Early Intestinal Th1 Inflammation and Mucosal T Cell Recruitment During Acute Graft-Versus-Host Reaction

Snider, Denis P.; Liang, Hong

doi:10.4049/jimmunol.166.10.5991

Cited by 22 publications

(20 citation statements)

References 60 publications

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“…Studies have shown that an increased level of cytokine production in the gut, mainly by infiltrating donor T cells, can mediate acute GVHD. 24,25 Increased histopathology scores were found in the colon of B7-H3 2/2 recipients at days 7 and 21 after transplant. Our data show that a higher percentage of both CD4 1 and CD8 1 donor T cells were secreting inflammatory cytokines (IFN-g, TNF-a, and IL-17) and had increased T effector proliferation in the intraepithelial layer of the colon in B7-H3 2/2 recipients at day 21 posttransplant.…”

Section: Discussionmentioning

confidence: 99%

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

Veenstra

Flynn

Kreymborg

et al. 2015

Blood

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Key Points• Absence of B7-H3 expression in allogeneic recipients or on allogeneic donor T cells leads to accelerated GVHD lethality.• Increased GVHD lethality is a result of increased T-cell proliferation, colon inflammatory cytokines, and intestinal permeability.Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3 2/2 vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3 2/2 vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3 2/2 Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. (Blood. 2015;125(21):3335-3346)

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Section: Discussionmentioning

confidence: 99%

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

Veenstra

Flynn

Kreymborg

et al. 2015

Blood

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“…1 This disease is commonly referred to as acute GVHD (aGVHD) if symptoms appear within 100 days after transplantation or as chronic GVHD (cGVHD) if symptoms occur later. aGVHD primarily involves the skin, liver, gastrointestinal tract and lymphoid tissues, 2 while cGVHD is a systemic and multiorgan syndrome that has many features suggestive of a range of spontaneous autoimmune diseases including primary scleroderma, dermatomyositis, systemic lupus erythematosus, primary biliary cirrhosis and Sjö gren's syndrome (SS). [3][4][5][6] In patients with cGVHD after HSCT, it is well known that SS-like xerostomia with a reduced production of saliva and oral lichenoid lesions frequently develop concomitantly.…”

Section: Introductionmentioning

confidence: 99%

Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD

Nakamura

Toyoshima

Moriyama

et al. 2012

Bone Marrow Transplant

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Chronic GVHD (cGVHD) after allogeneic hematopoietic SCT (HSCT) is characterized by an infiltration of T cells into target organs including the oral mucosa and salivary glands. This study was designed to clarify the molecular mechanism of the local accumulation of pathogenic T cells in cGVHD. The expression of cytokines, chemokines and chemokine receptors in the buccal mucosa (BM), labial salivary glands (LSG) and PBMC from 16 patients with cGVHD after allogeneic HSCT was examined. The mRNA expression of T helper 1 (Th1) and Th2 cytokines, and several chemokines and chemokine receptors was significantly increased in the BM and LSG from cGVHD patients, in comparison with both those in the BM and LSG from controls, respectively, and also with those in the PBMC from cGVHD patients. Furthermore, the mRNA expression of Th2 cytokines, macrophage-derived chemokine and CC chemokine receptor 4 was closely associated with a strong T-cell infiltration in the BM and LSG from cGVHD patients. These results suggest that cGVHD might be initiated and/or maintained by Th1/Th0 cells and thereafter progresses in association with Th2 cell accumulation via the interaction of particular chemokine and chemokine receptors.

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“…Studies have shown that an increased level of cytokine production in the gut, mainly by donor infiltrating T cells, can mediate acute GVHD. 33,34 Conversely, it has been shown that inhibiting cytokines (IFN-␥ or IL-12) can inhibit acute GVHD in murine models. 35,36 A reduced inflammatory response may be a mechanism responsible for the reduced epithelial damage and slowed GVHD lethality that we observed in recipients of Treg depleted Tim-3 Ϫ/Ϫ donor T cells.…”

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confidence: 99%

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

Veenstra

Taylor

Zhou

et al. 2012

Blood

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T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3 ؉ T cells encounter high gal-9 levels, they are deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/ gal-9 binding by infusion of a Tim-3-Ig fusion protein or Tim-3 ؊/؊ donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was associated with decreased colonic inflammatory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3 ؊/؊ donor T cells underwent increased activationinduced cell death because of increased IFN-␥ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death. (Blood. 2012;120(3):682-690) IntroductionGVHD remains the leading cause of morbidity and mortality after bone marrow transplantation (BMT). Patients are given immune suppressive therapy to prevent or diminish the severity of GVHD after allogeneic BMT that in turn increases the risk of infection and disease recurrence. Novel GVHD strategies remain a high priority.The T-cell immunoglobulin mucin (TIM) family consists of 3 proteins (TIM-1, -3, and -4), homologous in mouse and human. 1 Tim-3 was the first described member 2 and has been the most well studied. Differentiated T-effector cells (Teffs) express Tim-3 with the highest density on T-helper (Th)1, lower density on Th17, and no expression on Th2 cells. 3,4 The expression of galectin-9 (gal-9), identified as a ligand for Tim-3, is up-regulated in inflamed tissues. [5][6][7][8] When Tim-3 ϩ Teffs encounter high gal-9 levels, they are deleted. 5,9-11 A major function of the Tim-3/gal-9 pathway is to limit immune responses under conditions of tissue inflammation and injury. In vivo blockade of Tim-3/gal-9 interaction or the use of Tim-3 knockout (Ϫ/Ϫ) mice increases Th1 cells within inflamed tissues. 2,12,13 When Tim-3 binds with gal-9, Th1 responses are inhibited and peripheral tolerance is induced. 5,12,13 In vivo blocking strategies relying on monoclonal anti-Tim-3 antibody and Tim-3-Ig fusion protein showed exacerbation of experimental autoimmune encephalomyelitis and autoimmune diabetes. 2,12 Transplant tolerance induced by donor-specific transfusion and anti-CD154 treatment was impaired. 13 Thus, Tim-3/gal-9 signaling acts to dampen a Th1 immune response, whereas signaling ...

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Early Intestinal Th1 Inflammation and Mucosal T Cell Recruitment During Acute Graft-Versus-Host Reaction

Cited by 22 publications

References 60 publications

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality

Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

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