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M.P. Watson, A.J. T. George, D.F. P. Larkin; Differential Effects of Costimulatory Pathway Modulation on Corneal Allograft Survival . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5865.
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T lymphocytes have a central role in rejection of corneal grafts. The primary interaction leading to activation of T cells is the engagement of the MHC molecule on the APC with the T cell surface receptor. However, an additional costimulatory signal from APC to T cell is necessary for full T cell activation. It was investigated whether modulation of the recently described costimulatory pathways Programmed Death 1 (PD–1) and the Inducible costimulatory molecule (ICOS) play a role in corneal allograft rejection.
A dimeric PDL1 immunoglobulin (Ig) fusion protein was generated to stimulate the inhibitory receptor PD–1 and suppress a T cell response. A monoclonal antibody was used to block the costimulatory molecule ICOS resulting in T cell suppression. PDL1.Ig and anti ICOS antibody were then used in a mouse model of corneal transplantation.
Both reagents demonstrated T cell inhibition in vitro. Plate bound PDL1.Ig inhibited T cells proliferation in a dose dependent manner when tested in a splenocyte assay and the anti ICOS antibody showed blockade of the ICOS:ICOSL pathway when tested in a mixed lymphocyte reaction. Intraperitoneal treatment with PDL1.Ig alone showed prolongation of C3H corneal allograft survival with a median survival time (MST) of 21 days in BALB/c recipients. This was significantly prolonged compared to the control treated group P < 0.003 (MST 13 days). Allograft survival in recipients treated with anti ICOS showed no prolongation in survival compared to the control with both groups having a MST of 12 days (P< 0.232). At the time of rejection there were significantly reduced numbers of CD45+ cells in the PDL1.Ig treated compared to the control (P<0.001) whereas ICOS blockade show no significant difference in cell numbers.
Unlike ICOS, the PD–1 pathway appears to be important in corneal allograft survival. PDL1 is expressed on corneal endothelium and treatment with a soluble form of PDL1 prolongs corneal allograft survival, demonstrating a potential role for PDL1 in maintaining the immune privilege status of the cornea. In contrast to blockade of costimulatory signals by the proteins currently used in patients and experimental animal models, the novel strategy of stimulating the PD–1 receptor to suppress T cells provides a potential treatment for prolonging corneal transplants.
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