A metalloproteinase inhibitor prevents acute graft‐versus‐host disease while preserving the graft‐versus‐leukaemia effect of allogeneic bone marrow transplantation

Hattori, Koichi; Hirano, Toshio; Miyajima, Hiroaki; Yamakawa, Norifumi; Ikeda, Shoji; Yoshino, Kohichiro; Tateno, Masatoshi; Oshimi, Kazuo; Kayagaki, Nobuhiko; Yagita, Hideo; Okumura, Ko

doi:10.1111/j.1365-2141.1999.01318.x

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…Because MMP inhibitor prevented lethal acute graft-versus-host disease in mice (19,20), we hypothesized that in addition to the cytokinemodulating effect of MMPs, they might also be lesionally expressed and contribute to destruction on the tissue level. In this work, we studied the expression of MMPs and TIMPs previously shown to be abundantly expressed in intestinal ulcers related to inflammatory bowel disease.…”

Section: Discussionmentioning

confidence: 99%

“…The synthetic MMP inhibitor (KB-R7785), with activity against MMPs-1, -3, and -9, prevents acute graft-versus-host disease but preserves graft-versusleukemia effect in mice undergoing allogeneic bone marrow transplantation (19,20). TNF-␣ and FasL, both released and activated by MMPs (3,21), are implicated in the pathogenesis of acute graftversus-host disease (22).…”

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confidence: 99%

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Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Salmela

Karjalainen–Lindsberg

Jeskanen

et al. 2003

Modern Pathology

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Matrix metalloproteinases (MMPs) have been implicated in the pathobiology of various T-cell-mediated inflammatory disorders of the intestine and skin. Their synthetic inhibitor has been shown to prevent lethal acute graft-versus-host disease in animal models. We intended to determine the expression of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue inhibitors of metalloproteinases (TIMPs) 1 and 3 in intestinal and cutaneous lesions of patients suffering from graft-versus-host disease after bone marrow transplantation. In situ hybridizations for MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 were performed using 35 S-labeled cRNA probes on intestinal (n ‫؍‬ 13) and cutaneous specimens (n ‫؍‬ 9) from patients with graft-versus-host disease. Immunohistochemical stainings were carried out to localize MMP-9, MMP-19, TIMP-3, and TGF-␤1 proteins, and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cutaneous lesions in areas with vacuolar degeneration of the basal epidermal layer in all skin samples, and they colocalized with apoptotic keratinocytes and partly with staining for TGF-␤. None of the MMPs examined were overexpressed in skin lesions. Signals for MMP-1 and MMP-3 mRNA was found in 10/13 and 5/13 intestinal biopsies, respectively. In the gut, MMP-19 -positive epithelial cells, particularly in the crypts, were found in 10/13 samples. Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal cells in 12/13 and 10/13 gut samples, respectively. Whereas TIMP-1 was expressed particularly by subepithelial cells where epithelium had shed away, TIMP-3 was detected in deeper areas. We conclude that MMPs are differentially regulated in the skin and gut lesions of graft-versus-host disease. In agreement with previous data on cancer cells, TIMP-3, induced by TGF-␤1, may contribute to the apoptosis of keratinocytes in cutaneous graftversus-host disease lesions, leading to typical histopathological changes. We also conclude that MMPs play a less important role as effector molecules in intestinal graft-versus-host disease than in celiac or inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Salmela

Karjalainen–Lindsberg

Jeskanen

et al. 2003

Modern Pathology

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“…Such a pattern may not be surprising as murine studies have shown that TNF␣ plays a predominant role in GVHD manifestations in the intestinal tract. 53 A retrospective analysis by Couriel et al in 21 patients with steroid-refractory acute GVHD showed a response rate of 60% with infliximab, with most responses being complete. 54 The rate of infection, in particular with fungal organisms, was high (hazard ratio, 13.6).…”

Section: Primary Therapy and Its Impactmentioning

confidence: 99%

How I treat refractory acute GVHD

Deeg

2007

Blood

375

282

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Graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids (steroids). Approaches to therapy of acute GVHD refractory to "standard" doses of steroids have ranged from increasing the dose of steroids to the addition of polyclonal or monoclonal antibodies, the use of immunotoxins, additional immunosuppressive/chemotherapeutic interventions, phototherapy, and other means. While many pilot studies have yielded encouraging response rates, in most of these studies long-term survival was not improved in comparison with that seen with the use of steroids alone. A major reason for failure has been the high rate of infections, including invasive fungal, bacterial, and viral infections. It is difficult to conduct controlled prospective trials in the setting of steroidrefractory GVHD, and a custom-tailored therapy dependent upon the time after HCT, specific organ manifestations of GVHD, and severity is appropriate. All patients being treated for GVHD should also receive intensive prophylaxis against infectious complications. IntroductionGraft-versus-host disease (GVHD) is the most frequent complication after allogeneic hematopoietic cell transplantation (HCT). First described as "secondary disease" in mice 1 the syndrome was shown to be triggered by immunocompetent donor cells. 2,3 As soon as the clinical basis for human HCT was established, it was apparent that GVHD would be a formidable problem even with transplantation of marrow cells from sibling donors who were identical with the patient for the antigens of the major histocompatibility complex (MHC), termed HLA (human leukocyte antigen) in humans.The development of acute GVHD is dependent upon various risk factors, which affect the manifestations of the disease and, possibly, the response to first-line therapy. Furthermore, treatment responses may be incomplete or mixed, rendering the assessment of refractory acute GVHD difficult. It appears justified, therefore, to provide a brief background description of the pathophysiology and classification of GVHD and outline up-front therapeutic strategies, which often overlap with what we consider therapy for refractory GVHD. Pathophysiology and risk factorsUnderstanding the pathophysiology of GVHD is a prerequisite to designing effective prophylactic and therapeutic strategies. A 3-step process best reflects the current view of the development of GVHD (reviewed in Ferrara et al 4 ). In this model, total body irradiation (TBI) or other cytotoxic modalities used to prepare patients for HCT result in tissue damage and the release of inflammatory cytokines into the circulation. In this milieu, transplanted donor T lymphocytes (and other cellular compartments) are activated. Studies in mice have shown that host antigen-presenting cells, in particular dendritic cells, are essential, 5 and the cytokines released by tissue damage up-regulate ...

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“…Therefore, targeting the cleavage of membrane-bound TNF with a TACE inhibitor could be assessed as a new therapeutic strategy for attenuating gastrointestinal and hepatic GVHD without impacting GVT after allo-BMT. 18,19 …”

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Absence of donor T-cell–derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity

Borsotti

Franklin

et al. 2007

Blood

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Tumor necrosis factor (TNF) plays an important role in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) activity after allogeneic bone marrow transplantation (allo-BMT). TNF can be expressed in a membrane-bound form (memTNF) and as a soluble (solTNF) molecule after being cleaved by the TNF-alpha converting enzyme (TACE). To study the contribution of donor T-cell-derived memTNF versus solTNF in GVHD and GVT, we used mice containing a noncleavable allele in place of endogenous TNF (memTNF(Delta/Delta)) as donors in murine BMT models. Recipients of memTNF T cells developed significantly less GVHD than recipients of wild-type (wt) T cells. In contrast, GVT activity mediated by memTNF T cells remained intact, and alloreactive memTNF T cells showed no defects in proliferation, activation, and cytotoxicity. These data suggest that suppressing the secretion of solTNF by donor T cells significantly decreases GVHD without impairing GVT activity.

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A metalloproteinase inhibitor prevents acute graft‐versus‐host disease while preserving the graft‐versus‐leukaemia effect of allogeneic bone marrow transplantation

Cited by 11 publications

References 42 publications

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease

How I treat refractory acute GVHD

Absence of donor T-cell–derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity

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