Decay Accelerating Factor is Essential for Successful Corneal Engraftment

Abstract

In contrast to immune restrictions that pertain for solid organ transplants, the tolerogenic milieu of the eye permits successful corneal transplantation without systemic immunosuppression, even across a fully MHC disparate barrier. Here we show that recipient and donor expression of decay accelerating factor (DAF or CD55), a cell surface C3/C5 convertase regulator recently shown to modulate T cell responses, is essential to sustain successful corneal engraftment. Whereas wild type (WT) corneas transplanted into multiple minor histocompatibility antigen (mH), or HY disparate WT recipients were accepted, DAF’s absence on either the donor cornea or in the recipient bed induced rapid rejection. Donor or recipient DAF deficiency led to expansion of donor-reactive IFN-γ producing CD4+ and CD8+ T cells, as well as inhibition of antigen induced IL-10 and TGF-β, together demonstrating that DAF deficiency precludes immune tolerance. In addition to demonstrating a requisite role for DAF in conferring ocular immune privilege, these results raise the possibility that augmenting DAF levels on corneal endothelium and/or the recipient bed could have therapeutic value for transplants that clinically are at high risk for rejection.

Complement as a multifaceted modulator of kidney transplant injury

“…Studies performed in transplant models revealed WT mice reject Daf1 -/-heart allografts with accelerated kinetics (39), and that the accelerated rejection is due to a complement-dependent augmentation of antidonor T cell immunity. Collaborative work additionally showed that donor or recipient DAF deficiency accelerates skin graft rejection (34) and overcomes the immune privilege of the eye by enhancing pathogenic T cell alloimmunity induced by normally tolerogenic corneal transplants, resulting in rapid corneal rejection (40).…”

Molecules Great and Small

“…The accelerated rejection is caused by a complement-dependent augmentation of antidonor T-cell immunity. Donor or recipient DAF deficiency accelerated skin graft rejection (23), bypassed the requirement for CD4 help in murine heart transplant rejection (119), and overcame immune privilege of the eye to cause rapid corneal transplant rejection (120). Local complement production and C5a/C5aR interactions also influence effector CD8 1 T-cell responses to allogeneic vascular endothelial cells (121) in in vitro culture systems and in vivo in response to a heart transplant (8,121) as well as T cell-dependent kidney transplant rejection in rodents (122).…”

Novel roles of complement in T effector cell regulation

“…DAF deficiency also accelerates rejection and enhances T cell alloimmunity in a murine model of corneal transplantation via complement dependent mechanisms (Esposito et al 2010).…”