Decay accelerating factor (CD55)-mediated attenuation of complement: therapeutic implications for age-related macular degeneration
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Published on: July 14, 2016
Kelly N Ma1, Siobhan M Cashman, J Harry Sweigard
1Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA.
Insights
Increasing decay accelerating factor (CD55) expression on retinal pigment epithelium (RPE) cells reduced membrane attack complex (MAC) formation and cell lysis. This suggests CD55 may be a potential therapy for age-related macular degeneration (AMD).
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Sequence variations in complement proteins are linked to age-related macular degeneration (AMD).
- The complement cascade's terminal pathway forms the membrane attack complex (MAC), causing cell lysis.
- MAC has been observed in AMD-affected retinal pigment epithelium (RPE), choroidal vessels, and drusen.
Purpose of the Study:
- To investigate if increasing decay accelerating factor (CD55) expression on RPE cells can reduce MAC-mediated damage.
- To test the hypothesis that CD55 can protect RPE cells from complement-induced lysis.
Main Methods:
- Constructed a recombinant adenovirus (AdCAGCD55) for human CD55 expression.
- Infected mouse hepatocytes with AdCAGCD55 and challenged with normal human serum (NHS) to measure lysis and MAC formation.
- Injected AdCAGCD55 into the subretinal space of mice, then challenged with NHS to quantify MAC formation on RPE cells.
Main Results:
- AdCAGCD55-infected hepatocytes showed a significant reduction in lysis (29%) compared to controls (93-94%).
- MAC formation was reduced by 67% in AdCAGCD55-infected hepatocytes.
- Mice treated with AdCAGCD55 demonstrated a 55.7% decrease in MAC formation on RPE cells.
Conclusions:
- Adenovirus-mediated delivery of human CD55 (hCD55) to murine RPE provides protection against human complement.
- The expression of hCD55 on RPE cells is a promising therapeutic strategy for AMD that warrants further investigation.
Purpose:
Sequence variations in complement proteins are associated with age-related macular degeneration (AMD). The terminal pathway of complement results in the formation of the membrane attack complex (MAC) on the cell surface, resulting in their lysis. MAC has been documented on the retinal pigment epithelium (RPE), choroidal blood vessels, and drusen of AMD eyes. Here the investigators test the hypothesis that increasing the expression of decay accelerating factor (CD55) on RPE cells may result in reduced MAC-mediated damage.
Methods:
The investigators constructed a recombinant adenovirus expressing human CD55 (AdCAGCD55). Mouse hepatocytes were infected with AdCAGCD55 or negative controls and subsequently incubated with normal human serum (NHS). Cell lysis and MAC formation were measured by FACS and immunocytochemistry, respectively. Adult mice were injected in the subretinal space with either AdCAGCD55 or controls; after 1 week of CD55 transgene expression, the eyecups were excised, challenged with NHS, and quantified for human MAC formation.
Results:
Control-infected or uninfected mouse hepatocytes lyse at a rate of 93% and 94%, respectively. AdCAGCD55- infected mouse hepatocytes lyse at a rate of 29%. Lysis was confirmed to occur in the presence of MAC, which was reduced by 67% when cells were infected by AdCAGCD55. Mice injected in the subretinal space with AdCAGCD55 exhibited a 55.7% reduction in MAC formation on the RPE relative to controls.
Conclusions:
Adenovirus-mediated delivery of hCD55 to murine RPE confers protection against human complement. The investigators propose that the expression of hCD55 on RPE cells warrants investigation as a potential therapy for AMD.
