DONOR-SPECIFIC UNRESPONSIVENESS TO MURINE CARDIAC ALLOGRAFTS INDUCED BY INTRATHYMIC-SOLUBLE ALLOANTIGENS IS DEPENDENT ON ALTERNATE PATHWAY OF ANTIGEN PRESENTATION
Nc. Chowdhury et al., DONOR-SPECIFIC UNRESPONSIVENESS TO MURINE CARDIAC ALLOGRAFTS INDUCED BY INTRATHYMIC-SOLUBLE ALLOANTIGENS IS DEPENDENT ON ALTERNATE PATHWAY OF ANTIGEN PRESENTATION, The Journal of surgical research, 59(1), 1995, pp. 91-96
This study extends the finding that intrathymic (IT) inoculation of uv
-B irradiated donor spleen cells (SC) or soluble alloantigens (Ag) ind
uces peripheral tolerance to organ allografts in the rat to the murine
cardiac allograft model, In our initial experiment, we showed that IT
inoculation of uv-B irradiated SC combined with transient immunosuppr
ession of the recipient with either sublethal TBI or ALS on Day -7 led
to donor-specific, long-term cardiac allograft survival (>300 days) i
n the completely mismatched A/J-to-C57BL/6 mice combination. To test o
ur hypothesis that peripheral tolerance induced by IT injection of don
or Ag is dependent on presentation of the foreign MHC molecule by thym
ic APC to T cell precursors, we examined the effect of IT injection of
donor APC-free-soluble Ag inoculum obtained from 3 M KCl extracts of
purified MHC class I resting T cells on cardiac allograft survival in
the A/J-to-C3H mice combination. The results showed that IT injection
of the optimal dose of 500 mu g soluble Ag combined with 0.5 ml ALS on
Day -7 led to donor-specific permanent graft survival (>200 days). Th
is finding could not be reproduced by intravenous administration of so
luble Ag, thus confirming the privileged position of the thymus in tol
erance induction. To further define the role of host APC in allorecogn
ition, we studied the presentation of soluble Ag by responder APC in M
LR. The results showed that primed T cells obtained from A/J skin graf
t-sensitized C3H T cells specifically developed alloreactivity to A/J-
soluble Ag in MLR. Addition of anti-Ia mAb blocked the proliferative r
esponse, thus confirming that primed T cells can respond to soluble Ag
presented by responder-type APC. This study suggests that induction o
f peripheral tolerance by IT inoculation of soluble Ag is reproducible
in the murine cardiac allograft model, where tolerance is dependent o
n the Ag dose and the indirect pathway of Ag presentation. This approa
ch of immunologic manipulation of the adult thymus may have clinical t
herapeutic applications. (C) 1995 Academic Press, Inc.