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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-02-0419.
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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1894-1902
TRANSPLANTATION
Crucial role of timing of donor lymphocyte infusion in generating
dissociated graft-versus-host and graft-versus-leukemia responses in
mice receiving allogeneic bone marrow transplants
An D. Billiau,
Sabine Fevery,
Omer Rutgeerts,
Willy Landuyt, and
Mark Waer
From the Laboratory of Experimental Transplantation and
Laboratory of Experimental Radiobiology, University of Leuven, Belgium.
A murine model of minor histocompatibility antigen-mismatched bone
marrow transplantation (BMT) was used to study the role of timing of
donor lymphocyte infusion (DLI) in eliciting graft-versus-host (GVH)
and graft-versus-leukemia (GVL) reactivity. We gave DLI at weeks 3 and
12 after BMT and related its ability to induce a GVL effect with (1)
evolution of T cell chimeric status and (2) the extent to which DLI
could elicit lymphohematopoietic GVH (LHGVH) reactivity. All mice
remained free of GVH disease, but only week 3 DLI chimeras exhibited a
significant GVL response when challenged with host-type leukemia cells.
In these week 3 DLI chimeras, host-reactive T cells were found to
proliferate in vivo (5- [and-6]-carboxyfluorescein diacetate,
succinimidyl esther [CFSE]-labeled DLI inocula,
TCR-V 6+ T-cell frequency) and T-cell chimerism rapidly
converted from mixed into complete donor type, indicating the
occurrence of LHGVH reactivity. In week 12 chimeras, DLI elicited none
of the activities noted at week 3. Yet, in both instances, splenocytes,
recovered following DLI, generated an equally strong antihost
proliferative response in a mixed lymphocyte reaction, thereby
arguing against a decisive role of regulatory cells. The lack of in
vivo LHGVH reactivity after week 12 DLI was associated with a
substantially increased level of pre-existing host-type T-cell
chimerism. We conclude that elicitation of a GVL effect may require
LHGVH reactivity and that the reason why timing of DLI was critical for
obtaining LHGVH reactivity and the desired GVL effect may lie in the
evolution of chimeric status. A possible direct involvement of residual host-type antigen-presenting cells in eliciting LHGVH
reactivity after DLI should be studied using models that allow
chimerism analysis in non-T-cell lineages.
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