1. Understanding the role of your immune system:
Pitfalls and opportunities for cell therapy
Presenter:
Dr Matt Rutar

2. The Eye and Immunity Inflammation, why the fuss?
Keratitis – corneal inflammation
A well-regulated immune system in the eye is crucial for maintaining healthy vision.
However, imbalance of these processes during injury or infection can lead to inflammation – a recruitment of immune cells and secretion of powerful cytokines, inducing:
Swelling and vascular leakage.
Collateral damage of visual cells.
Scar tissue that inhibits tissue regeneration.
The structures of our eye are highly vulnerable to inflammation, as it has limited regenerative capacity.
AMD – retinal inflammation

3. The Eye and Immunity Inflammation, why the fuss?
Keratitis – corneal inflammation
Inflammation in vision disorders covers a broad spectrum of diseases.
One such example, age-related macular degeneration (AMD):
A retinal dystrophy that affecting macula region, particularly the retinal pigment epithelium (RPE).
Leading cause of blindness in the industrialised world, particularly in those >65 – estimated worldwide prevalence of 30 to 50 million.
Though a multifactorial disorder, chronic inflammation, arising from innate arm of the immune response, is now regarded as key factor driving its pathogenesis.
AMD – retinal inflammation

4. The Eye and Immunity
Given its susceptibility, does the eye have any capacity to help shield itself from inflammation?

5. The Eye and Immunity How does the eye help limit inflammation?
Highly specialised characteristics of the eye limit local immune responses to preserve vision. This phenomenon, is known as ocular immune privilege:
Limits day-to-day inflammatory insults, by restricting activation of the immune system (ie. recruitment of immune cells from the blood supply).
It also creates a tolerised environment in the eye:
Because of this, foreign tissue grafts can survive for extended, often indefinite periods of time, whereas similar grafts placed at regular sites in the body are acutely rejected
An good example of this are corneal transplants.
BEFORE
AFTER
Corneal Transplant.

6. The Eye and Immunity How does the retina help limit inflammation?
Choroidal
Blood Supply
Vitreous
Cornea
Iris
Retina
Lens
A number of factors enable ocular immune privilege, known as the ‘the blood-retinal barrier (BRB)’ .
Physical barriers are a prime example :
The RPE represents a mechanical and tight barrier which separates retinal environment
from the blood stream.
Other barriers include: (1) ciliary body epithelium (2) thick connective tissue surrounding iris vasculature.
Immune privilege is maintained
so long as these barriers remain intact!
Retina
RPE

7. The Eye and Immunity Ocular Immunity and Stem Cell Therapy
The specialized immune environment of the eye
presents a great opportunity regenerative therapies ….
… though also come with potential pitfalls that must be carefully navigated

8. The Eye and Immunity Ocular Immunity and Stem Cell Therapy
Opportunities
The immune-privileged status of eye allows for local introduction stem cell-based therapies, without the concern of graft rejection expected in non-privileged areas of the body.
Injection of stem cell-derived RPE cells into the subretinal space AMD patients is promising example of one such therapy.

9. Choroidal Blood Supply
The Eye and Immunity
Ocular Immunity and Stem Cell Therapy
RPE
Choroidal Blood Supply
Retina
Early AMD
Late AMD
Pitfalls
Immune-privilege is only maintained if the BRB remains intact.
BRB breakdown is a characteristic of a number of ocular dystrophies, including AMD.
This break in tolerance can trigger autoimmune responses.
In these circumstances, source of the donor cells requires careful consideration to prevent graft rejection.
BUT….

10. The Eye and Immunity Ocular Immunity and Stem Cell Therapy
RPE grafts derived from allogenic stem cells (ie. generic ESCs), have been shown to elicit immune responses, show signs of rejection, and necessitate immunosuppressant medication.
Induced pluripotent stem cells (iPSCs)
Human Embryonic stem cells (ESCs)
Alternatively, RPE grafts derived from autologous (ie. Patient-derived iPSCs) stem cells, have shown promise of being tolerated and remaining stable long term:
No rejection after 1 year
Halt in disease progression

11. The Eye and Immunity Ocular Immunity and Stem Cell Therapy
Not the End of the Story!
Though RPE from patient-specific iPSCs offer a potential solution that thwarts the breakdown of immune tolerance – their custom generation and evaluation can be both costly and time-consuming.
A shift toward iPS cell banks could supply donor cells that are immune-matched to recipients (HLA compatible) would save time, but would require means of long-term immunosuppression.
Induced pluripotent stem cells (iPSCs)
Human Embryonic stem cells (ESCs)
More research into immune processes that govern graft rejection and BRB breakdown are required to refine stem cell therapies in the eye.