Sf. Oluwole et al., INDUCTION OF TRANSPLANTATION TOLERANCE TO RAT CARDIAC ALLOGRAFTS BY INTRATHYMIC INOCULATION OF ALLOGENEIC SOLUBLE PEPTIDES, Transplantation, 56(6), 1993, pp. 1523-1527
Since intrathymic (i.t.) injection of UV-B-irradiated spleen cells (SC
) or purified resting allogeneic T cells, but not resting B cells, den
dritic cells, or macrophages induces specific tolerance in transiently
immunosuppressed recipients, we hypothesized that presentation of don
or MHC peptide Ag by the host thymic APCs may convey a tolerogenic sig
nal to the recipient. This study examined if i.t. inoculation of allog
eneic soluble Ag obtained from 3 M KCl extracts of purified resting T
cells can induce specific tolerance to cardiac allografts in transient
ly immunomodulated recipients. We have now shown that i.t. inoculation
of donor soluble Ag on day -7 combined with 1 ml ALS on days -7 and 0
leads to indefinite WF cardiac allograft survival (>200 days) in Lewi
s recipients. This finding was reproducible in sublethally irradiated
(200 rads TBI) ACI recipients of i.t. Lewis soluble Ag. In contrast, A
CI cardiac allografts were promptly rejected in ALS-treated Lewis reci
pients of i.t. WF soluble Ag, confirming the donor specificity of such
immunologic manipulation. Extrathymic inoculation of WF soluble Ag vi
a the intravenous route in controls failed to prevent normal graft rej
ection in ALS-treated recipients. The long-term unresponsive recipient
s specifically and permanently accepted donor-type, second-set cardiac
allografts. The observation that thymectomy performed 7 days after i.
t. Ag injection led to graft rejection strongly suggests that the earl
y phase of induction of donor-specific tolerance is dependent on the p
resence of donor alloantigens in the host thymus. This approach may ha
ve important clinical therapeutic potential in the induction of transp
lantation tolerance.