Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival

Dietlinde Wolf, Taylor H. Schreiber, Panagiotis Tryphonopoulos, Sen Li, Andreas G. Tzakis, Phillip Ruiz, Eckhard R. Podack

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

BACKGROUND: Thymic-derived Foxp3CD4 regulatory T cells (Tregs)-also called natural Tregs-are critical for the induction and maintenance of transplantation tolerance. Using an agonistic tumor necrosis factor-receptor super family (TNFRSF) 25 antibody, clone 4C12, we showed that TNFRSF25 is a powerful regulator of Treg proliferation-mediating expansion of natural Tregs in vivo. In the present study, we investigate the role of Tregs expanded in vivo by TNFRSF25 on cardiac allograft survival in a mouse model of fully major histocompatibility complex-mismatched ectopic heart transplants. METHODS: C57BL/6 mice were treated with 20 μg of TNFRSF25 agonist 4C12 4 days before heterotopic allogeneic heart transplantation. The survival of the graft was monitored daily by abdominal palpation until the cessation of cardiac contraction. The severity of immune rejection was evaluated by histopathology. Infiltration of inflammatory cells and Tregs into the graft were characterized by flow cytometry. The expression of cytokines and other regulatory proteins was measured by quantitative real-time polymerase chain reaction. RESULTS: Treatment with 4C12 resulted in expansion of Tregs to 30%-35% of CD4 cells and was associated with a significant prolongation of median graft survival from 8 days to 17 days (P=0.0049). On day 7 after transplantation, the time point when controls reject the graft, the transplants of 4C12-treated animals beat strongly and showed increased accumulation of Foxp3 Tregs within the graft and decreased infiltration of inflammatory cells. CONCLUSIONS: TNFRSF25 agonists expand Tregs in vivo and delay allograft rejection.

Original languageEnglish
Pages (from-to)569-574
Number of pages6
JournalTransplantation
Volume94
Issue number6
DOIs
StatePublished - Sep 27 2012

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Allografts
Transplants
Graft Survival
Heterotopic Transplantation
Transplantation Tolerance
Tumor Necrosis Factor Receptors
Palpation
Homologous Transplantation
Regulatory T-Lymphocytes
Heart Transplantation
Major Histocompatibility Complex
Inbred C57BL Mouse
Real-Time Polymerase Chain Reaction
Flow Cytometry
Clone Cells
Transplantation
Maintenance
Cytokines
Antibodies
Proteins

Keywords

  • Immune rejection
  • TL1A/TNFSF15
  • TNFRSF25
  • Transplantation tolerance
  • Treg-to-Teff ratio

ASJC Scopus subject areas

  • Transplantation

Cite this

Wolf, D., Schreiber, T. H., Tryphonopoulos, P., Li, S., Tzakis, A. G., Ruiz, P., & Podack, E. R. (2012). Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. Transplantation, 94(6), 569-574. https://doi.org/10.1097/TP.0b013e318264d3ef

Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. / Wolf, Dietlinde; Schreiber, Taylor H.; Tryphonopoulos, Panagiotis; Li, Sen; Tzakis, Andreas G.; Ruiz, Phillip; Podack, Eckhard R.

In: Transplantation, Vol. 94, No. 6, 27.09.2012, p. 569-574.

Research output: Contribution to journalArticle

Wolf, D, Schreiber, TH, Tryphonopoulos, P, Li, S, Tzakis, AG, Ruiz, P & Podack, ER 2012, 'Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival', Transplantation, vol. 94, no. 6, pp. 569-574. https://doi.org/10.1097/TP.0b013e318264d3ef
Wolf, Dietlinde ; Schreiber, Taylor H. ; Tryphonopoulos, Panagiotis ; Li, Sen ; Tzakis, Andreas G. ; Ruiz, Phillip ; Podack, Eckhard R. / Tregs expanded in vivo by TNFRSF25 agonists promote cardiac allograft survival. In: Transplantation. 2012 ; Vol. 94, No. 6. pp. 569-574.
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AU - Ruiz, Phillip

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AB - BACKGROUND: Thymic-derived Foxp3CD4 regulatory T cells (Tregs)-also called natural Tregs-are critical for the induction and maintenance of transplantation tolerance. Using an agonistic tumor necrosis factor-receptor super family (TNFRSF) 25 antibody, clone 4C12, we showed that TNFRSF25 is a powerful regulator of Treg proliferation-mediating expansion of natural Tregs in vivo. In the present study, we investigate the role of Tregs expanded in vivo by TNFRSF25 on cardiac allograft survival in a mouse model of fully major histocompatibility complex-mismatched ectopic heart transplants. METHODS: C57BL/6 mice were treated with 20 μg of TNFRSF25 agonist 4C12 4 days before heterotopic allogeneic heart transplantation. The survival of the graft was monitored daily by abdominal palpation until the cessation of cardiac contraction. The severity of immune rejection was evaluated by histopathology. Infiltration of inflammatory cells and Tregs into the graft were characterized by flow cytometry. The expression of cytokines and other regulatory proteins was measured by quantitative real-time polymerase chain reaction. RESULTS: Treatment with 4C12 resulted in expansion of Tregs to 30%-35% of CD4 cells and was associated with a significant prolongation of median graft survival from 8 days to 17 days (P=0.0049). On day 7 after transplantation, the time point when controls reject the graft, the transplants of 4C12-treated animals beat strongly and showed increased accumulation of Foxp3 Tregs within the graft and decreased infiltration of inflammatory cells. CONCLUSIONS: TNFRSF25 agonists expand Tregs in vivo and delay allograft rejection.

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