Eur. J. Immunol. 2011. 41: 2997–3005 DOI 10.1002/eji.201141683 Immunomodulation 2997 Arginine depletion as a mechanism for the immune privilege of corneal allografts Hongmei Fu1, Adnan Khan1, David Coe1, Sarah Zaher1, Jian-Guo Chai1, Pascale Kropf 4, Ingrid Mu¨ller4, Daniel F. P. Larkin1,2,3 and Andrew J. T. George1 1 Section of Immunobiology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK 2 Moorﬁelds Eye Hospital, London, UK 3 Institute of Ophthalmology, London, UK 4 Section of Immunology, Faculty of Medicine, Imperial College London, London, UK The cornea is an immune privileged tissue. Since arginase has been found to modulate T-cell function by depleting arginine, we investigated the expression of arginase in the cornea and its possible role in immune privilege using a murine transplant model. We found that both the endothelium and epithelium of murine corneas express functional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system. The administration of the speciﬁc arginase inhibitor N-hydroxy-nor-L-Arg to recipient mice resulted in an accelerated rejection of allogeneic C57BL/6 (B6) corneal grafts. In contrast, in vivo blockade of arginase activity had no effect in altering the course of rejection of primary skin grafts that express little, if any, arginase. In addition, the inhi- bition of arginase did not alter systemic T-cell proliferation. These data show that arginase is functional in the cornea and contributes to the immune privilege of the eye, and that modulation of arginase contributes to graft survival. Key words: Arginase . Cornea . Corneal graft . Immune privilege sites . Transplantation Introduction The cornea is immune privileged, as evidenced by the high success rate of corneal grafts (typically 90% at one year [1]) in the absence of systemic immunosuppression or HLA matching. There are several factors contributing to immune privilege [2], including (i) the absence of blood and lymphatic vessels in the graft bed [3], (ii) the expression of Fas ligand in corneal epithelial and endothelial cells [4], (iii) low expression levels of major histocompatibility complex class I and II molecules in corneal cells [5, 6], (iv) the atypical nature of the antigen- presenting cells within the cornea [7], (v) anterior chamber- Correspondence: Prof. Andrew J. T. George e-mail: a.george@imperial.ac.uk & 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim associated immune deviation (ACAID) where systemic delayed- type hypersensitivity is down-regulated following exposure of the anterior chamber to alloantigens [8], and (vi) the presence of immunomodulatory cytokines such as transforming growth factor-b in aqueous humour in the anterior chamber of the eye [9]. L-arginine (L-Arg) is a semi-essential amino acid for adult mammals. Thus, while the body can synthesize some L-arginine, in some conditions, such as trauma and pregnancy, in which demand increases, it is necessary to supplement with dietary L-Arg [10]. L-Arg is metabolized by two independent enzymatic pathways, involving the enzymes arginase and nitric oxide synthase (NOS) [11]. Arginase hydrolyzes L-Arg into urea and L-ornithine, the latter being a precursor of polyamines (putres- cine, spermidine and spermine) that are required for cell prolif- eration. NOS converts L-Arg into citruline and nitric oxide (NO), www.eji-journal.eu