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Prepublished online as a Blood First Edition Paper on May 13, 2002; DOI 10.1182/blood-2002-02-0419.
Submitted February 8, 2002
Accepted April 23, 2002
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*
* Corresponding author; email: mark.waer{at}med.kuleuven.ac.be.
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 (CFSE-labeled DLI-inocula, TCR-Vß6+ 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 anti-host proliferative response in MLR, 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 decreased level of preexisting 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 APCs in eliciting LHGVH reactivity after DLI should be studied using models that allow chimerism analysis in non-T cell lineages.
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