News:Expression of programmed death ligand-1 in donor hearts regulates chronic allograft rejection

January 27, 2008 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Our adaptive immune system (i.e. lymphocytes) has evolved a number of strategies to eliminate or suppress autoreactive lymphocytes. These include the clonal deletion of self-reactive lymphocytes in the bone marrow and thymus, as well as active suppression of self-reactive peripheral cells. One peripheral tolerance mechanism is expression of inhibitory co-receptors on lymphocytes that block cellular activation when engaged by their ligand. Programmed death-1 (PD-1) is a member of the CD28/CTLA-4 family of co-receptor molecules. Its expression is induced on activated lymphocytes, and it appears to inhibit antigen-receptor signaling when engaged by its ligand. PD-1 ligands (PDL1 and PDL2) are expressed on many immune cells, as well as non-hematopoietic tissues including the heart and kidneys.

The importance of PD-1 signaling for peripheral T cell tolerance was clear following initial studies of mice with targeted gene deletion of PD-1 (2,3). On one genetic background, these animals develop an immune complex glomerulonephritis and destructive arthritis that resembles the kidney disease seen in lupus patients, and the destructive joint disease seen in rheumatoid arthritis. On another genetic background, they die by as early as 5 weeks of age with dilated hearts, disrupted myofibrils, and immunoglobulin deposition in the myocardium.

It took only a short time before researchers to ask whether PD-1:PDL signaling could influence chronic allograft rejection. Previous studies have demonstrated that administration of a blocking antibody to PDL1 resulted in accelerated cardiac allograft rejection (4). Conversely, administration of a PDL1-Ig fusion protein to enhance PDL1 signaling can prolong graft survival when used in combination with other methods of immunosuppression (5). The work by Yang et al. published in Circulation has extended these findings, and demonstrated using genetic deletion, bone-marrow chimaeras, and blocking antibody studies that expression of PDL1 in transplanted cardiac allografts is essential for graft survival.

First, the researchers did a variety of transplant experiments using recipients and donors that differed at one MHC locus. They found that if PDL1 was genetically deleted in donors but not recipient tissues, graft rejection and vasculopathy was accelerated. The converse was not true, however – deletion of recipient PDL1 did not influence graft survival. Blocking antibodies to PDL1 similarly accelerated the allograft rejection. Interestingly, the same group of researchers recently demonstrated that when long-term allograft survival is ensured by blockade of T cell activation (with CTLA4-Ig), PDL1 knockout donor tissues still undergo the characteristic vasculopathy associated with chronic allograft rejection (6).

The cellular mechanism of the observed effects on graft survival is not entirely clear. PDL1 signaling has become complex in recent years, with data demonstrating binding of PDL1 and other co-stimulatory ligands, as well as effects on regulatory T cell function. Nonetheless, this current work clearly defines allograft PDL1 expression as a target for therapies aimed at preventing or treating chronic allograft rejection.