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

Abstract

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-versushost (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

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

“…[49] In murine allogeneic transplant models, others and we have shown that the severity of GVHD is reduced or abolished following delayed infusion of alloreactive donor T cells. [45,[51][52][53][54] The mechanism/s by which pre-transplant irradiation of NOD/SCID-β2m null recipients increases the incidence of lethal X-GVHD induced by huT cells remains unknown. One possibility is that TBI provides additional immunosuppression, thereby permitting increased huT cell engraftment and subsequent development of lethal X-GVHD [23].…”

The Host Environment Regulates the Function of CD8+ Graft-versus-Host-Reactive Effector Cells

“…Unfortunately, under conditions in which donor T cells are transferred immediately to lethally irradiated recipients, GVL responses are often associated with the development of graft-vs-host disease (GVHD). Delaying the timing of donor T cell administration by 2-3 wk may reduce the risk of GVHD in full allogeneic chimeras and still permit the induction of GVL, but by 4 -5 wk, graft-vs-host (GVH) reactivity cannot be induced (3,4). In sharp contrast, the GVL response remains intact when donor T cells are infused (at Ͼ8 wk) into established mixed chimeras (MC), where hematopoietic elements from both the donor and recipient are present at the time of transfer (5)(6)(7).…”

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction

“…The expanding CD11b þ population showed a CD11b þ F4/ 80 À GR1 hi phenotype, and a morphology typical of myeloid progenitor cells (not shown), similar to those previously described in BM chimeras after myeloablation. 9,21 We postulate therefore that this peripheral expansion of myeloid progenitor cells occurs as a consequence of the BM depression caused by alloreactive T cells. In conclusion, in addition to causing subclinical BMGvHD, the serial PSI regimen induces a profound disruption of the cellular composition of lymphohematopoietic organs.…”

“…3 Indeed, abatement of conditioning-induced inflammation is thought to contribute to the observed reduced GvHD risk when DLI is delayed with several weeks or months after a transplant. [4][5][6][7][8][9] In contrast, the GvL response of DLI has been shown in mice to result from the interaction between donor T cells and recipient APC in the lymphohematopoietic tissues, resulting in a lymphohematopoietic GvH reaction (LHGvHR). 2 In mice, mixed chimerism and a LHGvHR with conversion of mixed to full donor chimerism have been shown essential for GvL responses after DLI.…”

“…2 In mice, mixed chimerism and a LHGvHR with conversion of mixed to full donor chimerism have been shown essential for GvL responses after DLI. 8,9 Moreover in the clinical setting, antitumor responses after DLI frequently occur in association with conversion of mixed to full donor T-cell chimerism. 10,11 Parent-in-F1 models are frequently used to study the immunobiology of GvHD.…”