Xenoreactive CD4(+) T cells and acute rejection of orthotopic guinea pig corneas in mice

PURPOSE. TO explore immunologic issues involved in orthotopic corneal xenot ransplantation in a discordant combination using guinea pigs as donors and mice as recipients. METHODS. Two-millimeter-diameter guinea pig corneal buttons were transplant ed into 1.5-mm -diameter graft beds on mouse corneas using 12 interrupted s utures. Eyelids were maintained occluded with tarsorrhaphy except at the ti mes of clinical inspection. Grafts were considered to be rejected when the pupil margin was not visible clearly through the graft by slit-lamp microsc opy. RESULTS. Guinea pig corneas protected from desiccation by persistent tarsor rhaphy survived indefinitely in the eyes of C.B-17SCID mice but were reject ed 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 mu heavy chain or beta-2 microglobul in genes, slightly extended in mice deficient in the CS gene (MST of 21 ver sus 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 CD 4(+) T cells promoted acute rejection of corneal xenografts. CONCLUSIONS. Hyperacute rejection does not occur in guinea pig corneal xeno grafts in mouse eyes, indicating that corneal xenografts are less vulnerabl e to this type of rejection than other solid tissue xenografts. CD4(+) T ce lls are the primary mediators of acute graft rejection, although complement may contribute in a minor way. Neither antibodies nor CD8(+) T cells parti cipate in acute graft rejection. Because guinea pig cornea grafts in eyes o f CD4KO mice are rejected in a delayed fashion, other innate and/or adaptiv e immune effecters must also be able to cause rejection of orthotopic corne al xenografts.