1. Top of page
  2. Introduction
  3. References

Naïve alloantigen-specific T cells generally develop to a type 1 cytokine-producing phenotype in response to an allograft, and following infiltration into the allograft are activated to express effector functions, including production of interferon (IFN)-γ, that mediate allograft rejection. Many of the proinflammatory properties of IFN-γ, including up-regulated expression of class I and class II MHC molecules, up-regulated expression of integrins on endothelial cells, induction of T-cell chemoattractant chemokines, and stimulation of macrophage effector functions such as production of nitric oxide and reactive oxygen species, promote rejection of the graft (1). The frequent presence of IFN-γ and/or its stimulated products during rejection episodes implicate IFN-γ as a key effector cytokine during the progression of acute rejection, as well as in the development of transplant-associated vasculopathy (2,3).

In light of the presence and role of IFN-γ in promoting rejection, reports indicating the accelerated rejection of renal and heart allografts, as well as xenografts, in IFN-γ–/– (GKO) mice were unexpected (4–8). Notably, the accelerated rejection observed in these grafts was accompanied by extensive tissue necrosis and hemorrhage, in contrast to the mononuclear cell infiltration-mediated rejection normally observed in allografts with functional IFN-γ production and signaling. Complementary results were observed when allografts from donors deficient in IFN-γ receptor signaling were transplanted to wild-type recipients, suggesting that IFN-γ protects the allograft in some way. In this issue of the journal, Mele and coworkers have compared the outcome of liver allografts in wild-type vs. GKO recipients (9). In wild-type recipients MHC-mismatched allografts experience an initial rejection episode characterized by leukocyte infiltration, but this rejection resolves and the recipient develops donor-specific tolerance defined by the inability to reject subsequent skin allografts from the liver donor. In contrast, liver allografts in GKO recipients are rapidly rejected with a histopathology that is again accompanied by intense tissue necrosis and hemorrhage. Similar results are observed when liver allografts from IFN-γ R–/– donors are transplanted into wild-typerecipients. Collectively, these results provide strong evidence that IFN-γ delivers signal(s) to the allograft that induce protection from the tissue necrosis and hemorrhage observed in its absence.

The mechanism mediating this form of rejection in GKO recipients is unclear, as are the signals that IFN-γ delivers to protect allografts from the rejection. Two known down-regulatory effects of IFN-γ are potentially operative in response to the allograft and could inhibit the accelerated rejection and tissue necrosis/hemorrhage in the allografts. First, it is clear that IFN-γ restricts the extent of T-cell proliferation and cytotoxic T lymphocyte (CTL) generation during antigen priming for immune responses, including allograft rejection (4). Thus, unregulated alloantigen-specific T-cell expansion induced by the allograft in the absence of IFN-γ could result in a large compartment of alloreactive T cells that infiltrate the grafts and account for the rapid rejection of solid organ allografts. This unregulated expansion of alloreactive T cells, however, would not account for the severe tissue necrosis and hemorrhage observed in heart, renal, and, in the case of the current report, liver allografts transplanted to IFN-γ-deficient recipients. As a second mechanism of down-regulation, IFN-γ attenuates infiltration of specific leukocyte populations into parenchymal tissues. Neutrophils are the earliest leukocytes to infiltrate tissue sites of inflammation, including allografts, and their activation to degranulate at these sites results in the release of many tissue-digesting enzymes. IFN-γ down-modulates production of several neutrophil chemoattractant chemokines, including KC and MIP-2, the major neutrophil chemoattractant chemokines in mice (10). IFN-γ also down-modulates endothelial cell expression of P- and E-selectin, molecules that function to mediate neutrophil rolling on vascular endothelium and facilitate neutrophil arrest for transendothelial cell migration and infiltration into subendothelial spaces and tissue parenchyma (11).

Two recent studies have reported unregulated neutrophil infiltration into heart allografts and the necrotic/hemorrhagic rejection observed in GKO recipients (7,12). Similar to the allograft histology observed in the liver allografts by the Halloran group in the current report, heart allografts in IFN-γ-deficient recipients exhibit extensive parenchymal necrosis and hemorrhage. Depletion of recipient neutrophils in GKO heart allograft recipients circumvents this histopathology and accelerated rejection (7). It is important to note that the unregulated neutrophil allograft infiltration and subsequent necrotic rejection were not observed when the recipients were depleted of CD8+ T cells. Previous studies from the Halloran group have also indicated that treating the recipients with T-cell immunosuppressive drugs attenuated the necrotic rejection observed in renal allografts in GKO recipients (6). Considered together, these results suggest that the early production of IFN-γ by T cells may regulate neutrophil infiltration into allografts as well as other necrotic mechanisms. The characterization of these T cells will be important for understanding immune protection against this mechanism of rejection.

An important facet of the current report by Mele and coworkers is the inability of GKO recipients of liver allografts to develop tolerance to donor alloantigens. A potential mechanism for this inability is the unregulated leukocyte infiltration and expression of effector function leading to tissue necrosis/hemorrhage during the initial rejection episode. Such an unregulated attack on the graft would circumvent the resolution of this initial rejection episode that must be required for the subsequent development of donor-specific tolerance. In a similar vein, several studies have reported the inability to induce costimulatory blockade mediated tolerance in GKO recipients of heart and skin allografts (4,13). Collectively, studies using GKO recipients and IFN-γ R–/– allografts indicate a critical role for IFN-γ in protecting the allograft from unregulated leukocyte infiltration, and resulting tissue necrosis and hemorrhage. The development of donor-specific tolerance is likely to be undermined by these events. These studies have identified the yin and yang effects of IFN-γ as a protective cytokine for allografts early following transplantation when compared to properties of the cytokine that promote rejection of the allograft when produced in the tissue at later times.


  1. Top of page
  2. Introduction
  3. References
  • 1
    Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-γ. Annu Rev Immunol 1997; 15: 749795.
  • 2
    Nagano H, Mitchell RN, Taylor MK, Hasegawa S, Tilney NL, Libby P. Interferon-γ deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. J Clin Invest 1977; 100: 550557.
  • 3
    Tellides G, Tereb DA, Kirkiles-Smith NC et al. Interferon-γ elicits arteriosclerosis in the absence of leukoctyes. Nature 2000; 403: 207211.
  • 4
    Konieczny BT, Dai Z, Elwood ET et al. IFN-γ is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 1998; 160: 20592064.
  • 5
    Halloran PF, Afrouzian M, Ramassar V et al. Interferon-γ acts directly on rejection renal allografts to prevent graft necrosis. Am J Pathol 2001; 158: 215226.
  • 6
    Halloran PF, Miller LW, Urmson J et al. IFN-γ alters the pathology of graft rejection: protection from early necrosis. J Immunol 2001; 166: 70727081.
  • 7
    Miura M, El-Sawy T, Fairchild RL. Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-γ. Am J Pathol 2003; 162: 509519.
  • 8
    Wang H, DeVries ME, Deng S et al. The axis of interleukin 12 and gamma interferon regulates acute vascular xenogeneic rejection. Nat Med 2000; 6: 549555.
  • 9
    Mele TS, Kneteman NM, Zhu L-F et al. IFN-γ is an absolute requirement for spontaneous acceptance of liver allografts. Am J Transplant 2003; 3: 942951 .
  • 10
    Ohmori Y, Hamilton TA. IFN-γ selectively inhibits lipopolysaccharide-inducible JE/monocyte chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating activity gene expression in mouse peritoneal macrophages. J Immunol 1994; 153: 22042212.
  • 11
    Melrose J, Tsurushita N, Liu G, Berg EL. IFN-γ inhibits activation-induced expression of E- and P-selectin on endothelial cells. J Immunol 1998; 161: 24572464.
  • 12
    Bishop DK, Wood SC, Eichwald EJ, Orosz CG. Immunobiology of allograft rejection in the absence of IFN-γ: CD8+ effector cells develop independently of CD4+ cells and CD40–CD40 ligand interactions. J Immunol 2001; 166: 32483255.
  • 13
    Markees TG, Phillips NE, Gordon EJ et al. Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4+ T cells, interferon-gamma, and CTLA-4. J Clin Invest 1998; 101: 24462455.