Kinetics of transplant arteriosclerosis in MHC-Class I mismatched and fully allogeneic mouse aortic allografts.
Ensminger SM., Spriewald BM., Witzke O., Morrison K., Pajaro OE., Morris PJ., Rose ML., Wood KJ.
INTRODUCTION: Transplant arteriosclerosis is still the major complication for long-term allograft survival in clinical transplantation. The aim of our study was to investigate the impact of MHC disparity on the kinetics of the development of transplant arteriosclerosis. METHODS: MHC-class I mismatched CBK (H2k+Kb) or fully allogeneic C57BL/10 (H2b) aortic allografts were transplanted into CBA.CA (H2k) recipients; syngeneic grafts were used as controls. Aortic grafts were analyzed on days 7, 14, and 30 after transplantation by performing morphometry, immunohistochemistry and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of intragraft cytokine mRNA production. Donor specific alloantibody production was measured by FACS analysis. RESULTS: Intimal proliferation developed more rapidly in fully allogeneic grafts (direct and indirect allorecognition by CD4+ T cells) compared to MHC-class I mismatched grafts (indirect allorecognition only by CD4+ T cells) (day 7: 6+/-7 vs. 2+/-3%; day 14: 17+/-8 vs. 5+/-1%; day 30: 65+/-5 vs. 38+/-7% (C57BL/10 vs. CBK). However, by day 60, the level of intimal proliferation in the MHC-class I mismatched grafts was equivalent to that observed with fully allogeneic grafts on day 30. There was also a marked delay in the kinetics of graft infiltration by CD4+, CD8+, CD11b+, and CD40+ leukocytes and alloantibody production when CD4+ T cells were only activated via indirect presentation (MHC-class I mismatched grafts). Expression of interferon-gamma, interleukin-2, and interleukin-4 correlated with the kinetics of leukocyte infiltration, whereas interleukin-10, interleukin-12p40, iNOS, and TGF-beta1 showed a distinct pattern of expression. CONCLUSIONS: These data demonstrate that the degree of MHC incompatibility between donor and recipient markedly influences the kinetics of the development of transplant arteriosclerosis. The onset of disease was delayed when grafts were mismatched for only MHC-class I antigens, but ultimately reached the same levels as seen in fully allogeneic grafts. The pattern of leukocyte infiltration and the kinetics of cytokine production suggest that in the MHC-class I mismatched grafts CD4+ T cells responding via the indirect pathway might play an important role in the development of transplant arteriosclerosis.