Combined Costimulation Blockade Inhibits Accelerated Rejection Mediated by Alloantigen-primed Memory T Cells in Mice

Research output: Contribution to journalArticle

Abstract

Donor-reactive memory T cells threaten the survival of transplanted organs via multiple pathways. This study was undertaken to induce tolerance of cardiac allografts in mice, in which alloreactive memory T cells were adoptively transferred, by combined costimulatory blockade of both effector and memory T cells. We found that the median survival time (MST) of the grafts was 5.17 days in the untreated group, 10.33 days in the CTLA4Ig- and antiCD40L- treated (2-combined) group, and more than 100 days in the CTLA4Ig-, anti-CD40L-, anti-LFA-1-, and anti-OX40L-treated (4-combined) group. Histological analysis revealed that the mean rejection level was Grade 4 in the untreated group, Grade 3 in the 2-combined treatment group, and Grade 0 in the 4-combined treatment group. CD44(high) T cells were detected only in the untreated group. The in vitro proliferation of lymphocytes of both untreated and 2-combined group was higher than that of the 4-combined treatment group (p < 0.01). Compared with the untreated group, the expression levels of IL-2, IFN-gamma, and Foxp3 were lower in the 2-combined treatment group; the expression levels of these genes were the lowest in the 4-combined treatment group. IL-10 expression was significantly higher in the 4-combined treatment group than in the other groups. These results demonstrate the inhibition efficacy of combined costimulation blockade in accelerated-rejection models and the possible mechanisms underlying the suppression of cellular immunity in mice receiving grafts as well as in inducing the activation of IL-10-producing Tr1 cells in grafts.

Details

Authors
  • Baiyi Xie
  • Jibing Chen
  • Junjie Xia
  • Yongzhi Wang
  • Hua Liang
  • Henrik Ekberg
  • Matthias Corbascio
  • Zhongquan Qi
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Urology and Nephrology

Keywords

  • Immunological tolerance, transplantation, Cardiac, Memory T cells, Costimulation blockade, Accelerated rejection
Original languageEnglish
Pages (from-to)639-651
JournalImmunological Investigations
Volume38
Issue number7
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes