Immune mechanisms in inflammatory and degenerative eye disease

Renin angiotensin system (RAS) is a key hormonal system which regulates the cardiovascular function and is implicated in several autoimmune diseases. With the discovery of the angiotensin-converting enzyme 2 (ACE2), a protective axis of RAS namely ACE2/Ang-(1–7)/Mas that counteracts the deleterious ACE/AngII/AT1R axis has been established. This axis is emerging as a novel target to attenuate ocular inflammation. However, the underlying molecular mechanisms remain unclear. We investigated the hypothesis that enhancing the activity of the protective axis of RAS by subretinal delivery of an AAV8 (Y733F)-ACE2 vector would protect against the ocular inflammation in experimental autoimmune uveitis (EAU) mice through regulating the local immune responses. Our studies demonstrated that increased ACE2 expression exerts protective effects on inflammation in EAU mouse by modulating ocular immune responses, including the differentiation of Th1/Th17 cells and the polarization of M1/M2 macrophages; whereas the systemic immune responses appeared not affected. These effects were mediated by activating the Ang-(1–7)/Mas and inhibiting the MAPK, NF-κB and STAT3 signaling pathways. This proof-of-concept study suggests that activation of ocular ACE2/Ang-(1–7)/Mas axis with AAV gene transfer modulates local immune responses and may be a promising, long-lasting therapeutic strategy for refractory and recurrent uveitis, as well as other inflammatory eye diseases.

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“…Th1 and Th17 responses have also been reported in uveitis patients47. Recent studies illustrated a major role for the RAS in autoimmunity.…”

Section: Discussionmentioning

confidence: 93%

AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways

Qiu

Tao

Zheng

et al. 2016

Sci Rep

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“…When barriers are disrupted, immune-privileged sites initiate regulatory processes that: (1) limit the extent of immune activation and (2) select the potentially less damaging immune response. This has been well characterized in particular for the ocular immune privilege 5 but plays a role in the homeostasis of other immunologic sanctuaries, including the brain. 6 The skeletal muscle is the largest cellular compartment of the body, characterized in physiological conditions by a relatively slow turnover.…”

Section: Unique Immune Privileges Of the Skeletal Musclementioning

confidence: 99%

Cell death, clearance and immunity in the skeletal muscle

et al. 2016

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“…The presence of an inflammatory component to AMD is now well established [14]. Thus, there is also a rationale for the use of corticosteroids for treating neovascular AMD [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Triple combination therapy and zeaxanthin for the treatment of neovascular age-related macular degeneration: an interventional comparative study and cost-effectiveness analysis

et al. 2015

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BackgroundReports of triple combination therapy for neovascular age-related macular degeneration (AMD) suggest a benefit, as do reports for zeaxanthin. An interventional comparative study was thus undertaken to evaluate the efficacy of triple combination therapy with and without zeaxanthin, as well as the economic viability of the therapies.MethodsThe cases of 543 consecutive eyes of 424 patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were reviewed. All eyes were treated with triple combination therapy (triple therapy) consisting of: (1) reduced-fluence photodynamic therapy with verteporfin, (2) intravitreal bevacizumab and (3) intravitreal dexamethasone. Therapy was repeated as necessary. One cohort of patients was also given supplementation with 20 mg of oral zeaxanthin (Zx) daily.ResultsThe triple therapy group without Zx received a mean of 2.8 treatment cycles and 87 % of patients had stable or improved vision at 24 months. In the triple therapy group with Zx, the mean number of treatment cycles was 2.1, with 83 % of patients having stable or improved vision at 24 months. At 24 months, CNV developed in 12.5 % of fellow eyes treated with triple therapy alone; CNV developed in 6.25 % of eyes treated with triple therapy with Zx (p = 0.03). An average cost-utility analysis revealed that triple therapy was cost-effective with a cost-utility ratio of $26,574/QALY, while triple therapy with Zx was more cost-effective with an average cost-utility ratio of $19,962/QALY. The incremental cost-utility analysis assessing the addition of Zx to triple therapy disclosed Zx supplementation was very cost-effective at $5302/QALY. When it was assumed that triple therapy with Zx reduced fellow eye CNV development by 30.3 %, the incremental cost-utility dropped to (−$6332/QALY), indicating that adding Zx to triple therapy yielded greater patient value, and was also less expensive than using triple therapy alone.ConclusionsTriple therapy is comparatively effective and cost-effective. Considerably less treatment is needed than reported in monotherapy studies. The addition of oral Zx appears to further reduce the treatment cycles required, and possibly reduce the risk of CNV development in the fellow eye.

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Immune mechanisms in inflammatory and degenerative eye disease

Cited by 161 publications

References 91 publications

AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways

AAV8-Mediated Angiotensin-Converting Enzyme 2 Gene Delivery Prevents Experimental Autoimmune Uveitis by Regulating MAPK, NF-κB and STAT3 Pathways

Cell death, clearance and immunity in the skeletal muscle

Triple combination therapy and zeaxanthin for the treatment of neovascular age-related macular degeneration: an interventional comparative study and cost-effectiveness analysis

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