M. Coulombe et Rg. Gill, TOLERANCE INDUCTION TO CULTURED ISLET ALLOGRAFTS .2. THE STATUS OF ANTIDONOR REACTIVITY IN TOLERANT ANIMALS, Transplantation, 57(8), 1994, pp. 1201-1207
Murine islet tissue cultured in 95% O-2 to eliminate/inactivate donor
antigen-presenting cells can function indefinitely and induce a state
of tolerance in nonimmunosuppressed, allogeneic recipients. Such cultu
red grafts represent a model of antigen presentation in which antigen
(signal 1) is presented without the delivery of appropriate costimulat
ory activity (signal 2) necessary for T cell activation. As T cell ina
ctivation has been proposed to result from this form of antigen presen
tation, we determined whether the tolerance generated in response to s
uch cultured grafts was due to a passive (clonal deletion/inactivation
) mechanism. We have shown that, although tolerant in vivo, animals be
aring long-term cultured islet allografts are donorreactive in vitro a
s assessed by (1) CTL precursor frequency, (2) antidonor proliferative
and cytotoxic responses, and (3) lymphokine production (IL-2, IL-3, T
NF, and IFN-gamma). In addition, tolerance does not appear to be tissu
e (islet)-specific in that primed, donor-reactive T cells from toleran
t animals react to islet cells in vitro and are capable of destroying
donor-type islet grafts in vivo. Thus, the notion that ''signal 1'' an
tigen presentation, as represented by cultured islet allografts, leads
to the clonal deletion or inactivation (anergy) of donor-reactive T c
ells is not supported by these results. Since this form of tolerance d
oes not appear to be an intrinsic property of the donor-specific lymph
ocyte, these results are more consistent with a model of active regula
tory tolerance in vivo.