DEPENDENCE OF ACQUIRED SYSTEMIC TOLERANCE TO RAT ISLET ALLOGRAFTS INDUCED BY INTRATHYMIC SOLUBLE ALLOANTIGENS ON HOST RESPONSIVENESS, MHC DIFFERENCES, AND TRANSIENT IMMUNOSUPPRESSION IN THE HIGH RESPONDER RECIPIENT
P. Fiedor et al., DEPENDENCE OF ACQUIRED SYSTEMIC TOLERANCE TO RAT ISLET ALLOGRAFTS INDUCED BY INTRATHYMIC SOLUBLE ALLOANTIGENS ON HOST RESPONSIVENESS, MHC DIFFERENCES, AND TRANSIENT IMMUNOSUPPRESSION IN THE HIGH RESPONDER RECIPIENT, Transplantation, 63(2), 1997, pp. 279-283
Recent studies suggest that the adult immune system can be manipulated
by intrathymic (IT) inoculation of donor Ag to accept cardiac and isl
et allografts in the low responder rat combination of Lewis-to-WF. We
have now extended this study to examine the effect of IT inoculation o
f soluble protein Ag obtained from 3M KCl extracts of resting T cells
combined with transient ALS immunosuppression on islet allograft survi
val in the high responder combination of WF-to-Lewis. We first confirm
ed the earlier observation that IT injection of 2 mg soluble Ag on day
-7 led to permanent islet graft survival (>200 days) in the Lewis-to-
WF rat combination without the use of recipient immunosuppression and
found this to be true in the Lewis-to-ACI rat combination, In the high
responder combination of WF-to-Lewis, unmodified Lewis rats pretreate
d with IT inoculation of 2 mg soluble Ag acutely rejected WF and BN is
let allografts, IT inoculation of donor Ag combined with 1 ml ALS tran
sient immunosuppression on day -7 led to a modest graft prolongation [
24.8+/-10.1 days as compared with 15.2+/-3.6 days in ALS only treated
controls]. Intrathymic injection of soluble Ag on day -7 combined with
1 mi ALS on days -7 and 0 relative to allografting resulted in 100% p
ermanent islet graft survival (>200 days) compared with an MST of 20.6
+/-2.3 days in ALS only-treated controls. Similar treatment led to acu
te rejection of 3rd party (BN) grafts, thus demonstrating donor-specif
icity. In addition, extrathymic inoculation of donor Ag in similarly i
mmunosuppressed animals did not result in islet graft prolongation, on
ce again confirming the importance of the thymus in tolerance inductio
n. To examine them for donor-specific tolerance, long-term unresponsiv
e (>120 days) Lewis recipients of renal subcapsular islets underwent n
ephrectomy of the islet bearing kidneys and were challenged with intra
portal donor- or third party-type islets after becoming diabetic, All
the nonimmunosuppressed recipients of donor-type (WF) islets became pe
rmanently normoglycemic (>100 days) while the third-party (BN) grafts
were promptly rejected, with an MST of 10.6 days. These findings confi
rm that acquired thymic tolerance induced by IT inoculation of soluble
protein Ag in the low to moderate responder rat combinations is repro
ducible in the high responder combination provided that adequate perit
ransplant immunosuppression is used. This study suggests that acquired
thymic tolerance in the rat model is dependent on host responsiveness
to alloantigens, MHC differences between the donor-recipient pair, an
d the use of transient immunosuppression in the high responder recipie
nt. This model may have potential clinical application in the developm
ent of strategies for specific transplantation tolerance.