IL‐18‐independent cytotoxic T lymphocyte activation and IFN‐γ production during experimental acute graft‐versus‐host disease

Abstract Local catabolism of tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. N-(3,4-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is an active synthetic anthranilic acid derivative which was proved to be effective to treat type±helper T lymphocytes (Th1) mediated autoimmune diseases such as multiple sclerosis. In this report, we investigated the effects of 3,4-DAA on the acute graft versus host disease (aGVHD) following allogeneic bone marrow transplantation (allo-BMT) and its potential mechanism of action. we established a murine aGVHD model, 3,4-DAA was injected intraperitoneally at 200 mg/kg/day per mouse immediately after allo-BMT or at the onset of aGVHD for 14 consecutive days; the signs of aGVHD and the survival were recorded periodically; the histological changes of target organs were evaluated with hematoxylin-eosin staining; the IDO activity and cytokine levels in plasma were measured by reverse-phase high-performance liquid chromatography (HPLC) and enzyme linked immunosorbent assay (ELISA), respectively. We revealed that administration of 3,4-DAA after allo-BMT significantly reduced the severity and the histological score of aGVHD; The survival for mice receiving 3,4-DAA prophylaxis and treatment were prolonged in comparison to the vehicle control mice. The plasma levels of IFN-γ, TNF-α, IL-12 and IL-2 in 3,4-DAA treatment group were found to be decreased, while the IDO activity, the IL-10, IL-5 and IL-4 levels elevated in these mice. In consistent with the in vivo results, 3,4-DAA also inhibited IFN-γ and IL-2 production of spleen T lymphocytes in vitro. Our findings suggest that 3,4-DAA can diminish the murine experimental aGVHD through inhibition of Th1 response; this property makes it a potential alternative agent for prevention and treatment of GVHD in the clinic. Disclosures: No relevant conflicts of interest to declare.

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MicroRNA-181a, a potential diagnosis marker, alleviates acute graft versus host disease by regulating IFN-γ production

American Journal of Hematology ◽

10.1002/ajh.24136 ◽

2015 ◽

Vol 90 (11) ◽

pp. 998-1007 ◽

Cited By ~ 16

Author(s):

Wei Sang ◽

Cong Zhang ◽

Dianzheng Zhang ◽

Ying Wang ◽

Cai Sun ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Ifn Γ ◽

Acute Graft

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Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis

Journal of Experimental Medicine ◽

10.1084/jem.194.10.1433 ◽

2001 ◽

Vol 194 (10) ◽

pp. 1433-1440 ◽

Cited By ~ 132

Author(s):

Pavan Reddy ◽

Takanori Teshima ◽

Mark Kukuruga ◽

Rainer Ordemann ◽

Chen Liu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Host Disease ◽

Murine Bone Marrow ◽

Graft Versus Host ◽

Donor T Cells ◽

Ifn Γ ◽

Acute Graft

Interleukin (IL)-18 is a recently discovered cytokine that modulates both T helper type 1 (Th1) and Th2 responses. IL-18 is elevated during acute graft-versus-host disease (GVHD). We investigated the role of IL-18 in this disorder using a well characterized murine bone marrow transplantation (BMT) model (B6 → B6D2F1). Surprisingly, blockade of IL-18 accelerated acute GVHD-related mortality. In contrast, administration of IL-18 reduced serum tumor necrosis factor (TNF)-α and lipopolysaccharide (LPS) levels, decreased intestinal histopathology, and resulted in significantly improved survival (75 vs. 15%, P < 0.001). Administration of IL-18 attenuated early donor T cell expansion and was associated with increased Fas expression and greater apoptosis of donor T cells. The administration of IL-18 no longer protected BMT recipients from GVHD when Fas deficient (lpr) mice were used as donors. IL-18 also lost its ability to protect against acute GVHD when interferon (IFN)-γ knockout mice were used as donors. Together, these results demonstrate that IL-18 regulates acute GVHD by inducing enhanced Fas-mediated apoptosis of donor T cells early after BMT, and donor IFN-γ is critical for this protective effect.

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Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects

Blood ◽

10.1182/blood-2002-08-2566 ◽

2003 ◽

Vol 101 (7) ◽

pp. 2877-2885 ◽

Cited By ~ 47

Author(s):

Pavan Reddy ◽

Takanori Teshima ◽

Gerhard Hildebrandt ◽

Debra L. Williams ◽

Chen Liu ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Acute Gvhd ◽

Allogeneic Bone ◽

Interleukin 18 ◽

Host Disease ◽

Graft Versus Host ◽

Allogeneic Bmt ◽

Graft Versus Leukemia ◽

Ifn Γ ◽

Acute Graft

Interleukin-18 (IL-18) is a unique cytokine that modulates both TH1/TH2 responses, but its ability to modulate diseases through induction of TH2 cytokines is unclear. It has been shown to play an important role in allogeneic bone marrow transplantation (BMT). Because immune responses of allogeneic BM donors may affect acute graft-versus-host disease (GVHD), we investigated the effect of pretreating BM transplant donors with IL-18 on the severity of acute GVHD using a well-characterized experimental BMT model (BALB/c→B6). Pretreatment of allogeneic BM transplant donors with IL-18 significantly improved survival (80% vs 0%; P < .001), and reduced clinical, biochemical, and pathologic indices of acute GVHD in BM transplant recipients. IL-18 pretreatment was associated with reduced interferon γ (IFN-γ) and greater IL-4 secretion by donor T cells after BMT. Acute GVHD mortality was reduced when IL-18 was administered to donors deficient in IFN-γ and signal transducer and activator of transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8+ cytotoxic T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL) effects after allogeneic BMT (70% vs 10%; P < .01). Together these data illustrate that pretreatment of donors with IL-18 prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent mechanism while preserving GVL effects.

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Preventive and Therapeutic Effects of a Novel JAK Inhibitor SHR0302 in Acute Graft-Versus-Host Disease

Cell Transplantation ◽

10.1177/09636897211033778 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110337

Author(s):

Xi Sun ◽

Qiaomei He ◽

Jun Yang ◽

Andi Wang ◽

Fang Zhang ◽

...

Keyword(s):

T Cells ◽

Mouse Models ◽

Graft Versus Host Disease ◽

Janus Kinase ◽

Therapeutic Effects ◽

Jak Inhibitor ◽

Host Disease ◽

Graft Versus Host ◽

Ifn Γ ◽

Acute Graft

Acute graft-versus-host disease (aGVHD) is one of the most common complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Janus kinase (JAK) inhibitors are considered as reliable and promising agents for patients with aGVHD. The prophylactic and therapeutic effects of SHR0302, a novel JAK inhibitor, were evaluated in aGVHD mouse models. The overall survival (OS), progression-free survival (PFS), bodyweight of mice, GVHD scores were observed and recorded. The bone marrow and spleen samples of diseased model mice or peripheral blood of patients were analyzed. SHR0302 could prevent and reverse aGVHD in mouse models with preserving graft-versus-tumor effect. Functionally, SHR0302 improved the OS and PFS, restored bodyweight, reduced GVHD scores, and reduced immune cells infiltrated in target tissues. SHR0302 treatment also enhanced the hematopoietic reconstruction compared to the control group. Mechanistically, our results suggested that SHR0302 could inhibit the activation of T cells and modulate the differentiation of helper T (Th) cells by reducing Th1 and increasing regulatory T (Treg) cells. In addition, SHR0302 decreased the expression of chemokine receptor CXCR3 on donor T cells and the secretion of cytokines or chemokines including interleukin (IL)-6, interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), CXCL10, etc. thereby destroying the IFN-γ/CXCR3/CXCL10 axis which promotes the progression of GVHD. Besides, SHR0302 decreased the phosphorylation of JAK and its downstream STATs, AKT and ERK1/2, which ultimately regulated the activation, proliferation, and differentiation of lymphocytes. Experiments on primary cells from aGVHD patients also confirmed the results. In summary, our results indicated that JAK inhibitor SHR0302 might be used as a novel agent for patients with aGVHD.

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