Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions

Abstract

Following bone marrow transplantation, delayed donor leukocyte infusions (DLIs) can induce graft-versus-leukemia (GVL) effects without graft-versus-host disease (GVHD). These antitumor responses are maximized by the presence of host hematopoietic antigen-presenting cells (APCs) at the time of DLI. Using a tumor-protection model, we demonstrate here that GVL activity following administration of DLIs to established mixed chimeras is dependent primarily on reactivity to allogeneic MHC antigens rather than minor histocompatibility or tumorassociated antigens. CD8 ؉ T-celldependent GVL responses against an MHC class II-negative tumor following delayed DLI require CD4 ؉ T-cell help and are reduced significantly when host APCs lack MHC class II expression. CD4 ؉ T cells primed by host APCs were required for maximal expansion of graft-versus-host reactive CD8 ؉ T cells but not their synthesis of IFN-␥. In contrast, the GVL requirement for CD4 ؉ T-cell help was bypassed almost completely when DLI was administered to freshly irradiated recipients, indicating that the host environment is a major factor influencing the cellular mechanisms of GVL. IntroductionFollowing allogeneic bone marrow transplantation (BMT), donor T-cell alloreactivity can be co-opted to generate powerful antitumor activity, an effect termed the graft-versus-leukemia (GVL) response. 1,2 The GVL effect is associated with the presence of graft-versus-host disease (GVHD) and is linked to the degree of major MHC disparity and the presence of T cells within the graft, indicating that graft-versus-host (GVH) alloreactive donor T cells are important for this effect. 3 We have previously shown that administration of delayed donor leukocyte infusion (DLI) to established mixed chimeras (MCs; in which hematopoietic elements from both the donor and recipient are present) produces dramatically improved GVL effects compared with those seen following delayed DLI to full chimeras (FCs). 4 Host hematopoietic antigen-presenting cells (APCs) expressing MHC class I molecules are necessary for this optimization of GVL effects in MCs. 4 The importance of host APCs in inducing GVL has recently been confirmed in freshly irradiated mice, 5 and previous studies have shown their importance in inducing GVHD under such conditions. 6,7 The marked overlap of GVL and GVHD limit the wider application of allogeneic BMT, especially in those individuals who lack an HLA-identical donor. However, GVL can be achieved without GVHD by administration of DLI to established MCs that lack proinflammatory stimuli from recent conditioning. 4,8 A precise definition of the mechanisms that underlie the GVL effect of DLI in MCs will be important for the rational development of this strategy for achieving maximal GVL effects without GVHD in humans. Using a tumor protection model, we demonstrate here that GVL responses of DLI are due to alloresponses against recipient MHC antigens. We also demonstrate a requirement for CD4 ϩ T-cell help in generating maximal CD8 ϩ T-cell-mediated GVL activity against MH...

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

“…These and other factors have the potential to influence the precise cellular mechanisms of GVL operating in the two contexts. In support of this notion, CD4 cell help is not required for CD8 cellmediated GVL following immediate transfer of donor T cells but is an absolute requirement following delayed transfer to MC (5). Better definition of the properties of GVH-reactive CD8 cells emerging following delayed T cell transfer to MC will be important in the development of strategies that seek to use DLI to induce GVL in the clinical setting.…”

“…Importantly, the 3 ϫ 10 6 SC dose used in this experiment was 1 log lower than the SC dose (3 ϫ 10 7 SC) required to induce GVL in MC (Ref. [5][6][7] and unpublished data). TBI-allo mice receiving EL4 and TCD BM alone on day 0 showed rapid mortality (Fig.…”

“…In these experiments, established B10.A ϩ B6 3 B6 MC received the same SC dose as a cohort of TBI-allo B6 mice also receiving a mixture of B6 and B10.A TCD BM. This assay measures a CD8 cell-mediated GVL effect against EL4, a class II-negative T cell lymphoma of host origin (5). Since early SC transfer to TBI-allo mice is associated with lethal GVHD, we performed preliminary titration experiments to determine the dose of donor B10.A SC that did not lead to prohibitive rates of GVHD in this setting (3 ϫ 10 6 SC, not depicted).…”

“…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). This finding relates to the continued presence of large numbers of host hematopoietic APCs, which are required for maximal priming of donor T cells recognizing recipient class I (7) and class II (5) following MHC-mismatched transplantation.…”

“…F ollowing allogeneic bone marrow transplantation (BMT), 5 donor T cell alloreactivity can be exploited to generate a powerful anti-leukemia effect, a phenomenon termed the graft-vs-leukemia (GVL) response (1,2). 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).…”