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Inhibition of Chronic Rejection and Development of Tolerogenic T Cells after ICOS-ICOSL and CD40-CD40L Co-stimulation Blockade

ICOS-ICOSL Blockade: A Step Toward Tolerance? Chronic rejection is arguably the most significant remaining barrier to successful long-term allograft survival. Whereas current immunosuppressive strategies have largely overcome the onset of acute rejection, leading to impressive 1-year survival rates for many organs, chronic rejection continues to be an unresolved problem. The damage caused to a graft by chronic rejection varies depending on the organ involved, although it nearly always results in a progressive decrease in graft function and ultimately to graft failure. In addition to the problem of chronic rejection, the extensively described side effects of using immunosuppressive drugs have led to the pursuit of strategies that are able to achieve a state of donor-specific transplantation tolerance. The quest to achieve tolerance specifically to foreign organ transplants has led to numerous studies into the use of agents aimed at blocking particular stages in the immune response. In particular, much progress in experimental models has been made through blockade of key T-cell co-stimulatory signals such as CD28-B7 and CD40-CD154 (CD40L). These protocols often lead to long-term graft survival, with the absence of acute rejection episodes. However, to date, blockade of these interactions alone has failed to adequately prevent the onset of chronic rejection (1). To achieve transplantation tolerance, there is a need to develop clinically acceptable protocols that abrogate not only acute but also chronic rejection. Previously, Guillonneau et al. have demonstrated in a fully mismatched rat cardiac allograft model that although blockade of CD40-CD154 co-stimulatory interactions through CD40Ig gene transfer leads to long-term graft survival, these grafts show strong evidence of chronic rejection in the form of vasculopathy and fibrosis (1). Writing in this issue of Transplantation, the authors address the role of ICOS on the development of chronic rejection in this model (2). ICOS is a co-stimulatory molecule with homology to CD28 and CTLA-4. Unlike its homologues, ICOS is not constitutively expressed (Fig. 1). Instead, ICOS has been shown to be increased on activation and maintained on memory CD4 and CD8 T cells. ICOSL (B7 homolog (B7-H) in humans, B7-related protein 1 [B7RP-1] in mice) has been identified as the third B7 family member and can be found on both B cells and antigen-presenting cells. The article shows that co-blockade of ICOS-ICOSL and CD40-CD154 interactions results in indefinite graft survival with a significant decrease in vascular wall lesions, the degree of vessel occlusion, and the percentage of occluded vessels. Indeed, four of seven recipients showed a complete absence of chronic rejection lesions of the vessel wall despite a degree of perivascular fibrosis. Whereas other studies have investigated the role of ICOS-ICOSL interactions in prolonging graft survival, the authors are the first to confirm a previous report in a murine model of cardiac transplantation that demonstrated that blockade of both ICOS-ICOSL and CD40-CD154 pathways significantly inhibited the onset of chronic rejection (3). Importantly, Guillonneau et al. provide evidence that suggests that anti-ICOS monoclonal antibody inhibits graft rejection by preventing infiltration of ICOS -activated T cells to the graft, a finding consistent with the previous study (2, 3). Indeed, 120 days posttransplantation, the number of TCR , CD4 , and CD8 cells as well as macrophages and mast cells were reduced to syngeneic control levels in treated rats. T cells may be prevented from entering the graft after co-stimulatory pathway blockade in a number of ways. It has been shown previously that ICOS-ICOSL interactions are a potent stimulator of both T-helper type 1 and T-helper type 2 T cells, particularly effector and memory T cells, and that ICOS interactions play a role in the induction of T-cell effecNuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, United Kingdom. Received 4 February 2005. Accepted 25 February 2005. Copyright © 2005 by Lippincott Williams & Wilkins ISSN 0041-1337/05/8002-253 FIGURE 1. ICOS-ICOSL is an example of an inducible co-stimulatory pathway. T cells constitutively express a number of co-stimulatory molecules including CD28 that are crucial to T-cell activation. After activation, T cells may increase additional co-stimulatory molecules such as ICOS that may promote cell survival and the preferential differentiation of T cells into effector cells with specific functions.