Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation

Min, Chang Ki; Maeda, Yoshinobu; Lowler, Kathleen P.; Liu, Chen; Clouthier, Shawn G.; Lofthus, David M.; Weisiger, Elizabeth; Ferrara, James L.M.; Reddy, Pavan

doi:10.1182/blood-2004-02-0763

Cited by 53 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that ICOS costimulation has paradoxical effects on CD4 ϩ and CD8 ϩ T cells is indeed puzzling. Like ICOS, glucocorticoid-induced TNF receptor or IL-18 also have opposite effects on CD4 ϩ and CD8 ϩ T cells (38,39). The underlying mechanism why CD4 ϩ and CD8 ϩ T cells respond differently to ICOS costimulation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

ICOS, a CD28 family member expressed on activated CD4+ and CD8+ T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4+ or CD8+ T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS−/− CD4+ T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS−/− CD4+ T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-γ and TNF-α. Thus, ICOS−/− CD4+ T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS−/− CD8+ T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8+ T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS−/− CD8+ T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4+ and CD8+ T cells in GVHD.

show abstract

Section: Discussionmentioning

confidence: 99%

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Liang

Nurieva

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…11 Together, these data confirmed the now established principle that BMT conditioning has important effects on the incidence and severity of GVHD, 16,37 and that CD4 and CD8 T-cell effects may be differentially regulated after BMT. 38 With the benefit of simultaneous data generated using both IFN␥ Ϫ/Ϫ and IFN␥R Ϫ/Ϫ mice, we have now established the mechanism of action of this cytokine in GVHD pathogenesis, which has yielded highly surprising and novel results. Importantly, the proposed concept that IFN␥ inhibits GVHD by inhibition of donor T-cell function inferred from previous studies is not consistent with the data gained when IFN␥R Ϫ/Ϫ donor cells are transplanted.…”

Section: Discussionmentioning

confidence: 99%

IFNγ differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract

Burman

Banovic

Kuns

et al. 2007

Blood

168

174

View full text Add to dashboard Cite

Although proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFN␥ has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wildtype (wt), IFN␥ ؊/؊ , and IFN␥R ؊/؊ mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFN␥ augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFN␥ in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFN␥ is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT. IntroductionAllogeneic bone marrow transplantation (BMT) is a definitive curative therapy for most hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal (GI) tract, liver, and lung are preferentially damaged by the transplanted donor immune system. 1 GVHD occurs in most (50%-70%) recipients and is largely responsible for the high mortality associated with allogeneic BMT. Idiopathic pneumonia syndrome (IPS) is an acute noninfectious lung injury that typically occurs 3 to 4 weeks after BMT, responds poorly to therapy, and is associated with a high mortality. 2 There is thus a pressing need for new treatment approaches to both prevent and treat the full spectrum of GVHD, based on a logical understanding of the underlying disease pathophysiology.Current paradigms suggest that GVHD occurs via a complex cellular network initiated by the interaction of antigen-presenting cells (APCs) and naive donor T cells. [3][4][5] Subsequent T helper 1 (Th1) differentiation leads to the generation of donor cytotoxic T lymphocytes (CTLs) and large amounts of inflammatory cytokines that damage host tissue by both major histocompatibility complex (MHC)-dependent and -independent pathways. 6 Of the Th1 cytokines, IFN␥ is perhaps the most immunologically dominant, influencing a plethora of cell subsets during allograft rejection. 7 However the effects of this cytokine on GVHD are unclear, with a number of contradictory studies [8][9][10][11] suggesting that a clearer understanding of the mechanisms involved are needed. We have re-examined this issue using both IFN␥ Ϫ/Ϫ and IFN␥R Ϫ/Ϫ stem cell transplantation (SCT) donors or recipients following myeloablative conditioning. We demonstrate that donor-derived IFN␥ indeed has both positive and negative effects on GVHD due to differential effects on donor and host tissue, and individual target organs. First, IFN␥ augments acute GVHD via direct affects on the donor T cell to promote Th1 differen...

show abstract

“…However, caution with respect to the use of these cytokines in the post transplant setting is warranted, as they play significant roles in acute GVHD 91 and have been shown to exacerbate GVHD in allogeneic Tcell replete BMT recipients. 223,225 Moreover, combinations of these cytokines (IL-12, -15, and -18) have been shown to exacerbate inflammatory responses 226,227 and could further promote harmful alloimmune responses and mortality in the HSCT recipient. 228 Soluble factors targeting cellular function might also be used to ameliorate immune dysfunction such as replacing a deficient cellular response directed against residual tumor or infection.…”

Section: Soluble Factors and Their Targetsmentioning

confidence: 99%

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Auletta

Lazarus

2005

Bone Marrow Transplant

View full text Add to dashboard Cite

Summary:Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versushost disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplantrelated toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and antimicrobial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplantrelated toxicity in the transplant recipient. Bone Marrow Transplantation (2005) 35, 835-857.

show abstract

Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation

Abstract: Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graftversus-host disease (GVHD) in a

Cited by 53 publications

References 43 publications

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells

IFNγ differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract

Immune restoration following hematopoietic stem cell transplantation: an evolving target

Contact Info

Product

Resources

About