Comparison of Abeta(b-/-), H2-DM(-), and CIITA(-/-) in second-set skin allograft rejection.

BACKGROUND: Responses against donor MHC antigens are the major contributor to allograft rejection. Currently, it is unclear whether both direct and indirect recognition pathways are necessary and/or sufficient for allograft rejection. Previously, we found donor MHC class II and H2-DM to have dramatic effects on cardiac allograft survival.

METHODS: Here, we used H2-DM(-) mice, which express CLIP-MHC class II complexes, and CIITA(-/-) mice, which lack all class II proteins, to examine the role of direct and indirect recognition on skin allograft rejection. Recipients were primed with donor cultured keratinocytes and later tested for accelerated memory response by challenge with full-thickness tail skin grafts.

RESULTS: As previously reported, Abeta(b-/-) grafts survived longer than wild-type grafts, while H2-DM(-) grafts were rejected as rapidly as wild-type grafts. Skin grafts deficient for both beta2m and H2-DM survived longer than grafts lacking only H2-DM, but not as long as Abeta(b-/-) grafts. Additionally, CIITA(-/-) grafts survived as long as Abeta(b-/-) grafts.

CONCLUSIONS: The delayed rejection of Abeta(b-/-) compared to H2-DM(-) suggests that indirect recognition of surface-expressed donor MHC class II is sufficient to mediate rapid skin allograft rejection. The equivalent survival of CIITA(-/-) and Abeta(b-/-) grafts suggests that indirect presentation of donor class II molecules (Aalpha or Ebeta) present in Abeta(b-/-) but not CIITA(-/-) mice does not contribute to graft rejection. These results reveal a modest role for surface-expressed donor class II in primed keratinocyte rejection, but also reveal a dramatic contrast to the cardiac allograft system and indicate tissue/organ-specific mechanisms of rejection.