Abstracts (complete list) - Wissenschaft Online

K. Doser, J. Albrecht, T. J. Boeld, R. Eder, J. Stahl, R. Andreesen, P. Hoffmann, M.
Edinger
Protection from graft-versus-host disease by donor CD4+CD25
+ regulatory T cells improves B lymphocyte reconstitution
after allogeneic bone marrow transplantation
Allogeneic bone marrow transplantation (BMT) is a well-established therapy for
hematologic malignancies. However, graft-versus-host disease (GVHD) caused by cotransplanted
mature donor T cells, remains a significant problem. The major target
organs of GVHD are skin, liver and intestines, but also lymphoid organs, thereby
impairing immune reconstitution and increasing the susceptibility to opportunistic
infections. We, and others, previously demonstrated that the adoptive transfer of donor
CD4+CD25+ regulatory T (Treg) cells prevents GVHD. We now investigated how their
suppressive activity influences immune reconstitution after allogeneic BMT by examining
the regeneration of the B cell compartment. For this purpose, lethally irradiated BALB/c
recipients were transplanted with either 5 x 106 T cell-depleted bone marrow cells (TCD
BM) from C57BL/6 donors alone, or TCD BM plus 5 x 105 CD4+CD25- donor T cells
(Tconv) with or without equal numbers of donor Treg cells. As expected, mice that
received only TCD BM did not develop GVHD and reconstituted their B cell compartment
from transplanted BM within 20-40 d, whereas those that received additional Tconv cells
developed severe GVHD and lacked donor as well as host B lymphocytes in peripheral
blood (PB) until their early death or sacrifice by d 100. In contrast, most animals that
received Tconv and Treg cells at a 1:1 ratio were protected from GVHD and showed a
complete, yet delayed reconstitution of their B cell compartment, with appox. 50%
reconstitution by d45-60 and 100% by d100. Comparative analyses of BM, PB and
spleen revealed that GVHD interferes with B cell reconstitution not solely by destroying
peripheral lymphoid organs, but also by eliminating early B cell precursors in the BM.
We thus speculate that the dysregulated production of pro-inflammatory cytokines
during GVHD is toxic for early B cell precursors and/or that the alloresponse destroys
the BM niche for developing B cells. Importantly, co-transplanted donor Treg cells
prevent this pathology and therefore improve rather than impair immune reconstitution
after allogeneic BMT.