Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12.

Yang, Yong‐Guang; Dey, Bimalangshu R.; Sergio, Justin J.; Pearson, Denise A.; Sykes, Megan

doi:10.1172/jci4992

Cited by 168 publications

(156 citation statements)

References 50 publications

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“…Recently, Buhlmann et al (22) demonstrated that donor CD4 ϩ T cells that produce IL-2 and express CD40 ligand are required not only for the induction, but also for the sustained expansion of donor effector CD8 ϩ T cells in C57BL/6 cell-injected BDF 1 mice with acute GVHD. In addition, donor CD4 ϩ T cells seem to play a pivotal role in causing lethal acute GVHD (23). These findings suggest that the decrease in donor CD4 ϩ T cells in DBA/2 cell-injected BDF 1 mice treated with IL-18 may play a role as a negative feedback mechanism in the sustained expansion of donor CD8 ϩ CTL, resulting in the prevention of conversion to acute GVHD.…”

Section: Discussionmentioning

confidence: 90%

IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Okamoto

Kohno

Tanimoto

et al. 2000

The Journal of Immunology

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The development of chronic graft-versus-host disease (GVHD), which is induced by the transfer of DBA/2 spleen cells into (C57BL/6 × DBA/2)F1 (BDF1) mice, is closely related to diminished donor anti-host CTL activity and host B cell hyperactivation. Therefore, an approach which activates donor CD8+ T cells or suppresses donor CD4+ T cell-host B cell interaction may have clinical utility in the treatment of chronic GVHD. We have previously demonstrated that IL-18 induces the development of naive CD8+ T cells into type I effector cells in DBA/2 anti-BDF1 MLC. In this paper we examined the effect of IL-18 administration on the development of chronic GVHD in mice. The treatment was started before or after the onset of clinical evidence of the disease. Regardless of the treatment schedule, IL-18 significantly decreased immunological parameters indicative of chronic GVHD, such as elevated serum IgG antinuclear Abs, IgG1, and IgE levels, and host B cell numbers and their activation. Importantly, IL-18-treated mice did not show the same acute GVHD-like symptoms reported for IL-12 treatment, because there was no weight loss, death, or severe immunodeficiency as indicated by a decrease in IL-2 and IFN-γ production by Con A-stimulated spleen cells. In contrast, IL-18 treatment partially but significantly restored the production of these cytokines. Data further suggested that these IL-18-mediated therapeutic effects may be due to the induction of donor CD8+ CTL, the decrease in donor CD4+ T cell numbers, and a down-regulation of host B cell MHC class II expression. Thus, our results suggest that IL-18 has beneficial effects in the prevention and treatment of chronic GVHD.

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Section: Discussionmentioning

confidence: 90%

IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Okamoto

Kohno

Tanimoto

et al. 2000

The Journal of Immunology

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“…The role of IFN-␥ levels in regulating GVHD has not been entirely resolved; sustained high IFN-␥ production can result in more severe GVHD in some models (19,25). However, the link between high IFN-␥ and worse GVHD is not a universal finding, with some studies showing reduced GVHD associated with increased donor T cell apoptosis (20,26,27). Therefore, any propensity toward an increased division rate that might occur when the PD-1/PD-L pathway is blocked may be offset by an increased apoptosis rate caused by IFN-␥ elevation.…”

Section: Discussionmentioning

confidence: 99%

Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-γ-Dependent Mechanism

Blazar

Carreño²,

Panoskaltsis‐Mortari

et al. 2003

The Journal of Immunology

306

216

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Acute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4:B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-γ production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-γ production and suggest a novel therapeutic target for inhibiting GVHD lethality.

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“…[25][26][27] Other data have suggested that Th1 cytokines reduced acute GVHD or that Th2 cytokines worsened acute GVHD. [28][29][30] In any case, it may be important to regulate both Th1 and Th2 cytokines to control GVHD, and thus CD4 þ and CD4 À Va24 þ NKT cells likely play some roles in preventing acute GVHD.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

Haraguchi

Takahashi

Hiruma

et al. 2004

Bone Marrow Transplant

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Summary:Human Va24 þ natural killer T (NKT) cells have an invariant T-cell receptor-a chain and are activated in a CD1d-restricted manner. Va24 þ NKT cells are thought to regulate immune responses and to play important roles in the induction of allograft tolerance. In this report, we analyzed the recovery of Va24 þ NKT cells after hematopoietic stem cell transplantation and its correlation with graft-versus-host disease (GVHD). Patients who received a dose-reduced conditioning regimen, antithymocyte globulin-or CAMPATH-1H-containing conditioning regimen were excluded. NKT cells were reconstituted within 1 month after transplantation in peripheral blood stem cell transplantation recipients, while their numbers remained low for more than 1 year in bone marrow transplantation (BMT) recipients. The number of Va24 þ NKT cells in BMT recipients with acute GVHD was lower than that in patients without acute GVHD, and both the CD4 þ and CD4 À Va24 þ NKT subsets were significantly reduced. With regard to chronic GVHD, BMT recipients with extensive GVHD had significantly fewer Va24 þ NKT cells than other patients. Furthermore, the number of CD4 þ Va24 þ NKT cells was also significantly reduced in patients with chronic extensive GVHD. Our results raise the possibility that the number of Va24 þ NKT cells could be related to the development of GVHD.

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Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12.

Abstract: We have demonstrated that a single injection of interleukin (

Cited by 168 publications

References 50 publications

IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

IL-18 Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-γ-Dependent Mechanism

Recovery of Vα24+ NKT cells after hematopoietic stem cell transplantation

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