Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

Abstract

The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon-␥ (IFN-␥), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-␥-receptor-deficient (IFN-␥RKO) MHCmatched C57BL/6 recipients. In IFN-␥RKO recipients, host cells were unresponsive to IFN-␥, whereas wt donor cells were exposed to exceptionally high levels of IFN-␥. From an IFN-␥ perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-offunction on donor cells. We found that lack of IFN-␥R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-␥RKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-␥: Ccnd1 and Myc. We conclude that IFN-␥ produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD. IntroductionInterferon-␥ (IFN-␥) is a master regulator of adaptive immune responses. 1 IFN-␥ modulates hundreds of genes, regulating apoptosis and cell proliferation, antigen processing and presentation, and leukocyte trafficking and effector function. Although our comprehension of the molecular bases of IFN-␥ signaling in the immune system has evolved rapidly, our understanding of how IFN-␥ signals in various cell types are integrated in vivo and impinge on systemic immunopathologic conditions is still rudimentary.GVHD is the most important complication of allogeneic hematopoietic cell transplantation, accounting for most treatmentrelated morbidity and mortality. 2 It is a systemic disease affecting mostly the liver, intestine, skin, and lymphoid organs. [3][4][5] Studies in mouse models of GVHD have reported increased serum levels of IFN-␥ and induction of IFN-␥ transcriptional target genes in the skin and liver. 6,7 However, IFN-␥ was reported to have predominantly a protective influence on GVHD lethality in most though not all studies using IFN-␥-deficient donors, antibody-mediated depletion, or injection of IFN-␥. 4 Use of IFN-␥ receptor 1 chaindeficient (IFN-␥RKO) mice in MHC-mismatched transplants has further shown that the impact of IFN-␥ on GVHD lethality resulted from effects on both donor T cells and host nonhematopoietic cells. 8,9 Thus, alloreactive CD8 T cells from IFN-␥RKO and IFN-␥ deficient donors expand more extensively than CD8 T cells from wt donors. 8 Furthermore, lack of IFN-␥R on host pulmonary parenchyma enhances donor cell migration and expansion within the lu...

Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention

“…28 More recently, the same group suggested that IFN␥ produced by alloreactive T cells may cause a severe graft-versus-host reaction, responsible for the lymphopenia associated with GVHD. 29 These insights may explain the observations made in the present work: rsTreg may have a preferential suppressive effect on alloreactive T cells, leading to a qualitative as well as a quantitative improvement in immune reconstitution. The decrease in the fulminant alloactivation may lead to better survival of immune cells as well as promotion of a more "benevolent" cytokine environment.…”

Interferon-γ impairs proliferation of hematopoietic stem cells in mice

“…[12][13][14][15] In fact, IFN-g neutralization improves the in vitro capacity of hematopoietic progenitors from patients with aplastic anemia. 36 Furthermore, IFN-g also plays an important role in the pathogenesis of graft-versus-host disease 37 and disease progression of chronic myeloid leukemia. 38 Our study suggests that the negative impact of IFN-g on HSC proliferation contributes to the impaired hematopoietic function in multiple human diseases, and we speculate that repression of IFN-g signaling could alleviate the hematopoietic suppression in patients with chronic inflammation.…”

SOCS3 regulates graft-versus-host disease

“…33,41,42 Of note, the IL-17 produced after transplantation in these systems is concurrent with other Th1 cytokines (rather than in isolation of) and is predominantly from CD8 ϩ T cells, suggesting that acute GVHD is associated with T-cell differentiation that is not exclusive to Th1 or Th17 pathways, even at a cellular level. In contrast, the role of specific T-cell differentiation pathways on fibrosis after BMT (ie, scleroderma) is not well defined.…”