Adeno-Associated Virus-Mediated Overexpression of Interleukin-10 Affects the Immunomodulatory Properties of Equine Bone Marrow-Derived Mesenchymal Stem Cells

Cameron, Ashley D; Even, Kayla M.; Linardi, Renata L.; Berglund, Alix K.; Schnabel, Lauren V.; Engiles, Julie B.; Ortved, Kyla F.

doi:10.1089/hum.2020.319

Cited by 9 publications

(16 citation statements)

References 47 publications

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“… 22 The BM-MSCs overexpressing IL-10 (using adenovirus or lentivirus) reduced IL-1β and IL-6 expression in IL-1β/TNFα-stimulated cartilage explants. 32 Again, BM-MSCs transfected with AAV null had the same effects, suggesting that the anti-inflammatory effect is also not mediated by IL-10. 32 Indeed, overexpression of IL-10 using an adenoviral vector did not influence IL-1β or IL-6 production, but did, however, increase TNFα production.…”

Section: Resultsmentioning

confidence: 91%

“… 32 Again, BM-MSCs transfected with AAV null had the same effects, suggesting that the anti-inflammatory effect is also not mediated by IL-10. 32 Indeed, overexpression of IL-10 using an adenoviral vector did not influence IL-1β or IL-6 production, but did, however, increase TNFα production. 36 Similar to IL-4, IL-10 had also no effect on levels of arachidonic acid, PLA2, COX-2, mPGES-1, or PGE 2 expression in unstimulated human OA chondrocytes.…”

Section: Resultsmentioning

confidence: 91%

“…In contrast, BM-MSCs reduced MMP-13 expression in IL-1β/TNFα-stimulated cartilage explants, but BM-MSCs transduced with AAV null had the same effect, suggesting that the positive effect is not related to IL-10 expression. 32 Nevertheless, in isolated chondrocytes stimulated with inflammatory cytokines, IL-10 overexpression (using an adenovirus or lentivirus, respectively) upregulated collagen type II and aggrecan, 36 , 37 and downregulated collagen type X 37 mRNA and MMP-13 expression. 36 Recombinant (r)IL-10 also impaired MMP-13 expression, but had no effect on TNFα-mediated aggrecan expression.…”

Section: Resultsmentioning

confidence: 99%

“… 22 In line with this, overexpression of IL-10 in bone marrow mesenchymal stem cells (BM-MSCs) with Adeno-Associated Virus (AAV) IL-10 did not affect GAG release or content. 32 …”

Section: Resultsmentioning

confidence: 99%

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The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

et al. 2022

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Objective A fusion protein of interleukin-4 and interleukin-10 (IL4-10 FP) was developed as a disease-modifying osteoarthritis drug (DMOAD), and chondroprotection, anti-inflammation, and analgesia have been suggested. To better understand the mechanisms behind its potential as DMOAD, this systematic narrative review aims to assess the potential of IL-4, IL-10 and the combination of IL-4 and IL-10 for the treatment of osteoarthritis. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP. Design PubMed and Embase were searched for publications that were published from 1990 until May 21, 2021 (moment of search). Key search terms were: Osteoarthritis, Interleukin-4, and Interleukin-10. This yielded 2,479 hits, of which 43 were included in this review. Results IL-4 and IL-10 showed mainly protective effects on osteoarthritic cartilage in vitro and in vivo, as did IL4-10 FP. Both cytokines showed anti-inflammatory effects, but also proinflammatory effects. Only in vitro IL4-10 FP showed purely anti-inflammatory effects, indicating that proinflammatory effects of one cytokine can be counteracted by the other when given as a combination. Only a few studies investigated the analgesic effects of IL-4, IL-10 or IL4-10 FP. In vitro, IL-4 and IL4-10 FP were able to decrease pain mediators. In vivo, IL-4, IL-10, and IL4-10 FP were able to reduce pain. Conclusions In conclusion, this review describes overlapping, but also different modes of action for the DMOAD effects of IL-4 and IL-10, giving an explanation for the synergistic effects found when applied as combination, as is the case for IL4-10 FP.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

“… 22 In line with this, overexpression of IL-10 in bone marrow mesenchymal stem cells (BM-MSCs) with Adeno-Associated Virus (AAV) IL-10 did not affect GAG release or content. 32 …”

Section: Resultsmentioning

confidence: 99%

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The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

et al. 2022

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“…Dysregulation of IL10 is associated with an increased response to infection and also an increased risk for development of many autoimmune diseases [17,19,22]. Several studies have evaluated the anti-inflammatory effects of IL10 both as a systemic and localized treatment [21,[23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy

et al. 2022

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Equine recurrent uveitis (ERU) is a spontaneous, painful, and vision threatening disease affecting up to 25% of equine populations worldwide. Current treatments of ERU are non-specific and have many side effects which limits them to short-term use. In order to develop an effective therapy for ERU, we investigated the use of adeno-associated virus (AAV) gene therapy, exploiting a natural immune tolerance mechanism induced by equine interleukin-10 (Equine-IL10). The purpose of this study was to evaluate the therapeutic efficacy of a single intravitreal (IVT) dose of AAV8-Equine-IL10 gene therapy for inhibition of experimental autoimmune uveitis (EAU) in rats. Each rat was dosed intravitreally (IVT) in both eyes with either balanced salt solution (BSS) (control; n = 4), AAV8-Equine-IL10 at a low dose (2.4x109 vg; n = 5) or high dose (2.4x1010 vg; n = 5). EAU was induced in all groups of rats 7 days after IVT injections and euthanized 21 days post-injection. Ophthalmic examination and aqueous humor (AH) cell counts were recorded with the observer blinded to the treatment groups. Histopathology and qPCR were performed on selected ocular tissues. Data presented herein demonstrate that AAV8-Equine-IL10 treated rats exhibited a significant decrease in clinical inflammatory scores and AH cell counts compared to BSS-treated EAU eyes on days 10, 12 and 14 post EAU induction at both administered vector doses. Mean cellular histologic infiltrative scores were also significantly less in AAV8-Equine-IL10 dosed rats compared to the BSS group. Intravitreal injection of AAV8-Equine-IL10 resulted in Equine-IL10 cDNA expression in the ciliary body, retina, cornea, and optic nerve in a dose-dependent manner. A single IVT injection of AAV8-Equine-IL10 appeared to be well-tolerated and inhibited EAU even at the lowest administered dose. These results demonstrate safety and efficacy of AAV8-Equine-IL10 to prevent EAU and support continued exploration of AAV gene therapy for the treatment of equine and perhaps human recurrent uveitis.

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Administration and detection of gene therapy in horses: A systematic review

Haughan

Ortved

Robinson

2022

Drug Testing and Analysis

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Gene therapy uses genetic modification of cells to produce a therapeutic effect.Defective or missing genes can be repaired or replaced, or gene expression can be modified using a variety of technologies. Repair of defective genes can be achieved using specialized gene editing tools. Gene addition promotes gene expression by introducing synthetic copies of genes of interest (transgenes) into cells where they are transcribed and translated into therapeutic proteins. Protein production can also be modified using therapies that regulate gene expression.Gene therapy is currently prohibited in both human and equine athletes because of the potential to induce production of performance-enhancing proteins in the athlete's body, also referred to as "gene doping." Detection of gene doping is challenging and necessitates development of creative, novel analytical methods for doping control. Methods for detection of gene doping must be specific to and will vary depending on the type of gene therapy. The purpose of this paper is to present the results of a systematic review of gene editing, gene therapy, and detection of gene doping in horses.Based on the published literature, gene therapy has been administered to horses in a large number of experimental studies and a smaller number of clinical cases. Detection of gene therapy is possible using a combination of PCR and sequencing technologies. This summary can provide a basis for discussion of appropriate and inappropriate uses for gene therapy in horses by the veterinary community and guide expansion of methods to detect inappropriate uses by the regulatory community.

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Adeno-Associated Virus-Mediated Overexpression of Interleukin-10 Affects the Immunomodulatory Properties of Equine Bone Marrow-Derived Mesenchymal Stem Cells

Cited by 9 publications

References 47 publications

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy

Administration and detection of gene therapy in horses: A systematic review

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