In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens

Abstract

Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.

Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation

“…Moreover, surface expression of CD107a by T cells upon co-culture with patient cells strongly suggests that donor T cells participate in ongoing GVL and GVHD. Importantly, our results support data from studies in animal models, 42 suggesting that GVL and GVHD are the results of distinct responses, possibly involving separate targets. Future identification and characterization of the antigens involved in GVL and GVHD, may set the stage for separation of GVHD and GVL, which in turn may ease the way to further improvements of the effect of GVL, for example, by vaccination or adoptive transfer of specific T cells.…”

“…However, another possibility could be that the onset of GVHD initiates an immunological alertness in turn leading to GVL. This hypothesis is in compliance with the demonstration that GVL and GVHD may in fact be separated, 42 and also more appropriately abide the fact that some hematological malignancies are far more susceptible to GVL than others. In this respect, there are major differences in the clinical efficacy associated with HCT -depending to a large extent on disease entity.…”

Long-term remission of APL with a second allogeneic BMT after CNS relapse following HLA-identical allogeneic BMT

“…Here, there may exist relevant differences in donor/recipient immunoreactivity among sibling donors. 20 Based on our experience in a single patient, we conclude that a second allogeneic BMT for leukaemia relapse after first allogeneic BMT should be considered even with a fully myeloablative conditioning regimen, if the patient is in good condition and if remission of the disease can be achieved, especially, when new drugs for induction therapy are available. In patients relapsing after BMT, when no GvHD occurred after the first BMT, switching to another HLA-identical donor, if available, might be helpful in achieving higher donor/recipient immunoreactivity and a better GvL effect.…”

Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen–specific cytotoxic T lymphocytes

“…2 HA-1 and HA-2 display hematopoietic-restricted tissue distribution and relevant expression on leukemic cells and their progenitors. [3][4][5][6] Moreover, cytotoxic T lymphocytes (CTLs) directed against these mHags do not cause graft-versus-host disease in an ex vivo skin explant model, 7 and coincide with complete remission of relapsed leukemia and multiple myeloma after HLA-matched HA-1-or HA-2-mismatched donor lymphocyte infusions. 8 HA-1-and HA-2-specific CTLs can be generated in vitro using peptide-pulsed or mHag-transduced autologous dendritic cells (DCs) as antigen-presenting cells (APCs).…”