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Xenoreactive CD4⁺ T Cells and Acute Rejection of Orthotopic Guinea Pig Corneas in Mice

From the Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.

PURPOSE. To explore immunologic issues involved in orthotopic corneal xenotransplantation in a discordant combination using guinea pigs as donors and mice as recipients.

METHODS. Two-millimeter-diameter guinea pig corneal buttons were transplanted into 1.5-mm-diameter graft beds on mouse corneas using 12 interrupted sutures. Eyelids were maintained occluded with tarsorrhaphy except at the times of clinical inspection. Grafts were considered to be rejected when the pupil margin was not visible clearly through the graft by slit-lamp microscopy.

RESULTS. Guinea pig corneas protected from desiccation by persistent tarsorrhaphy survived indefinitely in the eyes of C.B-17SCID mice but were rejected acutely (but not hyperacutely) in eyes of normal BALB/c and C57BL/6 mice (median survival times, MST, 16 and 10 days, respectively). Graft survival was not extended in mice deficient in µ heavy chain or ß-2 microglobulin genes, slightly extended in mice deficient in the C3 gene (MST of 21 versus 17 days) and greatly extended in mice deficient in the CD4 gene (MST of 26 versus 9 days). Reconstitution of CD4 knock-out (KO) mice with CD4⁺ T cells promoted acute rejection of corneal xenografts.

CONCLUSIONS. Hyperacute rejection does not occur in guinea pig corneal xenografts in mouse eyes, indicating that corneal xenografts are less vulnerable to this type of rejection than other solid tissue xenografts. CD4⁺ T cells are the primary mediators of acute graft rejection, although complement may contribute in a minor way. Neither antibodies nor CD8⁺ T cells participate in acute graft rejection. Because guinea pig cornea grafts in eyes of CD4KO mice are rejected in a delayed fashion, other innate and/or adaptive immune effectors must also be able to cause rejection of orthotopic corneal xenografts.

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