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Millennium Pharmaceuticals, Inc., Cambridge, MA 02139

Address correspondence to Wayne W. Hancock, Dept. of Pathology, 802 Abramson Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. Phone: 215-590-8709; Fax: 215-590-7384; E-mail: hancock{at}email.chop.edu

LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT^-/- mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT^-/- mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT^+/+ mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT^+/+ mice (7 days). However, mean allograft survival in CsA-treated LIGHT^-/- allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT^-/- mice or CsA-treated LIGHT^+/+ controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-, plus IFN-–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT^+/+ allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection.

Key Words: transplantation • allograft rejection • T cell activation • costimulation • TNF superfamily

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