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Skin Graft Rejection Elicited by ₂-Microglobulin as a Minor Transplantation Antigen Involves Multiple Effector Pathways: Role of Fas-Fas Ligand Interactions and Th2-Dependent Graft Eosinophil Infiltrates¹

Murielle Surquin^2,*,, Alain Le Moine^*,, Véronique Flamand^*, Nathalie Nagy, Katia Rombaut, François-Xavier Demoor^*, Patrick Stordeur^*, Isabelle Salmon, Jean-Charles Guéry, Michel Goldman^* and Daniel Abramowicz

^* Laboratory of Experimental Immunology, Université Libre de Bruxelles, and Departments of Nephrology and Pathology, Hôpital Erasme, Brussels, Belgium; and Institut National de la Santé et de la Recherche Médicale, Unité 28, Hôpital Purpan, Toulouse, France

₂-Microglobulin (₂m)-derived peptides are minor transplantation Ags in mice as ₂m-positive skin grafts (₂m^+/+) are rejected by genetically ₂m-deficient recipient mice (₂m^-/-). We studied the effector pathways responsible for the rejection induced by ₂-microglobulin-derived minor transplantation Ags. The rejection of ₂m^+/+ skin grafts by naive ₂m^-/- mice was dependent on both CD4 and CD8 T cells as shown by administration of depleting mAbs. Experiments performed with ₂m^-/-CD8^-/- double knockout mice grafted with a ₂m^+/+ MHC class I-deficient skin showed that sensitized CD4 T cells directed at ₂m peptides-MHC class II complexes are sufficient to trigger rapid rejection. Rejection of ₂m^+/+ grafts was associated with the production of IL-5 in vitro, the expression of IL-4 and IL-5 mRNAs in the grafted tissue, and the presence within rejected grafts of a considerable eosinophil infiltrate. Blocking IL-4 and IL-5 in vivo and depleting eosinophils with an anti-CCR3 mAb prevented graft eosinophil infiltration and prolonged ₂m^+/+ skin graft survival. Lymphocytes from rejecting ₂m^-/- mice also displayed an increased production of IFN- after culture with ₂m^+/+ minor alloantigens. In vivo neutralization of IFN- inhibited skin graft rejection. Finally, ₂m^+/+ skin grafts harvested from B6^lpr/lpr donor mice, which lack a functional Fas molecule, survived longer than wild-type ₂m^+/+ skin grafts, showing that Fas-Fas ligand interactions are involved in the rejection process. We conclude that IL-4- and IL-5-dependent eosinophilic rejection, IFN--dependent mechanisms, and Fas-Fas ligand interactions are effector pathways in the acute rejection of minor transplantation Ags.

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