Promoting regulation via the inhibition of DNAM-1 after transplantation

Koyama, Motoko; Kuns, Rachel D.; Olver, Stuart D.; Lineburg, Katie E.; Lor, Mary; Teal, Bianca E.; Raffelt, Neil C.; Lévêque, Lucie; Chan, Christopher J.; Robb, Renee J.; Markey, Kate A.; Alexander, Kylie A.; Varelias, Antiopi; Clouston, Andrew D.; Smyth, Mark J.; MacDonald, Kelli P. A.; Hill, Geoffrey R.

doi:10.1182/blood-2012-07-444026

Cited by 42 publications

(31 citation statements)

References 47 publications

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“…In addition to the molecules associated with Treg survival mentioned in the results, G-CSF significantly upregulated molecules known to be involved in pathways that regulate T cell function including neuropilin-1 (29), Hdac4 (30), Bcl6 (31), Jak1 (32), CD83 (33), Atg2a (34), Tgfb1 (35), chd4 (36), ccr5 (37). Similarly, DNAM-1 (38), pim1 (39), IER3 (40) and IL10 were down regulated, the latter consistent with the finding here that natural regulatory T cells do not need to make IL-10 themselves for effective function. Together, these data confirm profound transcriptional regulation by G-CSF, an effect that our data suggests may at least in part mediated by direct receptor ligation.…”

Section: Discussionsupporting

confidence: 87%

Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10

MacDonald

Texier

Zhang

et al. 2014

The Journal of Immunology

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The majority of allogeneic stem cell transplants are currently undertaken using G-CSF mobilized peripheral blood stem cells. G-CSF has diverse biological effects on a broad range of cells and IL-10 is a key regulator of many of these effects. Using mixed radiation chimeras in which the haematopoietic or non-haematopoietic compartments were wild-type (WT), IL-10−/−, G-CSFR−/− or combinations thereof we demonstrated that the attenuation of alloreactive T cell responses after with G-CSF mobilization required direct signalling of the T cell by both G-CSF and IL-10. IL-10 was generated principally by radio-resistant tissue, and was not required to be produced by T cells. G-CSF mobilization significantly modulated the transcription profile of CD4+CD25+ regulatory T cells, promoted their expansion in the donor and recipient and their depletion significantly increased graft-versus-host disease (GVHD). In contrast, stem cell mobilization with the CXCR4 antagonist AMD3100 did not alter the donor T cell's ability to induce acute GVHD. These studies provide an explanation for the effects of G-CSF on T cell function and demonstrate that IL-10 is required to license regulatory function but T cell production of IL-10 is not itself required for the attenuation GVHD. Although administration of CXCR4 antagonists is an efficient means of stem cell mobilization, this fails to evoke the immunomodulatory effects seen during G-CSF mobilization. These data provide a compelling rationale for considering the immunological benefits of G-CSF in selecting mobilization protocols for allogeneic stem cell transplantation.

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Section: Discussionsupporting

confidence: 87%

Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10

MacDonald

Texier

Zhang

et al. 2014

The Journal of Immunology

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“…Although NK cells have long been of interest in GVHD (24, 25), NK cells of donor origin, which reduce GVHD while enhancing graft anti-tumor activity (26–33), are the most well-studied. With regard to recipient NK cells, a recent study suggested that recipient NK cells control proliferation of antigen-stimulated donor T cells by a perforin-independent, Fas-dependent mechanism (16).…”

Section: Discussionmentioning

confidence: 99%

Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease

et al. 2014

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Previous studies have shown a correlation between pre-transplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, since irradiation and other forms of pre-transplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pre-transplant variables. First, intestinal damage was required for the induction of minor mismatch (MHC-matched) GVHD, but was not necessary for major mismatch GVHD, demonstrating fundamental pathogenic distinctions between these forms of disease. Moreover, recipient NK cells prevented minor mismatch GVHD by limiting expansion and target organ infiltration of alloreactive T cells via a perforin-dependent mechanism, revealing a previously unrecognized immunoregulatory function of recipient NK cells in GVHD. Minor mismatch GVHD required MyD88-mediated TLR4 signaling on donor cells, and intestinal damage could be bypassed by parenteral LPS administration, indicating a critical role for the influx of bacterial components triggered by intestinal barrier loss. In all, the data demonstrate that pre-transplant conditioning plays a dual role in promoting minor mismatch GVHD by both depleting recipient NK cells and inducing intestinal barrier loss.

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“…To test this hypothesis, B6 into BALB/c and B6 into bm1 GVHD models were used as CD4-and CD8-dependent models, respectively. 27 Weight curves and mortality rates in BALB/c mice administered dnRARa-CD4 Cre CD4…”

Section: Blood 19 September 2013 X Volume 122 Number 12 Vitamin a Mmentioning

confidence: 99%

Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration

Aoyama

Saha

Tolar

et al. 2013

Blood

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• Expression and function of vitamin A metabolizing enzymes are increased in the intestine and mesenteric lymph nodes during GVHD.• Inhibiting donor T-cell RAR signaling reduces Th1 differentiation, gut homing, and GVHD while preserving graft-versus-lymphoma effects.Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARa (dnRARa) showed markedly diminished lethality. The dnRARa transgenic T cells showed reduced Th1 differentiation and a4b7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4 1 T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties. (Blood. 2013; 122(12):2125-2134

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Promoting regulation via the inhibition of DNAM-1 after transplantation

Cited by 42 publications

References 47 publications

Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10

Modification of T Cell Responses by Stem Cell Mobilization Requires Direct Signaling of the T Cell by G-CSF and IL-10

Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease

Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration

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