Donor CD4+ T-cell production of tumor necrosis factor alpha significantly contributes to the early proinflammatory events of graft-versus-host disease

Ewing, Patricia C.; Miklos, Sandra; Olkiewicz, Krystyna M.; Müller, G.; Andreesen, Reinhard; Holler, Ernst; Cooke, Kenneth R.

doi:10.1016/j.exphem.2006.09.012

Cited by 20 publications

(15 citation statements)

References 58 publications

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“…Although CD4 þ T-cells recognize MHC class II molecules and have been shown to induce GVHD in a class II-mismatched (class I-matched) murine HSCT model, 32 the importance of CD4 þ T-cells in GVHD pathogenesis has been demonstrated in fully MHC-mismatched (both class I and class II) murine models [33][34][35] and even in an HLA class I-mismatched HSCT. 36 Beilhack et al 33 visualized initial proliferation of CD4 þ T-cells followed by CD8 þ T-cells in secondary lymphoid organs, and Ewing et al 34 and Yu et al 35 have demonstrated that the activity of CD4 þ T-cells in the early phase contributes to subsequent development of aGVHD by CD8 þ T-cells. Accordingly, CD4 þ T-cells would likely have a leading role during the priming phase of aGVHD, and only then would activation and proliferation of CD8 þ T-cells proceed.…”

Section: Discussionmentioning

confidence: 99%

Frequency of CD4+FOXP3+ regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD

Fujioka

Tamaki

Ikegame

et al. 2012

Bone Marrow Transplant

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Acute GVHD (aGVHD) is a major obstacle to allogeneic hematopoietic SCT (alloHSCT). Although it is thought that aGVHD is initiated in secondary lymphoid organs at a very early stage of alloHSCT, whether CD4 þ FOXP3 þ regulatory T-cells (Tregs) have an impact on aGVHD development during this period remains unclear. Here, we measured Tregs in peripheral blood as early as possible after HLA-mismatched alloHSCT, and assessed the incidence of aGVHD. Flow cytometric analyses revealed that at the second week after HSCT, patients with aGVHD had significantly (P ¼ 0.018) lower Treg:CD4 þ T-cell ratios than those without aGVHD. As these differences were seen before the development of aGVHD, these ratios can predict the incidence of aGVHD. The cumulative incidence of aGVHD in patients with ratios of o9% was significantly higher than that in patients with ratios of X9% (P ¼ 0.0082, log-rank test). Additionally, the specific ratio of Tregs:CD4 þ T-cells was the most significant value among all other possible lymphocyte-associated ratios and absolute cell counts. These findings suggest that the ratio of Tregs:CD4 þ T-cells at the second week post HLA-mismatched alloHSCT might be a potent predictor of aGVHD in these patients. The practical efficacy of this finding should be verified in further interventional studies.

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Section: Discussionmentioning

confidence: 99%

Frequency of CD4+FOXP3+ regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD

Fujioka

Tamaki

Ikegame

et al. 2012

Bone Marrow Transplant

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“…In contrast, allogeneic recipients developed severe clinical aGVHD within the first week after BMT in parallel to systemic inflammation (Figures 1c and d) and early T-cell expansion. 34,35 During this period, prominent histopathological changes were already seen in the GI tract, whereas injury to other aGVHD target organs such as the liver, lung and skin was only of minor severity and extent (Figure 1e), reflecting the combined damaging effects of conditioning toxicity and inflammatory cytokines, such as tumor necrosis factor-a (TNFa) and interferon-g (IFNg), on the GI tract. Subsequently, subsiding levels of serum TNFa and IFNg indicated a decrease in systemic inflammation in allogeneic recipients, but clinical recovery was only partial and temporary, and was observed before progressive clinical symptoms along with increasing target organ injury to the gut, liver, lung and skin developed.…”

Section: Development Of Agvhd After Allo-bmtmentioning

confidence: 99%

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

et al. 2009

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Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyzed using real-time PCR at 1, 2, 3 and 6 weeks after BMT during the development of clinical aGVHD and target organ histopathology. CXCL9-11 expression was linked to elevated expression of CXCR3 in the gut, lung and tongue. In contrast, hepatic CXCR3 expression was not changed, whereas a clear association was seen for CXCL16 and CXCR6 expression. An elevated intestinal CCL3 expression 1 week after allo-BMT was associated with an increased expression of CCR5 but not CCR1 or CCR3, and in the lung and liver CCL3-CCL5 expression was associated with increases in CCR1 and CCR5. Overexpression of CCL2, CCL8, CCL12 and their receptor CCR2 was found in the liver and lung, but not in the gut and tongue. On the basis of the differences in kinetics and organ distribution, more studies are required to better characterize specific targets within this network, as this will allow the development of novel preventive and therapeutic approaches by using single or multiple targeting reagents.

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“…These results are consistent with the previously reported findings that CD4 ϩ T cells are a primary source of TNF␣ during the early phases of GVHD. 12 …”

Section: Differential Cytokine Profiles Of Donor T-cell Subsets Durinmentioning

confidence: 99%

“…12,23 We assessed the effect of donor CD4 ϩ T cell-derived TNF␣ on bortezomib-induced GVHD lethality using T cells from Tnf Ϫ/Ϫ mice. Transplantation of Tnf Ϫ/Ϫ CD4 ϩ T cells with Tnf ϩ/ϩ BMCs followed by delayed bortezomib administration (day 5 after BMT) resulted in significant protection and survival (P Ͻ .005; Figure 4) compared with mice receiving CD4 ϩ T cells from Tnf ϩ/ϩ donors.…”

Section: Use Of Tnf ؊/؊ Donor Cd4 ؉ T Cells Protects Bortezomib-treatmentioning

confidence: 99%

“…11 In addition, donor CD4 ϩ T cell-derived tumor necrosis factor-␣ (TNF␣) significantly contributes to the early proinflammatory events of GVHD. 12 Proteasome inhibition using bortezomib has emerged as an effective anticancer therapy and may have far-reaching potential in allogeneic bone marrow transplantation (allo-BMT) due to its antitumor and immunomodulatory effects. 13 We and others have independently demonstrated that bortezomib administered immediately after allogeneic HSCT resulted in marked inhibition of acute GVHD while still preserving GVT responses.…”

Section: Introductionmentioning

confidence: 99%

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Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

Sun

Sayers

et al. 2008

Blood

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Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-␣ (TNF␣) and interferon-␥ (IFN␥) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4 ؉ but not CD8 ؉ T cells from the donor graft. The improved survival correlated with markedly reduced serum TNF␣ but not IFN␥ levels. Transfer of Tnf Ϫ/Ϫ T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8 ؉ T cells resulted in enhanced GVT response, which was dependent on donor CD8 ؉ T cellderived IFN␥. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4 ؉ T cells from the graft or by inhibiting TNF␣. (Blood. 2008; 112:1522-1529) IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for many hematologic malignancies due, in part, to the graft-versus-tumor (GVT) responses mediated by donor T cells in the graft. However, significant obstacles such as tumor relapse and graft-versus-host disease (GVHD) still limit the efficacy of this procedure. [1][2][3][4][5] Even though GVHD and GVT are closely linked, recent clinical and experimental data indicate that separation of effective GVT from acute GVHD can be achieved. 6 Although both CD4 ϩ and CD8 ϩ T cells can independently induce GVHD target organ damage, there are significant differences in their mechanisms of action. 7,8 CD4 ϩ T cells rely predominantly on the Fas/FasL pathway, whereas CD8 ϩ T cells mediate pathology via the perforin/granzyme pathway. 9 Cytokine-mediated cytotoxicity also has a central role in CD4 ϩ T cell-mediated acute GVHD. 10 Donor CD4 ϩ T cells are the predominant T-cell population to produce interleukin (IL)-2 in the first several days after GVHD induction, which increases both the severity and mortality of GVHD. 7,8 In vitro, the bulk of cytokine production occurs in human CD4 ϩ T-cell populations after alloantigen stimulation. 11 In addition, donor CD4 ϩ T cell-derived tumor necrosis factor-␣ (TNF␣) significantly contributes to the early proinflammatory events of GVHD. 12 Proteasome inhibition using bortezomib has emerged as an effective anticancer therapy and may have far-reaching potential in allogeneic bone marrow transplantation (allo-BMT) due to its antitumor and immunomodulatory effects. 13 We and others ha...

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Donor CD4+ T-cell production of tumor necrosis factor alpha significantly contributes to the early proinflammatory events of graft-versus-host disease

Cited by 20 publications

References 58 publications

Frequency of CD4+FOXP3+ regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD

Frequency of CD4+FOXP3+ regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

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