Stimulating PD-1–negative signals concurrent with blocking CD154 co-stimulation induces long-term islet allograft survival1

W Gao, G Demirci, TB Strom, XC Li - Transplantation, 2003 - journals.lww.com
W Gao, G Demirci, TB Strom, XC Li
Transplantation, 2003journals.lww.com
Background. A balanced network of positive and negative T-cell co-stimulatory signals is
important in regulating T-cell activation. Blocking CD28, CD154 (CD40L), or both co-
stimulatory molecules has been efficacious in preventing acute allograft rejection in certain
but not all transplantation models. In the present study, the authors tested the hypothesis that
stimulating programmed death 1 (PD-1)–triggered negative signals concurrent with blocking
CD154 co-stimulatory signals would facilitate islet allograft tolerance. Methods. The authors …
Abstract
Background.
A balanced network of positive and negative T-cell co-stimulatory signals is important in regulating T-cell activation. Blocking CD28, CD154 (CD40L), or both co-stimulatory molecules has been efficacious in preventing acute allograft rejection in certain but not all transplantation models. In the present study, the authors tested the hypothesis that stimulating programmed death 1 (PD-1)–triggered negative signals concurrent with blocking CD154 co-stimulatory signals would facilitate islet allograft tolerance.
Methods.
The authors used a dimeric PD-L1 immunoglobulin (Ig) fusion protein to stimulate the inhibitory receptor PD-1, and a monoclonal antibody to block CD154. The effects of PD-1 engagement and CD154 blockade on lymphocyte activation were determined by cell proliferation, flow cytometry, and a model of islet transplantation.
Results.
PD-L1Ig inhibited the proliferation of both CD4+ and CD8+ T cells stimulated by anti-CD3. The inhibitory effect of PD-L1Ig was enhanced by concurrent blockade of CD154 co-stimulatory signals, as demonstrated by T-cell proliferation and expression of cell surface activation markers. PD-L1Ig and anti-CD154 also synergistically blocked the activation and maturation of antigen-presenting cells. In an islet transplantation model, treatment of recipient C57BL/6 (H-2 b) mice with PD-L1Ig and anti-CD154 induced long-term survival of DBA/2 (H-2 d) islet allografts, whereas treatment with each reagent alone failed to prevent islet allograft rejection.
Conclusions.
These results suggest that engaging the negative receptor PD-1 exhibits critical immunoregulatory effects in the allograft response, and blocking positive co-stimulatory molecules with active delivery of inhibitory signals may represent a novel therapeutic strategy in transplantation.
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