INDUCTION OF PERIPHERAL TOLERANCE BY INTRATHYMIC INOCULATION OF SOLUBLE ALLOANTIGENS - EVIDENCE FOR THE ROLE OF HOST ANTIGEN-PRESENTING CELLS AND SUPPRESSOR-CELL MECHANISM
Sf. Oluwole et al., INDUCTION OF PERIPHERAL TOLERANCE BY INTRATHYMIC INOCULATION OF SOLUBLE ALLOANTIGENS - EVIDENCE FOR THE ROLE OF HOST ANTIGEN-PRESENTING CELLS AND SUPPRESSOR-CELL MECHANISM, Cellular immunology, 162(1), 1995, pp. 33-41
Intrathymic (IT) inoculation of soluble alloantigens (Ag) obtained fro
m 3 M KCl extracts of resting T-cells induces donor-specific tolerance
to cardiac allografts and islet allografts. This study examined the c
ellular basis of induction of transplantation tolerance by IT injectio
n of soluble Ag. Our results show that while IT inoculation of 2 mg so
luble donor Ag on Day -7 relative to Lewis islet transplantation induc
ed specific unresponsiveness to islet allografts (>200 days) in naive
diabetic recipients, IT inoculation of 2 mg soluble Ag on the same day
as islet transplantation did not prolong islet allograft survival in
the same Lewis-to-WF rat combination. To define the role of donor APCs
in intrathymic tolerance, we showed that IT injection of an admixture
of 1 x 10(4) donor DC and 2 mg soluble Ag caused acute islet graft re
jection. In contrast, addition of 1 x 10(4) recipient-type DC to the I
T inoculum did not prevent long-term graft survival. This finding sugg
ests that while the presence of donor APCs in the inoculum does not ap
pear neccessary for IT-alloantigen to induce peripheral tolerance, pre
sentation of the soluble Ag in the thymus is dependent on host APCs. T
his conclusion is supported by our in vitro MLR experiments which show
ed that in vivo WF-Ag-primed Lewis T-cells proliferated specifically t
o WF-soluble Ag and that the response was enhanced 14-fold by the addi
tion of responder-type DC. Addition of anti-lewis MHC class II mAb spe
cifically blocked the alloresponse, thus suggesting that in vivo Ag-pr
imed T-cells are capable of recognizing and proliferating in response
to allopeptides presented by responder APCs. We also showed that adopt
ive transfer of syngeneic naive T-cells into unresponsive recipients f
ailed to break tolerance to long-term surviving islet allografts. This
finding suggests that tolerance in this model is not due to a lack of
T help. On the other hand, the adoptive transfer of spleen cells, but
not sera, from the unresponsive WF recipients bearing long-term (>120
days) functioning Lewis islets resulted in prolonged survival of dono
r-type but not third-party islet allografts in secondary syngeneic hos
ts. Our data suggest that the tolerogenic effect of IT inoculation of
soluble Ag is dependent on the indirect pathway of Ag presentation and
clonal deletion of alloreactive T-cells in the thymus, while suppress
or/regulatory mechanism may be involved in the maintenance of peripher
al tolerance. (C) 1995 Academic Press, Inc.