Type I-IFNs control GVHD and GVL responses after transplantation

Abstract

Although the effects of type II-IFN (IFN-␥) on GVHD and leukemia relapse are well studied, the effects of type I-interferon (type I-IFN, IFN-␣/␤) remain unclear. We investigated this using type I-IFN receptordeficient mice and exogenous IFN-␣ administration in established models of GVHD and GVL. Type I-IFN signaling in host tissue prevented severe colontargeted GVHD in CD4-dependent models of GVHD directed toward either major histocompatibility antigens or multiple minor histocompatibility antigens. This protection was the result of suppression of donor CD4 ؉ T-cell proliferation and differentiation. Studies in chimeric recipients demonstrated this was due to type I-IFN signaling in hematopoietic tissue. Consistent with this finding, administration of IFN-␣ during conditioning inhibited donor CD4 ؉ proliferation and differentiation. In contrast, CD8-dependent GVHD and GVL effects were enhanced when type I-IFN signaling was intact in the host or donor, respectively. This finding reflected the ability of type I-IFN to both sensitize host target tissue/leukemia to cell-mediated cytotoxicity and augment donor CTL function. These data confirm that type I-IFN plays an important role in defining the balance of GVHD and GVL responses and suggests that administration of the cytokine after BM transplantation could be studied prospectively in patients at high risk of relapse. (Blood. 2011;118(12):3399-3409) IntroductionAlthough allogeneic BM transplantation is curative therapy for a majority of hematologic malignancies, its application has been limited by the development of GVHD. GVHD is the result of immunologic damage to the host tissue by alloreactive T cells from the incoming donor graft. Unfortunately, the development of detrimental GVHD is closely intertwined with therapeutic GVL responses. GVL responses are important for eradication of residual host malignancy and are primarily mediated by alloreactive donor T and natural killer (NK) cells. Therapeutic approaches to separate these phenomena are urgently needed.The IFNs were first discovered as a result of their capacity to confer cell resistance to viral infection. 1 There are 2 distinct IFN types, type I and type II, and although both groups induce antiviral defense mechanisms in cells, primarily by limiting replication, they exhibit distinct immunologic properties. After allograft rejection, it is well established that the type II-IFN, IFN-␥, is a dominant Th1 cytokine, exerting pleotropic effects on both hematopoietic and nonhematopoietic cells. Importantly, IFN-␥ has differential effects on both donor and host tissue, with a protective role dominating within GVHD of the lung and pathogenic effects dominating in the gastrointestinal tract. [2][3][4] In addition, the cellular subsets producing IFN␥ and the timing of production may also impact the effect of the cytokine after BM transplantation. 5 In contrast, the role of type I-IFN after BM transplantation remains largely unknown.All type I-IFNs act through the same receptor, which is composed of 2 subunits, IFNAR...

The interferon-dependent orchestration of innate and adaptive immunity after transplantation

“…43,44 The effects of IFN-␣ and mechanism of disease control were recently addressed by our group in preclinical models. This study demonstrated differential effects on donor CD4 ϩ and CD8 ϩ T cells 45 (Figure 1). Type I IFN signaling indirectly inhibits donor CD4 ϩ T cells, putatively via recipient APCs, resulting in alleviation of GVHD.…”

“…However, it will be interesting to investigate the role of IFN-in GVHD, particularly considering the surprising colon-specific GVHD observed in recipients of BMT who lack the IFNAR1. 45 In conclusion, the broad range of outcomes and complex interactions after signaling with the various IFNs has resulted in conflicting studies observed in multiple experimental models and disease states. Although there has been limited investigation into cross-regulation between the IFNs, there is evidence that this does occur.…”

Cytokines in Graft-versus-Host Disease

“…Type I IFN is an example of a cytokine for which signaling through recipient APCs results in less severe class II-dependent GVHD in the colon, whereas signaling through donor APCs may amplify GVHD responses. The former is mediated through decreased donor CD4 proliferation, and the latter is mediated through more effective cross-presentation of alloantigens to CD8 T cells (19). IL-4 is another example.…”

“…T cells expressing IL-17 are also rare, although this may reflect the plasticity of this lineage (16). Increased quantities of Th1-associated cytokines, TNF and IFN-g, in aGVHD are associated with earlier onset and more severe disease in preclinical models and clinical BMT (4,14,(17)(18)(19). Although the dominance of Th1 subsets is well established, Th2 and Th17 subsets are also involved in pathology, and the balance between subsets determines aGVHD severity (20), in addition to organ specificity (15,20), and the pathogenic or protective effects of any subset cannot be viewed in isolation.…”

Identification and expansion of highly suppressive CD8+FoxP3+ regulatory T cells after experimental allogeneic bone marrow transplantation

“…Donor CD8 T cells are known to be highly cytolytic during GVHD. [23][24][25][26][27][28][29] However, the CD8 ϩ FoxP3 ϩ T reg did not exhibit high levels of cytolytic activity against host targets relative to CD8 ϩ FoxP3 Ϫ effectors ( Figure 2D), suggesting that FoxP3 expression and suppression are independent of cytolysis.We next compared the capacity of the CD4 ϩ FoxP3 ϩ and CD8 ϩ FoxP3 ϩ cells to suppress proliferation in vitro. The CD8 ϩ FoxP3 ϩ cells suppressed CD4 ϩ and CD8 ϩ T-cell proliferation in response to Fc-bound CD3 to a greater extent than CD4 ϩ FoxP3 ϩ T reg ( Figure 3A).…”