Intragraft interleukin-4 mRNA expression after short-term CD154 blockade may trigger delayed development of transplant arteriosclerosis in the absence of CD8+T cells

Background. It has recently been shown that, although anti-CD154 induces CD 4(+) T-cell tolerance, it is unable to prevent allograft rejection mediated by CD8(+) T cells. We have also shown that anti-CD154 monotherapy does not protect the graft from the development of transplant arteriosclerosis even in the absence of CD8(+) T cells. This study was designed to investigate a nd characterize possible mechanisms responsible for the development of tran splant arteriosclerosis after CD154 blockade in the absence of CD8(+) T cel ls. Methods. C57BL/6 (H2(b)) recipients received a fully MHC-mismatched BALB/c donor aorta (H2(d)). Animals were either treated with anti-CD154 monoclonal antibody (mAb) in the presence or absence of CD8(+) T cells. Histology, mo rphometric measurements, immunohistochemistry, and the production of alloan tibodies (IgM, IgG1, IgG2a) were analyzed on days 14, 30, and 50 after tran splantation. Cytokine production within the graft was investigated by compe titive reverse transcription-polymerase chain reaction on day 14, Results. Combined treatment with anti-CD154 and a depleting CD8 mAb resulte d in a delay in the development of transplant arteriosclerosis (intimal pro liferation: 33+/-10% vs. 67+/-11% untreated control, day 30) but ultimately did not prevent its progression (intimal proliferation: 55+/-10% vs. 78+/- 9% untreated control, day 50). Although there was a significant decrease in the number of CD4(+), CD11b(+), and CD40(+) graft-infiltrating cells and a reduction in the formation of donor-specific IgG1 alloantibodies in recipi ents treated with anti-CD154 and anti-CD8 mAbs, mRNA for interleukin (IL)-4 was increased, suggesting a shift in the intragraft cytokine profile towar ds a Th2-like pattern. Conclusions. Our data provide evidence that short-term CD154 blockade is in sufficient to prevent transplant arteriosclerosis, even in combination with CD8(+) T-cell depletion. Moreover, the increased expression of the Th2 cyt okine interleukin-4 within the graft may be responsible for the development of transplant arteriosclerosis in the long term.