Limits...
AAV2-mediated combined subretinal delivery of IFN-α and IL-4 reduces the severity of experimental autoimmune uveoretinitis.

Tian L, Lei B, Shao J, Wei L, Kijlstra A, Yang P - PLoS ONE (2012)

Bottom Line: IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically.AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α.The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone.

View Article: PubMed Central - PubMed

Affiliation: The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.

ABSTRACT
We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×10(7) vg), AAV2.IL-4 alone (3.55×10(7) vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×10(7) vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response.

Show MeSH

Related in: MedlinePlus

Histological examinations on day 14 of EAU.Images of histological analysis show severe intraocular inflammation in PBS (a,b) and AAV2.GFP injected eyes (c,d) compared with AAV2.IFN-α treated (e,f), AAV2.IL-4 treated (g,h), and AAV2.IFN-α combined with AAV2.IL-4 treated eyes (i,j). (haematoxylin eosin staining, original magnification×100). EAU was significantly reduced in AAV2.IL-4 treated group, AAV2.IL-4 combined with AAV2.IFN-α treated group as compared with controls (k) (p<0.0001, Mann-Whitney U test). The AAV2.IFN-α treated group also shows a significantly decreased uveitis (p = 0.005). Each point is the score of an individual eye. The mean scores of each group are denoted by the horizontal bars.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369876&req=5

pone-0037995-g004: Histological examinations on day 14 of EAU.Images of histological analysis show severe intraocular inflammation in PBS (a,b) and AAV2.GFP injected eyes (c,d) compared with AAV2.IFN-α treated (e,f), AAV2.IL-4 treated (g,h), and AAV2.IFN-α combined with AAV2.IL-4 treated eyes (i,j). (haematoxylin eosin staining, original magnification×100). EAU was significantly reduced in AAV2.IL-4 treated group, AAV2.IL-4 combined with AAV2.IFN-α treated group as compared with controls (k) (p<0.0001, Mann-Whitney U test). The AAV2.IFN-α treated group also shows a significantly decreased uveitis (p = 0.005). Each point is the score of an individual eye. The mean scores of each group are denoted by the horizontal bars.

Mentions: Histological analysis showed a severe uveitis in the AAV2.GFP injected and PBS injected control mice as evidenced by massive infiltration of inflammatory cells into the iris, vitreous cavity, throughout all retinal layers and the choroid, intensive retinal vasculitis, destruction of the retinal architecture with severe folding and detachment, as well as photoreceptor damage (Figs. 4a–d). However, in AAV2.IFN-α alone treated, AAV2.IL-4 alone treated, AAV2.IFN-α and AAV2.IL-4 combined treated eyes, only scattered infiltration of inflammatory cells into the vitreous body and retina was observed (Figs. 4e, g, i). Additionally, the inflammatory changes in the anterior segment of treated eyes were less than those in the AAV2.GFP injected eye and PBS injected eyes (Figs. 4f, h, j). Pathological grading showed that the AAV2.IFN-α alone treated eyes showed a significantly decreased uveitis when compared with PBS and AAV2.GFP injected controls (p = 0.01, p = 0.012). AAV2.IL-4 alone injected eyes and AAV2.IL-4 combined with AAV2.IFN-α treated eyes showed more significantly decreased inflammation compared with controls (p<0.0001) than AAV2.IFN-α alone (Fig. 4k).


AAV2-mediated combined subretinal delivery of IFN-α and IL-4 reduces the severity of experimental autoimmune uveoretinitis.

Tian L, Lei B, Shao J, Wei L, Kijlstra A, Yang P - PLoS ONE (2012)

Histological examinations on day 14 of EAU.Images of histological analysis show severe intraocular inflammation in PBS (a,b) and AAV2.GFP injected eyes (c,d) compared with AAV2.IFN-α treated (e,f), AAV2.IL-4 treated (g,h), and AAV2.IFN-α combined with AAV2.IL-4 treated eyes (i,j). (haematoxylin eosin staining, original magnification×100). EAU was significantly reduced in AAV2.IL-4 treated group, AAV2.IL-4 combined with AAV2.IFN-α treated group as compared with controls (k) (p<0.0001, Mann-Whitney U test). The AAV2.IFN-α treated group also shows a significantly decreased uveitis (p = 0.005). Each point is the score of an individual eye. The mean scores of each group are denoted by the horizontal bars.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369876&req=5

pone-0037995-g004: Histological examinations on day 14 of EAU.Images of histological analysis show severe intraocular inflammation in PBS (a,b) and AAV2.GFP injected eyes (c,d) compared with AAV2.IFN-α treated (e,f), AAV2.IL-4 treated (g,h), and AAV2.IFN-α combined with AAV2.IL-4 treated eyes (i,j). (haematoxylin eosin staining, original magnification×100). EAU was significantly reduced in AAV2.IL-4 treated group, AAV2.IL-4 combined with AAV2.IFN-α treated group as compared with controls (k) (p<0.0001, Mann-Whitney U test). The AAV2.IFN-α treated group also shows a significantly decreased uveitis (p = 0.005). Each point is the score of an individual eye. The mean scores of each group are denoted by the horizontal bars.
Mentions: Histological analysis showed a severe uveitis in the AAV2.GFP injected and PBS injected control mice as evidenced by massive infiltration of inflammatory cells into the iris, vitreous cavity, throughout all retinal layers and the choroid, intensive retinal vasculitis, destruction of the retinal architecture with severe folding and detachment, as well as photoreceptor damage (Figs. 4a–d). However, in AAV2.IFN-α alone treated, AAV2.IL-4 alone treated, AAV2.IFN-α and AAV2.IL-4 combined treated eyes, only scattered infiltration of inflammatory cells into the vitreous body and retina was observed (Figs. 4e, g, i). Additionally, the inflammatory changes in the anterior segment of treated eyes were less than those in the AAV2.GFP injected eye and PBS injected eyes (Figs. 4f, h, j). Pathological grading showed that the AAV2.IFN-α alone treated eyes showed a significantly decreased uveitis when compared with PBS and AAV2.GFP injected controls (p = 0.01, p = 0.012). AAV2.IL-4 alone injected eyes and AAV2.IL-4 combined with AAV2.IFN-α treated eyes showed more significantly decreased inflammation compared with controls (p<0.0001) than AAV2.IFN-α alone (Fig. 4k).

Bottom Line: IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically.AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α.The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone.

View Article: PubMed Central - PubMed

Affiliation: The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.

ABSTRACT
We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×10(7) vg), AAV2.IL-4 alone (3.55×10(7) vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×10(7) vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response.

Show MeSH
Related in: MedlinePlus