Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival

Xiaojie Wang, Jianqiang Hao, Daniel L. Metzger, Alice Mui, I. Fang Lee, Noushin Akhoundsadegh, C. Lieping Chen, Dawei Ou, Ziliang Ao, C. Bruce Verchere, Garth L. Warnock

Research output: Contribution to journalArticle

Abstract

Costimulation blockade is an effective way to prevent allograft rejection. In this study, we tested the efficacy of two negative co-signaling molecules in protecting islet allograft function. We used local expression of B7-H4 by adenoviral transduction of islets (Ad-B7-H4) and systemic administration of CTLA-4.Ig to investigate the outcomes of allograft survival. Five groups of streptozotocin-induced diabetic C57BL/6 mice received 400 islets each from BALB/c donors. The groups consisted of control (G1); CTLA-4.Ig (G2); Ad-LacZ (G3); Ad-B7-H4 (G4); and Ad-B7-H4 and CTLA-4.Ig combined (G5). G1 and G3 developed graft failure on average of two weeks. G2, G4 and G5 survived for 43.8 ± 34.8, 54.7 ± 31.2 and 77.8 ± 21.5 d, respectively. Activated T and B cells in the lymph nodes were significantly controlled by CTLA-4.Ig treatment. Significantly reduced infiltrates were also detected in the allografts of G2 compared with G1. By contrast, B7-H4 significantly inhibited Th1-associated IFN-gamma secretion in the early stage and increased Foxp3+ T cells in the long-term surviving allografts. Our study suggests that CTLA-4 and B7-H4 inhibit alloimmune responses through distinct mechanisms, and that combination therapy which activates two negative co-signaling pathways can further enhance islet allograft survival.

Original languageEnglish (US)
Pages (from-to)284-295
Number of pages12
JournalIslets
Volume4
Issue number4
StatePublished - Jul 2012
Externally publishedYes

Fingerprint

Allografts
T-Lymphocytes
Streptozocin
Inbred C57BL Mouse
B-Lymphocytes
Lymph Nodes
Transplants
Control Groups

Keywords

  • Allograft survival
  • B7-H4
  • Combination therapy
  • Costimulation blockade
  • CTLA-4
  • Islet transplantation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Wang, X., Hao, J., Metzger, D. L., Mui, A., Lee, I. F., Akhoundsadegh, N., ... Warnock, G. L. (2012). Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival. Islets, 4(4), 284-295.

Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival. / Wang, Xiaojie; Hao, Jianqiang; Metzger, Daniel L.; Mui, Alice; Lee, I. Fang; Akhoundsadegh, Noushin; Chen, C. Lieping; Ou, Dawei; Ao, Ziliang; Verchere, C. Bruce; Warnock, Garth L.

In: Islets, Vol. 4, No. 4, 07.2012, p. 284-295.

Research output: Contribution to journalArticle

Wang, X, Hao, J, Metzger, DL, Mui, A, Lee, IF, Akhoundsadegh, N, Chen, CL, Ou, D, Ao, Z, Verchere, CB & Warnock, GL 2012, 'Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival', Islets, vol. 4, no. 4, pp. 284-295.
Wang X, Hao J, Metzger DL, Mui A, Lee IF, Akhoundsadegh N et al. Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival. Islets. 2012 Jul;4(4):284-295.
Wang, Xiaojie ; Hao, Jianqiang ; Metzger, Daniel L. ; Mui, Alice ; Lee, I. Fang ; Akhoundsadegh, Noushin ; Chen, C. Lieping ; Ou, Dawei ; Ao, Ziliang ; Verchere, C. Bruce ; Warnock, Garth L. / Blockade of both B7-H4 and CTLA-4 co-signaling pathways enhances mouse islet allograft survival. In: Islets. 2012 ; Vol. 4, No. 4. pp. 284-295.
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