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Am J Transplant
2017[Jul]; 17
(7
): 1742-1753
PMID28066981
show ga
Several approaches successfully achieve allograft tolerance in preclinical models
but are challenging to translate into clinical practice. Many clinically relevant
factors can attenuate allograft tolerance induction, including intrinsic genetic
resistance, peritransplant infection, inflammation, and preexisting antidonor
immunity. The prevailing view for immune memory as a tolerance barrier is that
the host harbors memory cells that spontaneously cross-react to donor MHC
antigens. Such preexisting "heterologous" memory cells have direct reactivity to
donor cells and resist most tolerance regimens. In this study, we developed a
model system to determine if an alternative form of immune memory could also
block tolerance. We posited that host memory T cells could potentially respond to
donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to
which the host is immune. Results show that immunity to a model nonself antigen,
ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial
reactivity to donor MHC antigens. Importantly, this blockade of tolerance was
CD8(+) T cell-dependent and required linked antigen presentation of alloantigens
with the test OVA antigen. As such, this pathway represents an unapparent, or
"incognito," form of immunity that is sufficient to prevent tolerance and that
can be an unforeseen additional immune barrier to clinical transplant tolerance.
|Animals
[MESH]
|Antigen Presentation/*immunology
[MESH]
|CD8-Positive T-Lymphocytes/*immunology
[MESH]
|Female
[MESH]
|Graft Rejection/*immunology
[MESH]
|Immunologic Memory/*immunology
[MESH]
|Islets of Langerhans Transplantation/*methods
[MESH]
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