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Steiner D, Brunicki N, Bachar-Lustig E, Taylor PA, Blazar BR,
Reisner Y.
Exp Hematol. 2006 Jun;34(6):802-8.
Overcoming T cell-mediated rejection of bone marrow allografts by
T-regulatory cells: synergism with veto cells and rapamycin.
Department of Immunology, Weizmann Institute of Science, Rehovot,
Israel.
Recently, we have shown that anti-third-party cytotoxic T
lymphocytes (CTLs) depleted of alloreactivity against the host are endowed with
marked veto activity and can facilitate bone marrow (BM) allografting without
graft-versus-host disease. We also demonstrated synergism between rapamycin
(RAPA) and the veto cells. CD4(+)CD25(+) T-regulatory (Treg) cells are
suppressor cells that can enhance alloengraftment. We investigated whether donor
Tregs would be synergistic with veto CTLs and RAPA in augmenting alloengraftment
or, conversely, would suppress veto CTL effects. Lethally irradiated C3H mice
were transplanted at day 2 after irradiation with Balb-nude BM. Graft rejection
was induced by purified host-type T cells infused 1 day prior to BMT. The
addition of Tregs led to moderate enhancement of engraftment. RAPA at different
doses was synergistic with Tregs. The addition of veto CTLs to Tregs enabled
reducing the effective RAPA dose fourfold. Combining all three agents was
necessary to overcome rejection at low-dose RAPA. Chimerism analysis at 5 to 9
months revealed a significant presence of host-type cells coexisting with the
predominant donor T cells, suggesting that tolerance had been attained. The
synergistic effects between Tregs, veto CTLs, and RAPA offer an attractive
approach for facilitating alloengraftment.
PMID: 16728286
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