Interestingly, suppression of the CTL response caused an increase
in rejection scores after the acute phase of rejection
(Fig. 6B) , with
rejection scores and CTL responses showing an inverse correlation
(Fig. 4) . This suggests that development of CTL responses might have an
inhibitory effect on alloepithelial rejection. The animals that
developed strong CTL responses may have concomitantly acquired
suppressor CD8
+ subsets, which in turn regulated
DTH responses by CD4
+ subsets. Depletion of
CD8
+ cells might impair this suppressor activity,
and thus contribute to increased rejection scores. Another possible
explanation of this phenomenon may be the unique kinetics of the
grafted epithelium. In the KEP model, the denuded host cornea is
resurfaced by donor-derived epithelium within a few days after surgery;
however, subsequent epithelial rejection results in destruction of the
donor-derived epithelium and centripetal movement of host-derived
epithelium. Consequently, after the onset of rejection, the host
corneal bed is surfaced by a mosaic-like mixture of both recipient- and
donor-derived epithelium (unpublished observations). When activated
allospecific CTLs lyse donor-derived epithelium in the early phases of
rejection, a decrease in alloantigen density may develop. Although this
destruction of donor-derived epithelium by CTLs would itself constitute
rejection, antigen-specific CTLs attack individual donor-derived
epithelial cells in a pinpoint fashion as Ando et al.
14 demonstrated in the CTL-mediated liver disease model. In the PKP model,
the attacked corneal endothelium suffers a devastating blow that leads
to graft failure. In contrast, in KEP grafting CTLs will not affect the
endothelium, only the corneal epithelium, the latter of which has a
strong ability to proliferate. Thus, CTL-induced inflammation may not
have a fatal impact on KEP grafting. The resultant decrease in antigen
load, in turn, might alter or diminish enhancement of allospecific DTH.
To the contrary, when a substantial amount of donor-derived epithelium
remains as a result of insufficient CTL activity, the major
histocompatibility complex–restricted stimulation of Th1 appears to
elicit sufficient interferon γ release to induce a DTH
response.
15 Moreover, Yamada and Streilein
16 suggest that the corneal epithelium on the graft itself promotes the
development of DTH by secretion of inflammatory cytokines. Taken
together, these observations suggest that the CTL response does not
play a major role in rejection in KEP, but rather that it modifies
development of alloepithelial rejection.