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,§,§,
,§
*
Section of Immunobiology,
Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, and Departments of
Pathology and
§
Dermatology, Yale University School of Medicine, New Haven, CT 06520
Graft endothelial cells are primary targets of host CTL-mediated
injury in acute allograft rejection. As an in vitro trial of gene
therapy to reduce CTL-mediated endothelial injury, we stably transduced
early passage HUVEC with a caspase-resistant mutant form (D34A) of the
anti-apoptotic gene Bcl-2. Bcl-2 transductants were
compared with HUVEC transduced in parallel with an enhanced green
fluorescent protein (EGFP) gene. Both transduced HUVEC have equivalent
growth rates in complete medium and both show contact inhibition of
growth. However, compared with EGFP-transduced HUVEC, the
Bcl-2-transduced cells are resistant to the apoptotic effects of serum
and growth factor withdrawal and are also resistant to the induction of
apoptosis by staurosporine or by ceramide, with or without TNF.
Transduced Bcl-2 did not reduce TNF-mediated NF-
B activation or
constitutive expression of class I MHC molecules. HUVEC expressing D34A
Bcl-2 were significantly more resistant to lysis by either class
I-restricted alloreactive or PHA-redirected CTL than were HUVEC
expressing EGFP. We conclude that transduction of graft endothelial
cells with D34A Bcl-2 is a possible approach for reducing allograft
rejection.
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