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Departments of
*
Medicine and
Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Although interruption of CD40-CD40L interactions via their
respective mAbs yields prolonged allograft survival, the relative
importance of CD40 or CD40L on donor or host cells remains unknown.
Moreover, it is uncertain whether any allospecific tolerance occurring
with CD40-CD40L blockade will also prevent allograft arteriopathy, the
major long-term limitation to transplantation. Therefore, we performed
cardiac transplantations using CD40L-deficient (CD40L-/-)
mice to investigate the mechanisms underlying prolonged allograft
survival. Without immunosuppression, wild-type (WT) hosts rejected
allo-mismatched WT or CD40L-/- heart allografts within 2
wk. Conversely, allografts in CD40L-/- hosts beat
vigorously for 12 wk. Anti-CD40 treatment did not induce graft failure
in CD40L-/- recipients. Although graft-infiltrating cells
were reduced 
50% in CD40L-/- hosts, the relative
percentages of macrophages and T cell subsets were comparable to WT.
IFN-
, TNF-
, and IL-10 were diminished commensurate with the
reduced cellular infiltrate; IL-4 was not detected.
CD40L-/- recipients did not develop IgG alloantibodies
and showed diminished B7 and CD28 expression on subsets of
graft-infiltrating cells. CD40L-/- transplant recipients
developed allospecific tolerance to the donor haplotype; second set
donor skin grafts engrafted well, whereas third-party skin grafts were
vigorously rejected. By MLR, splenocytes from CD40L-/-
allograft recipients also demonstrated allo-specific
hyporesponsiveness. Nevertheless, allografts in CD40L-/-
hosts developed significant graft arteriosclerosis by 8–12 wk
posttransplant. Therefore, we propose that early alloresponses, without
CD40-CD40L costimulation, induce allospecific tolerance but may trigger
allo-independent mechanisms that ultimately result in graft
vasculopathy.
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