scholarly journals Survival Improvements Following Omega-3 Polyunsaturated Fatty Acid Dietary Enrichment, Acetylsalicylic Acid, and Aspirin-Triggered Lipoxin Administration in a Lethal Mouse Model of Acute Graft-Versus-Host Disease

2013 ◽  
Vol 19 (2) ◽  
pp. S322
Author(s):  
Geoff Cuvelier ◽  
Yuri Lissitsyn ◽  
Khuong Le ◽  
Mohammed Moghadasian ◽  
Cindy Ellison
Keyword(s):  
Fatty Acid ◽  
Mouse Model ◽  
Acetylsalicylic Acid ◽  
Polyunsaturated Fatty Acid ◽  
Graft Versus Host Disease ◽  
Omega 3 ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Effect of An Omega-3 Polyunsaturated Fatty Acid Enriched Diet, Acetylsalicylic Acid, and Aspirin-Triggered Lipoxin on Survival in a Murine Model of Acute Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4708-4708
Author(s):  
Geoff D. E. Cuvelier ◽  
Yuri V Lissitsyn ◽  
Mohammed H Moghadasian ◽  
Khuong Le ◽  
Cynthia A Ellison
Keyword(s):  
Fatty Acid ◽  
Mouse Model ◽  
Acetylsalicylic Acid ◽  
Graft Versus Host Disease ◽  
Lipid Mediators ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Significant Survival ◽  
Dosing Strategy ◽  
Acute Graft

Abstract Abstract 4708 Background: Systemic inflammation is well appreciated to play a role in the pathogenesis of acute graft-versus-host disease (aGVHD). Recent studies have focused on homeostatic mechanisms that counteract inflammation and heal damaged tissues. These include the generation of lipoxins, resolvins, and protectins, eicosanoid molecules collectively referred to as the anti-inflammatory and pro-resolving lipid mediators. These lipid mediators have biologic activities known to antagonize mechanisms underlying the development of aGVHD, including downregulation of pro-inflammatory cytokines such as TNFα. Resolvins and protectins are derived from the Ω3-polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. Diets enriched for Ω3-PUFAs (high fish oil) are protective against inflammatory conditions, whereas “Western” diets with higher Ω6-PUFA promote inflammation. Furthermore, the anti-inflammatory properties of acetylsalicylic acid (ASA) are increasingly being attributed to its ability to enhance the generation of aspirin-triggered lipoxins, epimers of endogenously produced lipoxins. Hypothesis: We hypothesized that a diet enriched for Ω3-PUFAs, ASA ingestion or the injection of a purified aspirin triggered lipoxin would mitigate the development of aGVHD and provide a survival advantage in a major histocompatibility mismatched mouse model of aGVHD. Methods: The C56BL/6→(C57BL/6 × DBA/2)F1-hybrid mouse model was used to induce lethal aGVHD. Five groups (n=10) were established and treated as follows: Recipients were fed the diets for 8-weeks before transplantation. The Ω6-diet (control) was enriched to 2% total FA with arachidonic acid (ARASCO, Martek). The Ω3-diet was enriched to 1% each of EPA (ROPUFA-30, DSM Nutritionals) and DHA (DHASCO, Martek). Chromatography was used to confirm the fatty acid (FA) composition of each diet, and the FA content (Ω6 and Ω3 tissues stores) of the mouse livers (n=4/diet) after 8-weeks of feeding. Diets were the same for each group pre- and post-transplant. Using identical methodology, a second experiment was performed in which the recipients were treated as follows: Ω6-diet plus 15-epi-LxA4 100 mcg/kg/day, i.p. daily from day 0 until death (n=10). Survival post-transplant was the primary outcome. Mice were euthanized when they showed signs of GVHD-associated morbidity and had reached their humane endpoint as defined in our animal protocol. Results: Compared to mice fed the Ω6 or Ω6 plus ASA diets, the Ω3 and Ω3 plus ASA diets resulted in a higher hepatic content of both EPA and DHA after 8-weeks of feeding, suggesting differential tissue stores of these Ω3-PUFAs immediately before transplant in the mice fed the Ω3-diets (mean EPA as % of total FA: 0.22% and 0.19% vs. 0.92% and 1.03%, respectively; mean DHA as % of total FA: 1.58% and 1.79% vs. 6.99% and 8.15%, respectively: p<0.05). No significant survival differences were seen post- transplant in groups 1–4 (figure 1). Similarly, mice injected with 200 mcg/kg/day of 15-epi-LxA4 at days 0 and 7 (Group 5) failed to show a significant survival advantage, although a non-significant trend towards improved survival by a couple of days was suggested (figure 1). Since no dosing strategy for 15-epi-LxA4 is known, we repeated the experiment using a lower (100 mcg/kg/day) but more frequent (daily) dosing of 15-epi-LxA4. No significant improvements in survival were observed compared to the control group (figure 2). Conclusions: We were unable to demonstrate a significant improvement in survival in any of the treatment groups in this model of aGVHD. Possible reasons for this may include a suboptimal dosing strategy (frequency and/or cumulative dose) or the intense systemic inflammatory response that develops in this mouse model of acute GVHD. Alternatively, the treatments used in this study may be insufficient to have any therapeutic benefit on the relevant outcomes such as survival from aGVHD, when administered as stand-alone treatments. Since little is known about these interventions in transplantation, we continue to explore different combinations and dosing strategies. Disclosures: No relevant conflicts of interest to declare.

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.

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

scholarly journals A novel mouse model of acute graft-versus-host disease based on chemotherapy conditioning and G-CSF mobilized graft

2019 ◽  
Vol 55 (3) ◽  
pp. 570-577
Author(s):  
Yishan Ye ◽  
Laure Ricard ◽  
Nicolas Stocker ◽  
Mohamad Mohty ◽  
Béatrice Gaugler ◽  
...  
Keyword(s):  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

IL-35 inhibits acute graft-versus-host disease in a mouse model

2015 ◽  
Vol 29 (2) ◽  
pp. 383-392 ◽  
Author(s):  
Xiao-Hui Zhang ◽  
Yi Zhou ◽  
Jia-Min Zhang ◽  
Shi-Yuan Zhou ◽  
Min Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease

2021 ◽  
Vol 65 ◽  
pp. 101373
Author(s):  
Jennifer M. Corbett ◽  
Ian Hawthorne ◽  
Ivan S. Coulter ◽  
Karen English
Keyword(s):  
Drug Delivery ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals PS1565 REPETITIVE SUPPLEMENTS OF TGF-B1 INDUCED REGULATORY T CELLS PREVENTS ACUTE GRAFT-VERSUS-HOST DISEASE IN MOUSE MODEL

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 721-722
Author(s):  
T.-J. Chiou ◽  
Y.-C. Ke ◽  
C.-T. Kuo ◽  
H.-Y. Huang ◽  
S.-C. Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Therapeutic Efficacy of Cord Blood-Derived Mesenchymal Stromal Cells for the Prevention of Acute Graft-Versus-Host Disease in a Xenogenic Mouse Model

2012 ◽  
Vol 21 (10) ◽  
pp. 1616-1626 ◽  
Author(s):  
Joëlle Gregoire-Gauthier ◽  
Silvia Selleri ◽  
François Fontaine ◽  
Mame Massar Dieng ◽  
Natalie Patey ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cord Blood ◽  
Mesenchymal Stromal Cells ◽  
Graft Versus Host Disease ◽  
Stromal Cells ◽  
Therapeutic Efficacy ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

scholarly journals Cyclosporine A and IFNγ licencing enhances human mesenchymal stromal cell potency in a humanised mouse model of acute graft versus host disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer M. Corbett ◽  
Ian Hawthorne ◽  
Hazel Dunbar ◽  
Ivan Coulter ◽  
Mairead Ni Chonghaile ◽  
...  
Keyword(s):  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Cyclosporine A ◽  
Limiting Factor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cytokine Activation ◽  
Acute Graft

AbstractImmunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo.

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