Critical role of IFN-γ in CFA-mediated protection of NOD mice from diabetes development

Mori, Yoshiko; Kodaka, Tetsuro; Katō, Takako; Kanagawa, Edith M.; Kanagawa, Osami

doi:10.1093/intimm/dxp097

Cited by 18 publications

(14 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This hypothesis is further supported by the failure to induce protection with Freund's Complete Adjuvant (CFA) in IFN-g signaling-deficient NOD mice. 32 That study indicated that IFN-g signaling control the susceptibility of pathogenic T cells to the inhibitory activity of Figure 1. Diabetes onset age correlates with Treg, tolerogenic and activated DCs, and IFNg producing (T) cells.…”

Section: Discussionmentioning

confidence: 97%

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

Krych¹,

et al. 2015

View full text Add to dashboard Cite

Gut microbiota regulated imbalances in the host's immune profile seem to be an important factor in the etiology of type 1 diabetes (T1D), and identifying bacterial markers for T1D may therefore be useful in diagnosis and prevention of T1D. The aim of the present study was to investigate the link between the early gut microbiota and immune parameters of non-obese diabetic (NOD) mice in order to select alleged bacterial markers of T1D. Gut microbial composition in feces was analyzed with 454/FLX Titanium (Roche) pyro-sequencing and correlated with diabetes onset age and immune cell populations measured in diabetic and non-diabetic mice at 30 weeks of age. The early gut microbiota composition was found to be different between NOD mice that later in life were classified as diabetic or non-diabetic. Those differences were further associated with changes in FoxP3 C regulatory T cells, CD11b C dendritic cells, and IFN-g production. The model proposed in this work suggests that operational taxonomic units classified to S24-7, Prevotella, and an unknown Bacteriodales (all Bacteroidetes) act in favor of diabetes protection whereas members of Lachnospiraceae, Ruminococcus, and Oscillospira (all Firmicutes) promote pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 97%

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

Krych¹,

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In contrast, immunisation with complete Freund's adjuvant (CFA) increases T cell numbers and protects NOD mice from diabetes [29,33]. Mori et al have reported that IFN-γR deficiency abrogates cyclophosphamide-induced acceleration of diabetes and CFA-mediated protection in NOD mice [34,35]. Thus, Th17 cell development and IFN-γ signalling may play a critical role in diabetes susceptibility mediated by lymphopenia-induced homeostatic expansion in NOD mice, although the precise kinetics and mechanisms of severe lymphopenia in these mice are still being elucidated.…”

Section: Discussionmentioning

confidence: 99%

Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokinedeficient NOD mice develop diabetes similarly to wildtype NOD mice. Methods We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis. Results IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4 + T cells compared with the IL-17 single-deficient mice and wildtype NOD mice. An adoptive transfer study with CD4 + CD25 − T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice. Conclusions/interpretation These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.

show abstract

“…In addition, our in vivo competitive assay also suggests that IFN␥R Ϫ/Ϫ T cells are equally capable of differentiating into Th1 cells (and Th2 and Th17 cells as well; supplemental Figure 10), which is in agreement with the previous reports that IFN␥R Ϫ/Ϫ T cells can normally differentiate into IFN␥-producing Th1 cells and IL-17 ϩ Th17 cells. 38,39 Because the ratio of Tregs to non-Tregs is inversely correlated with GVHD severity, 20 we also measured the ratio of donor T cell-derived CD4 ϩ FOXP3 ϩ Tregs to CD4 ϩ FOXP3 Ϫ T cells in the peripheral blood from mice transplanted with either WT or IFN␥R Ϫ/Ϫ Tconvs on day 30 after allo-HSCT and found no statistical difference between the groups (P ϭ .1063, n ϭ 5). Alternatively, it is also possible the IFN␥R Ϫ/Ϫ Tconvs secrete more Treg-specific chemokines/chemo attractants.…”

Section: Org Frommentioning

confidence: 99%

IFNγR signaling mediates alloreactive T-cell trafficking and GVHD

Choi¹,

Ziga²,

Ritchey³

et al. 2012

Blood

130

156

View full text Add to dashboard Cite

The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon ␥ receptor-deficient (IFN␥R ؊/؊ ) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFN␥R ؊/؊ Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFN␥R-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3 ؊/؊ Tconv recapitulate the reduced GVHD potential of IFN␥R ؊ IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia, and marrow failure states such as myelodysplasia and aplastic anemia. However, the infusion of allogeneic donor T cells (conventional T cells or "Tconv") for allo-HSCT results in 2 distinct biologic effects: graft-versus-host disease (GVHD), which may be mild, moderate, or life-threatening 1,2 ; and a beneficial graft-versus-leukemia (GvL) effect, which results in enhanced leukemia cell clearance. 3,4 Thus, the clinical goal in allo-HSCT is to prevent GVHD while maintaining the beneficial GvL effect. Recent studies have suggested that this might be achieved by infusing regulatory T cells (Tregs), which in some preclinical models suppress GVHD-causing alloreactive Tconv but have only limited effects on GvL-promoting alloreactive Tconv. [5][6][7][8] Unfortunately, Tregs exist in low frequency in the peripheral blood, are difficult to purify and expand, and after expansion are difficult to isolate because of the lack of cell-surface markers, all of which prevent their routine use in the clinic. Thus, alternative therapeutic approaches that do not require Tregs are needed.Interferon ␥ (IFN␥) is a well-known proinflammatory cytokine. Serum levels of IFN␥ after allo-HSCT have been correlated with the severity of GVHD and the treatment of murine allo-HSCT recipients with blocking antibodies to IFN␥ mitigates GVHD. [9][10][11][12] In addition, IFN␥ facilitates T cell-mediated GvL. 11 In contrast, several reports suggest that IFN␥ Ϫ/Ϫ T cells induce more severe GVHD, especially in the lung, than WT T cells when infused into WT MHC-mismatched recipients that are lethally irradiated, [10][11][12][13][14] suggesting that IFN␥ may also have anti-inflammatory properties.Possible mechanisms underlying this anti-inflammatory effect of IFN␥ on lung GVHD have been proposed by several groups. [14][15][16] First, donor T cell-derived IFN␥ prevents allogeneic donor T-cell trafficking and expansion in the lung by inducing PDL1 expression on host lung tissue. 14,15,17 Second, donor T cell-derived IFN␥ induces indoleamine 2,3-dioxygenase (IDO) expression in donor bone marrow-derived dendritic cells, which in turn suppress GVHD. 16 All of these observations suggest that GVHD and GvL can be regulated by modi...

show abstract

Critical role of IFN-γ in CFA-mediated protection of NOD mice from diabetes development

Cited by 18 publications

References 58 publications

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD Mice

Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse

IFNγR signaling mediates alloreactive T-cell trafficking and GVHD

Contact Info

Product

Resources

About