factor Receptor Superfamily Member 25 induces pronounced in vivo T regulatory cell expansion and promotes prolonged allograft survival.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1600-6135 1600-6143
DOI:	10.1111/ajt.16940