Retinal transplantation represents a reasonable approach for restoring sight to patients with irreparable damage to the retina. There are formidable barriers to successful accomplishment of retinal transplantation in the clinic. Among the barriers that must be overcome is the capacity of the immune system to recognize foreign tissues implanted within the eye and to cause their destruction. The field of transplantation immunology has reached a high level of knowledge about solid tissue grafts placed at conventional sites in the body, but the phenomenon of immune privilege in the eye renders it difficult to translate that knowledge directly to the benefit of retinal transplants. This application describes a series of experiments which explore critical issues in the immunobiology of intraocular retinal transplants: (1) the ability of microglia of graft-origin to function as passenger leukocytes and thereby dictate the immunogenicity of neuronal retinal grafts; (2) the status of immune privilege in the subretinal space, and its relation to immune privilege within the entire eye; (3) the extent to which neuronal retinal tissue and retinal pigment epithelium display the properties of immune privileged tissues; and (4) the nature of inflammatory/immune reactions within the subretinal space and the influence of these reactions on immune privilege and retinal graft survival in this space. While the entire set of experiments will be conducted in inbred strains of mice, the knowledge gained will have relevance to the human situation. The anticipated results of these experiments will lead to novel strategies that will enable (1) the reduction of the alloantigenic load and the immune vulnerability to rejection of neuronal retina and RPE grafts, and (2) the promotion of positive features of immune privilege of retinal tissues as well as the subretinal site of engraftment in order to secure allograft acceptance. Since immune/inflammatory and immunomodulatory cytokines and growth factors can act on retinal cells, a further hope is that the results obtained from the described experiments may also give insight into means by which these factors can be used to promote neurobiologic health among retinal grafts.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009595-09
Application #
2888402
Study Section
Visual Sciences C Study Section (VISC)
Project Start
1992-05-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02114
Klassen, Henry; Warfvinge, Karin; Schwartz, Philip H et al. (2008) Isolation of progenitor cells from GFP-transgenic pigs and transplantation to the retina of allorecipients. Cloning Stem Cells 10:391-402
Klassen, Henry; Schwartz, Philip H; Ziaeian, Boback et al. (2007) Neural precursors isolated from the developing cat brain show retinal integration following transplantation to the retina of the dystrophic cat. Vet Ophthalmol 10:245-53
Klassen, Henry; Kiilgaard, Jens Folke; Zahir, Tasneem et al. (2007) Progenitor cells from the porcine neural retina express photoreceptor markers after transplantation to the subretinal space of allorecipients. Stem Cells 25:1222-30
Zamiri, Parisa; Masli, Sharmila; Kitaichi, Nobuyoshi et al. (2005) Thrombospondin plays a vital role in the immune privilege of the eye. Invest Ophthalmol Vis Sci 46:908-19
Zahir, Tasneem; Klassen, Henry; Young, Michael J (2005) Effects of ciliary neurotrophic factor on differentiation of late retinal progenitor cells. Stem Cells 23:424-32
Schwartz, Philip H; Nethercott, Hubert; Kirov, Ivan I et al. (2005) Expression of neurodevelopmental markers by cultured porcine neural precursor cells. Stem Cells 23:1286-94
Klassen, Henry J; Ng, Tat Fong; Kurimoto, Yasuo et al. (2004) Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest Ophthalmol Vis Sci 45:4167-73
Zamiri, Parisa; Zhang, Qiang; Streilein, J Wayne (2004) Vulnerability of allogeneic retinal pigment epithelium to immune T-cell-mediated damage in vivo and in vitro. Invest Ophthalmol Vis Sci 45:177-84
Klassen, Henry; Ziaeian, Boback; Kirov, Ivan I et al. (2004) Isolation of retinal progenitor cells from post-mortem human tissue and comparison with autologous brain progenitors. J Neurosci Res 77:334-43
Klassen, Henry J; Imfeld, Karen L; Kirov, Ivan I et al. (2003) Expression of cytokines by multipotent neural progenitor cells. Cytokine 22:101-6

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