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2015 ; 6
(1-2
): 21-6
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Transient mixed chimerism for allograft tolerance
#MMPMID26517761
Oura T
; Hotta K
; Cosimi AB
; Kawai T
Chimerism
2015[Apr]; 6
(1-2
): 21-6
PMID26517761
show ga
Mixed chimerism discovered in Freemartin cattle by Ray Owen 70 years ago paved
the way for research on immune tolerance. Since his discovery, significant
progress has been made in the effort to induce allograft tolerance via mixed
chimerism in various murine models. However, induction of persistent mixed
chimerism has proved to be extremely difficult in major histocompatibility
complex mismatched humans. Chimerism induced in humans tends to either disappear
or convert to full donor chimerism, depending on the intensity of the
conditioning regimen. Nevertheless, our studies in both NHPs and humans have
clearly demonstrated that renal allograft tolerance can be induced by transient
mixed chimerism. Our studies have shown that solid organ allograft tolerance via
transient mixed chimerism 1) requires induction of multilineage hematologic
chimerism, 2) depends on peripheral regulatory mechanisms, rather than thymic
deletion, for long-term maintenance, 3) is organ specific (kidney and lung but
not heart allograft tolerance are feasible). A major advantage of tolerance
induction via transient mixed chimerism is exclusion of the risk of
graft-versus-host disease. Our ongoing studies are directed toward improving the
consistency of tolerance induction, reducing the morbidity of the conditioning
regimen, substituting clinically available agents, such as Belatacept for the now
unavailable anti-CD2 monoclonal antibody, and extending the protocol to
recipients of deceased donor allografts.
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