Strategies to elicit an effective graft-versus-leukemia (GVL) response without graft-versus-host disease (GVHD) post-allogeneic bone marrow transplantation or stem cell transplantation (BMT) have been an elusive goal. Host antigen presenting cells (APCs) have been shown to be crucial in inducing GVHD. Using a series of mouse BMT models, Reddy et al. shed insight on the role of host versus donor APCs in GVL and raised intriguing questions about the kinetics of GVL over time. The authors first established that in their model, inoculation of syngeneic tumor cells into syngeneic BMT recipients led to no GVHD but death from tumor, while the majority of allogeneic (minor histocompatibility, mHC) recipients developed GVHD but not disseminated tumor. To generate differential alloantigen expression between hematopoietic cells and epithelial target tissues, they generated bone marrow chimeric mice with beta-2-microglobulin-deficient (unable to express MHC I and thereby present antigens) syngeneic cells. When given allogeneic BMT, these chimeric recipients did not develop GVHD, but died of tumor progression. This suggests that MHC I expression (and thereby antigen presentation) by host hematopoietic cells was necessary for both GVHD and GVL in this model. To further dissect the relative contributions of T cells versus APCs, T cells and APCs of the same or different genetic backgrounds were given in BMT. When donor T cells were allogeneic to both APCs and tumor but syngeneic to host tissues, moderate GVHD and robust GVL response developed. In contrast, when donor T cells were allogeneic to both APC and target tissues but syngeneic to tumor, no GVL developed and mice died from tumor. When donor T cells were allogeneic to APCs but syngeneic to target tissues and tumor, recipients developed GVHD without GVL. Together, these data show the important role of APCs in both GVHD and GVL, and the need for shared alloantigens on tumor cells and APCs in driving optimal GVL responses. Lastly, to address the relative roles of residual host APCs early versus engrafted donor APCs late post-BMT, tumor cell numbers were titrated down such that recipients survived longer to observe possible late GVL effects. When tumor burden was reduced, small but significant GVL responses from donor APCs could be detected.
This study confirms and extends previous findings of the critical and central role of APCs in driving GVL and GVHD. It also demonstrates the prominent role of alloantigens in driving not only GVHD, but also GVL. Furthermore, it raises an intriguing possibility that GVL may arise in two waves. In the first (acute) wave, GVL is mediated by residual host APC presenting host mHC and leukemia antigens. In the second (chronic) wave, GVL is mediated by donor APC presenting host mHC and leukemia antigens from residual leukemic cells. This is somewhat akin to acute and chronic GVHD and raises issues regarding the optimal timing of donor lymphocyte infusion (DLI) to maintain the late GVL response. Going back to the elusive goal of separating GVL from GVHD, this study suggests that these processes share key common mechanisms BE APCs and alloantigen expression. Hence, while strategies which block APC function may reduce GVHD, they may also reduce GVL and should be used with caution in the clinical setting.
