Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1258-1263
An oral CD40 ligand gene therapy against lymphoma using
attenuated Salmonella typhimurium
Mitsuyoshi Urashima,
Hideaki Suzuki,
Youki Yuza,
Masaharu Akiyama,
Noriko Ohno, and
Yoshikatsu Eto
From the Department of Pediatrics, The Jikei University School of
Medicine, Tokyo, Japan.
CD40 ligand (CD40L) has a great potential as a novel treatment for
B-cell lymphoma (BCL). It has previously been demonstrated that a
nonvirulent strain of Salmonella typhimurium mutant (ST) can be
used not only as a vehicle in oral genetic immunization via the
intestinal mucosa, but also as an enhancer of interferon 
- and
tumor necrosis factor 
-mediated immunity. After confirming that
human CD40L can up-regulate expression of Fas, B7-1, and B7-2 molecules
on murine BCL cells in vitro, we transfected the human CD40L gene into
S typhimurium mutant (ST40L), which was administrated orally to
determine whether it was able to prevent the growth of BCL in mice.
Expression of human CD40L was confirmed immunohistochemically with
protein being detected in the Peyer's patches of mice immunized with
ST40L. Moreover, human soluble CD40L had been detectable until 7 to 8 weeks after oral administration of ST40L. Although ST alone exhibited
some protective effects, ST40L demonstrated a significantly greater
protection against the development of CD40 positive BCL compared with
the control. In the surviving mice that had been treated with ST40L, a
small and hard nodule was formed at the injection site, which was found to be composed of infiltrating lymphocytes expressing Fas ligand. These
results have the potential to be a simple, effective, and above all,
safe immune-gene therapy against BCL.
