A. Valujskikh et al., A role for TGF beta and B cells in immunologic tolerance after intravenousinjection of soluble antigen, TRANSPLANT, 72(4), 2001, pp. 685-693
Background. Intravenous injection of soluble antigen has been reported to i
nduce immunologic tolerance through a variety of mechanisms including T-cel
l deletion, anergy, and suppression. To clarify the reported discrepancies,
we studied mechanisms of intravenous tolerance to a defined transgenic min
or transplantation antigen in mice.
Methods. Wild-type C57BL6 (B6) mice or congenic B6 B-cell knockout mice wer
e made tolerant to beta -galactosidase (beta -gal). Clinical tolerance was
assessed by placement of B6 beta -gal transgenic (tg) and third-party skin
grafts. In vitro analysis of T- and B-cell immunity and in vivo treatment w
ith anti-TG beta antibodies were used to define mechanisms of induced toler
ance.
Results. Intravenous injection of beta -gal induced true immunologic tolera
nce to beta -gal tg skin in wild-type but not in B-cell-deficient recipient
s, suggesting that antigen presentation by B cells was required for the eff
ect. The tolerogenic manipulation primed a population of CD4(+), beta -gal-
specific, TGF beta -producing T cells. Although evidence for both anergy an
d suppression were observed, subsequent data demonstrated that TGF beta was
a critical immunoregulatory mediator of the tolerant state: neutralizing a
nti-TGF beta antibodies fully prevented the induction of tolerance to B6 be
ta -gal tg skin grafts. Second male beta -gal tg grafts placed onto female
recipients that were previously made tolerant to female beta -gal tg skin w
ere rapidly rejected, however, suggesting that this TGF beta -induced toler
ance could not be linked to additional antigenic determinants.
Conclusions. The studies demonstrate a critical role for TGF beta in mediat
ing tolerance after intravenous injection of antigen but additionally raise
concerns about the stability of this tolerant state.