Topical neurokinin-1 receptor antagonist Fosaprepitant ameliorates ocular graft-versus-host disease in a preclinical mouse model

2021 ◽  
pp. 108825
Author(s):  
Romina Mayra Lasagni Vitar ◽  
Filippo Bonelli ◽  
Ayça Atay ◽  
Francesca Triani ◽  
Philippe Fonteyne ◽  
...  
Keyword(s):  
Mouse Model ◽  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Neurokinin 1 Receptor ◽  
Graft Versus Host ◽  
Neurokinin 1

scholarly journals Compound a Increases Cell Infiltration in Target Organs of Acute Graft-versus-Host Disease (aGVHD) in a Mouse Model

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4237
Author(s):  
Abdellatif Bouazzaoui ◽  
Ahmed A. H. Abdellatif ◽  
Faisal A. Al-Allaf ◽  
Neda M. Bogari ◽  
Mohiuddin M. Taher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Cell Infiltration ◽  
Compound A ◽  
Host Disease ◽  
Graft Versus Host ◽  
Target Organs ◽  
Acute Graft

Systemic steroids are used to treat acute graft-versus-host disease (aGVHD) caused by allogenic bone marrow transplantation (allo-BMT); however, their prolonged use results in complications. Hence, new agents for treating aGVHD are required. Recently, a new compound A (CpdA), with anti-inflammatory activity and reduced side effects compared to steroids, has been identified. Here, we aimed to determine whether CpdA can improve the outcome of aGVHD when administered after transplantation in a mouse model (C57BL/6 in B6D2F1). After conditioning with 9Gy total body irradiation, mice were infused with bone marrow (BM) cells and splenocytes from either syngeneic (B6D2F1) or allogeneic (C57BL/6) donors. The animals were subsequently treated (3 days/week) with 7.5 mg/kg CpdA from day +15 to day +28; the controls received 0.9% NaCl. Thereafter, the incidence and severity of aGVHD in aGVHD target organs were analyzed. Survival and clinical scores did not differ significantly; however, CpdA-treated animals showed high cell infiltration in the target organs. In bulk mixed lymphocyte reactions, CpdA treatment reduced the cell proliferation and expression of inflammatory cytokines and chemokines compared to controls, whereas levels of TNF, IL-23, chemokines, and chemokine receptors increased. CpdA significantly reduced proliferation in vitro but increased T cell infiltration in target organs.

Post‐transplant cyclophosphamide limits reactive donor T cells and delays the development of graft‐versus‐host disease in a humanised mouse model

Immunology ◽  
2021 ◽  
Author(s):  
Sam Raj Adhikary ◽  
Peter Cuthbertson ◽  
Leigh Nicholson ◽  
Katrina M. Bird ◽  
Chloe Sligar ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Donor T Cells

scholarly journals Protective effect of neutralizing anti-IL-18α monoclonal antibody on a mouse model of acute graft-versus-host disease

2015 ◽  
Vol 34 (4) ◽  
pp. 2031-2039 ◽  
Author(s):  
XIAOCUI LI ◽  
CUIPING ZHANG ◽  
WEI CHEN ◽  
BIN PAN ◽  
FANYUN KONG ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mouse Model ◽  
Protective Effect ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease

2005 ◽  
Vol 130 (4) ◽  
pp. 568-574 ◽  
Author(s):  
Martin Schmidt-Hieber ◽  
Thomas Fietz ◽  
Wolfgang Knauf ◽  
Lutz Uharek ◽  
Werner Hopfenmuller ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Host Disease ◽  
Graft Versus Host ◽  
Interleukin 2 Receptor ◽  
Steroid Refractory ◽  
Acute Graft

scholarly journals Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease

Blood ◽  
1994 ◽  
Vol 84 (4) ◽  
pp. 1342-1348 ◽  
Author(s):  
JH Antin ◽  
HJ Weinstein ◽  
EC Guinan ◽  
P McCarthy ◽  
BE Bierer ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
Response To Therapy ◽  
Mrna Levels ◽  
Steroid Resistant ◽  
Host Disease ◽  
Graft Versus Host

Abstract Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL- 1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.

Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 100 (10) ◽  
pp. 3479-3482 ◽  
Author(s):  
Joseph H. Antin ◽  
Daniel Weisdorf ◽  
Donna Neuberg ◽  
Roberta Nicklow ◽  
Shawn Clouthier ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Receptor Antagonist ◽  
Graft Versus Host Disease ◽  
Interleukin 1 ◽  
Double Blind ◽  
Host Disease ◽  
Double Blind Placebo ◽  
Graft Versus Host ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) is thought to derive from direct T-cell injury of target tissues through perforin/granzyme, Fas/FasL interactions, and the effects of inflammatory cytokines. Animal models and some clinical trials support the notion that inhibition of inflammatory mediators such as interleukin-1 (IL-1), tumor necrosis factor α, and interferon γ may ameliorate or prevent GVHD. We hypothesized that blockade of IL-1 during the period of initial T-cell activation would reduce the risk of severe GVHD. We tested this hypothesis in a double-blind, placebo-controlled randomized trial of recombinant human IL-1 receptor antagonist (IL-1Ra) in 186 patients undergoing allogeneic stem cell transplantation. Randomization was stratified by degree of histocompatibility and stem cell source. All patients were conditioned with cyclophosphamide and total body irradiation. GVHD prevention consisted of cyclosporine and methotrexate in all patients. Recombinant human IL-1Ra or saline placebo was given from day −4 to day +10. Randomization was stratified according to GVHD risk. The 2 groups were well-matched for pretreatment characteristics. Moderate to severe GVHD (grades B-D) developed in 57 (61%) of 94 patients receiving IL-1Ra and in 51 (59%) of 86 patients on placebo (P = .88). There was no difference in hematologic recovery, transplantation-related toxicity, event-free survival, or overall survival. We conclude that blockade of IL-1 using IL-1Ra during conditioning and 10 days immediately after transplantation is not sufficient to reduce GVHD or toxicity or to improve survival.

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages

2017 ◽  
Vol 76 (6) ◽  
pp. 1133-1141 ◽  
Author(s):  
Christiane Maier ◽  
Andreas Ramming ◽  
Christina Bergmann ◽  
Rita Weinkam ◽  
Nicolai Kittan ◽  
...  
Keyword(s):  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Interleukin 6 ◽  
Skin Fibrosis ◽  
M2 Macrophages ◽  
Preclinical Models ◽  
Host Disease ◽  
Graft Versus Host ◽  
Fibroblast Activation ◽  
Phosphodiesterase 4

ObjectivesTo investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).MethodsWe studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.ResultsSpecific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.ConclusionsPDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.

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