Immune privilege sites: Bringing down the barriers of regenerative medicine

The immune system, a defence network designed to protect us against invading pathogens, has been the chief interest of drug design in recent years. Now, in a time of advancing technology and molecular methods, more emphasis is being placed upon developing treatments by investigating the natural defence mechanisms present within humans. “Immune privilege sites” appear to offer some promise in these advancements.

Identified as early as the 19th century, immune privilege sites are regions in the body that prevent the expression of inflammation within an immune-mediated environment [1]. That is, when a tissue graft or foreign antigens are introduced into the immune privilege site, the zone does not induce an auto-immune response, something which would usually occur in other areas of the body. This remarkable phenomenon is witnessed in several areas including: the cornea, the testicles, and some regions of the brain [2].

Immune privilege sites are thought to have evolved in order to protect sensitive areas of the body that are unable to regenerate their tissues and have vital bodily functions [3]. If such organs become inflamed, the loss of function could potentially jeopardise an individual’s welfare or cause possible reproductive failure. The mechanisms that lead to immune privilege are not fully understood, although research now suggests that those involved are believed to be active mechanisms that suppress a response to antigens or other foreign molecules [4]. For example, experiments have shown that immune privilege is achieved in the eye through Fas Ligand-Induced Apoptosis [5]. In this mechanism, inflammatory cells that enter the eye in response to a bacterial or viral infection, undergo apoptosis induced by Fas ligand, where the tissue shows no resultant damage. Further research in mice that lack the Fas ligand showed an infiltration of inflammatory cells, causing tissue damage. Thus, the manifestation of Fas expression appears to be important in maintaining immune privilege in the eye [5].

Other hypothesised immune privilege mechanisms involve the production of immunosuppressive and anti-inflammatory cytokines [6]. This mechanism, observed in ocular macrophages and dendritic cells, is thought to regulate immune response [7]. The testis is another organ that has shown to possess anti-inflammatory cytokines. In addition to this, there appear to be diminished numbers of macrophages within the testis, reducing the likelihood of an inflammatory response [8].

As well as innate immune privilege, parts of the body can acquire immune privilege. Acquired immune privilege is when CD4 T-cells actively prevent rejection of a cell, even though it may present harmful antigens [11]. This form of immune privilege is usually observed in cells located in low tolerance sites after allotransplantation. Acquired immune privilege has also been identified in tumour cells that have escaped surveillance from the immune system [11].

If researchers are successful in identifying and manipulating these methods, this will have profound effects on future clinical treatment and prevention of disease.

A particular area of interest and extensive research is the eye. The eye, as a well-known privilege site, has been at the forefront of immune privilege research in animals, and as a result, curing blindness is becoming a conceivable possibility [9]. Examples of current research projects involve testing whether immune privilege tissues promote their characteristics when transplanted in other tissue types, and if this specifically holds true for retinal pigment epithelium (RPE), an area of the eye responsible for performing specialised metabolic functions [10]. Research such as this is opening many potential therapeutic opportunities for patients and is providing great optimism for these forthcoming applications.

Particular significance is also being placed on both embryonic and adult stem cells and how these can be manipulated in cell replacement therapy. It is generally accepted that stem cells have been identified as exhibiting immune privilege, and when tissues derived from embryonic stem cells have been presented to the recipient, the immune system can react to the allograft and recognise it as foreign, producing an autoimmune response. A potential solution would be triggering immune privilege mechanisms within a specific area, allowing the body to accept the transplanted tissue. This is what further research in immune privilege aims to resolve [11].

The final frontier for immune privilege research will be attempting to apply these currently researched mechanisms to the entire body of an organism in an attempt to challenge autoimmune response in bodies. By mastering the control of autoimmune response within the body, the full potential of regenerative medicine therapies can finally be realised. These therapies could revolutionize the treatment of some of today’s most crippling diseases.

1. Niederkorn, J.Y. and Stein-Streilein, J. 2010. History and physiology of immune privilege. Occular Immunology and Inflammation 18:19-23
2. Streilein, J.W. 2003. An interview about Immune Privilege with J.Wayne Streilein. Mod. Asp. Immunobiol 3:14
3. Benhar, I., London, A., Schwartz, M. 2012. The privileged immunity of immune privileged organs: the case of the eye. Frontiers in Immunology 3:1-6
4. Mellor, A.L. and Munn, D.H. 2008. Creating immune privlege: active local suppression that benefits friends, but protects foes. Nature Reviews Immunology 8:78-80
5. Griffith, T.S., Brunner, T., Fletcher, S.M., Green, D.R., Ferguson, T.A. 1995. Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege. Science 270: 1189-1192
6. Niederkorn, J. 2003. Mechanisms of Immune Privilege in the Eye and Hair Follicle. Journal of Investigative Dermatology Symposium Proceedings 8:168-172
7. Taylor, A.W. 2010. Immunology, Inflammation and Diseases of the Eye. Oxford: Elsevier
8. Fijak, M. and Meinhardt, A. 2006. The testis in immune privilege. Immunological Reviews 213:66-81
9. Wenkel, H. and Streilein, J.W. 2000, Evidence that retinal pigment epithelium functions as an immune privileged tissue. Invest. Ophtal. Vis. Sci. 41: 3467-3473
10. Bonilha, V. 2008. Age and disease-related structural changes in the retinal pigment epithelium. Clin. Ophthalmol. 2: 413-424
11. Ichiryu, N. and Fairchild, P.J. 2013. Embryonic Stem Cell Immunobiology: Methods and Protocols. Iowa City: Humana Press
Image Credit: A cluster of nascent retinae generated from 3D embryonic stem cell cultures, by Anai Gonzalez-Cordero, Flickr.

Jonida Tafilaku is a second year biology student at the University of Edinburgh. Follow The Triple Helix Online on Twitter and join us on Facebook.