Interferon-?? Is Necessary for Initiating the Acute Rejection of Major Histocompatibility Complex Class Ii-Disparate Skin Allografts1

Abstract

The data demonstrate that IFNgamma is not necessary for generating effector mechanisms associated with acute transplant rejection but that it is required for initiating alloimmune responses to MHC class II-disparate skin grafts.

An Essential Contribution by IFN-γ to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts

“…1), indicating that islet donor-derived IFN-␥ is not responsible for the rejection observed in IFN-␥-deficient hosts. Thus IFN-␥, like perforin and FasL, does not appear to be generally required for the overall rejection response, a result consistent with findings in other models (16,32,33).…”

“…In accordance with these observations, Ring et al (32) recently showed that host-derived IFN-␥ is required for the efficient rejection of MHC class II-disparate skin allografts by CD4 ϩ T cells. However, rejection of fully allogeneic heart (33) and skin (16,32) grafts has been clearly shown to occur in the absence of hostderived IFN-␥, suggesting that there must also exist IFN-␥-independent mechanisms of allograft destruction. In contrast, IFN-␥ also appears to be required for the induction of allograft tolerance following costimulatory blockade, perhaps due to the inhibitory effect of this cytokine on T cell proliferation (15,16,34).…”

“…Subsequently, several other investigators demonstrated a strong correlation between elevated intragraft levels of Th1/Tc1-type cytokines, particularly IFN-␥, and the rejection of various types of allografts (13). In accordance with these observations, Ring et al (32) recently showed that host-derived IFN-␥ is required for the efficient rejection of MHC class II-disparate skin allografts by CD4 ϩ T cells. However, rejection of fully allogeneic heart (33) and skin (16,32) grafts has been clearly shown to occur in the absence of hostderived IFN-␥, suggesting that there must also exist IFN-␥-independent mechanisms of allograft destruction.…”

IFN-γ Alters the Pathology of Graft Rejection: Protection from Early Necrosis

“…After withdrawal of immunosuppression, grafts in GKO hosts show less chronic vascular rejection, indicating that IFN-␥ accelerates graft vessel disease (8,35,36). Similarly in the special circumstance of nonvascularized class IIdisparate skin allografts, IFN-␥ is actually essential for graft rejection (7,37). Thus, the net effect of IFN-␥ will depend on the details of the system studied: whether the graft is vascularized, whether there are strong antigenic differences, whether temporary immunosuppression is used, and the time posttransplant.…”

“…The effect of IFN-␥ is usually considered to promote tissue injury, which it does effectively in autoimmunity (5) and in some transplant models. For example, IFN-␥ is needed for rejection of established islet transplants by CD8 T cells in a TCR-transgenic model (6), for rejection of class II-disparate skin grafts (7), and aggravates chronic vascular injury in heart transplants (8 -10). Yet despite the association of IFN-␥ with inflammation and MHC regulation, mice with disrupted IFN-␥ genes (GKO mice, BALB/c mice with disrupted IFN-␥ genes) reject transplants briskly (11)(12)(13).…”