Tumor necrosis factor-α blockade for the treatment of acute GVHD

Couriel, Daniel R.; Saliba, Rima M.; Hicks, Krystal; Ippoliti, Cindy; Lima, Marcos de; Hosing, Chitra; Khouri, Issa F.; Andersson, Börje S.; Gajewski, J.; Donato, Michèle; Anderlini, Paolo; Kontoyiannis, Dimitrios P.; Cohen, A.; Martin, Thomas G.; Giralt, Sergío; Champlin, Richard E.

doi:10.1182/blood-2003-12-4241

Cited by 251 publications

(191 citation statements)

References 47 publications

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“…As many of these chemokines are synthesized by macrophages, we speculate that their increased expression in mice infected with the Δ gliP mutants was due to reduced death of macrophages in the fungal lesions. In mice infected with the Δ gliP mutant, there was also elevated expression of IL-6 and TNF-α, suggesting that gliotoxin also inhibits the production of these cytokines, both of which are required for the host defense against invasive aspergillosis [36–38]. …”

Section: Discussionmentioning

confidence: 99%

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Liu

Solis

et al. 2018

Virulence

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Gliotoxin contributes to the virulence of the fungus Aspergillus fumigatus in non-neutropenic mice that are immunosuppressed with corticosteroids. To investigate how the absence of gliotoxin affects both the fungus and the host, we used a nanoString nCounter to analyze their transcriptional responses during pulmonary infection of a non-neutropenic host with a gliotoxin-deficient ΔgliP mutant. We found that the ΔgliP mutation led to increased expression of aspf1, which specifies a secreted ribotoxin. Prior studies have shown that aspf1, like gliP, is not required for virulence in a neutropenic infection model, but its role in a non-neutropenic infection model has not been fully investigated. To investigate the functional significance of this up-regulation of aspf1, a Δaspf1 single mutant and a Δaspf1 ΔgliP double mutant were constructed. Both Δaspf1 and ΔgliP single mutants had reduced lethality in non-neutropenic mice, and a Δaspf1 ΔgliP double mutant had a greater reduction in lethality than either single mutant. Analysis of mice infected with these mutants indicated that the presence of gliP is associated with massive apoptosis of leukocytes at the foci of infection and inhibition of chemokine production. Also, the combination of gliP and aspf1 is associated with suppression of CXCL1 chemokine expression. Thus, aspf1 contributes to A. fumigatus pathogenicity in non-neutropenic mice and its up-regulation in the ΔgliP mutant may partially compensate for the absence of gliotoxin.Abbreviations:PAS: periodic acid-Schiff; PBS: phosphate buffered saline; ROS: reactive oxygen species; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling

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Section: Discussionmentioning

confidence: 99%

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Liu

Solis

et al. 2018

Virulence

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“…24 Other phase II studies that addressed blocking of proinflammatory cytokines (for example, TNF-a and IL-2) with MoAbs resulted in overall CR rates of 47, 53 and 62% for daclizumab, basiliximab and infliximab, respectively. [25][26][27] In the study by Przepiorka et al using daclizumab, a specific CR rate of 37% was reported for GI GVHD. A CR rate of 67% was reported for infliximab by Couriel et al However, only 3 of 12 subjects had grade X3 GI GVHD.…”

Section: Discussionmentioning

confidence: 99%

Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis

Schmitt

Luft

Hegenbart

et al. 2010

Bone Marrow Transplant

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“…In a retrospective study, infliximab has been shown to be associated with significant response although the proportion of patients with grade III-IV aGVHD was low and treatment was complicated by infections particularly aspergillus which could be explained by elimination of monocytes-macrophages by infliximab [97,98]. Etanercept also increased infections in clinical trials but not as much as infliximab [81,86].…”

Section: Anti-tnfα Agentsmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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Tumor necrosis factor-α blockade for the treatment of acute GVHD

Cited by 251 publications

References 47 publications

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis

State-of-the-art acute and chronic GVHD treatment

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