Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease

Abstract

Adoptive transfer of T cells reactive to minor histocompatibility antigens has the unmatched ability to eradicate malignant hematopoietic cells. Unfortunately, its use is hampered by the associated graft-versus-host disease. The critical issue of a possible dissociation of the antileukemic effect and graft-versus-host disease by targeting specific minor histocompatibility antigens remains unresolved because of the unknown nature and number of minor histocompatibility antigens necessary or sufficient to elicit anti-leukemic activity and graft-versus-host disease. We found that injection of T lymphocytes primed against a single major histocompatibility complex class I-restricted immunodominant minor histocompatibility antigen (B6dom1) caused no graft-versus-host disease but produced a curative anti-leukemic response. Avoidance of graft-versus-host disease required that no other host-reactive T cells be co-injected with T cells primed with B6dom1. Here we show that effective and non-toxic immunotherapy of hematologic malignancies can be achieved by targeting a single immunodominant minor histocompatibility antigen.

New perspectives on the biology of acute GVHD

“…13 Furthermore, the impact of mHAs is likely to be expanded further by the process of epitope spreading, which is a process in which the target of an immune response extends from the intended antigen to other epitopes. 14 Damage induced by conditioning regimens and underlying diseases. Under most circumstances, the initiation of an adaptive immune response is triggered by the innate immune response.…”

Recognition of allo-peptide is governed by novel anchor imposition and limited variations in TCR contact residues

“…The only difference between the allelic H7 peptides is an additional methylene (-CH 2 ) group in the side chain that is present in the glutamic acid in H7a (KAPDNRETL) that is absent in the aspartic acid in H7b (KAPDNRDTL). Such a subtle difference in the antigenic epitope still evokes a strong CTL-mediated immune response leading to graft rejection and GvL effects (Fontaine et al, 2001). Our current study provides a model system to understand the molecular mechanisms by which the host-derived T cells vigorously recognize a peptide that is of exceptional structural homology to a self-peptide.…”

“…Thus, H7a and H7b peptides differ by a single methylene (-CH 2 ) side chain. However, this small change in the side chain of p7 residue has been shown to result in significant T cell responses leading to graft rejections and GvL responses (Fontaine et al, 2001). To understand the contribution of peptide abundance towards this strong T cell response, we quantified the peptide copy numbers on per cell basis.…”

“…Epitopes derived from mH antigens (Ags) provide an excellent model system to address many issues regarding interactions between peptide/MHC complexes and the TCR. Murine mH-Ag, H7 is one such antigen used to describe MHC restriction (Bevan, 1977), immunodominance (Eden et al, 1999), and the role of a single mH-Ag in skin graft rejection and GvL (Fontaine et al, 2001). H7 is a bi-allelic mH-Ag restricted to D b MHC class I and the antigenic epitopes have been defined as KAPDNRETL (H7a) and KAPDNRDTL, (H7b) (McBride et al, 2002;Malarkannan and Pooler, 2004).…”

“…Thus, the allelic peptides differ by an additional methylene in the side chain (-CH 2 ) between the glutamic acid (E) to aspartic acid (D) at position 7 (p7). This conserved amino acid variation between the allelic peptide leads to a significant reciprocal CD8 + T cell responses during graft and tumor rejections (Fontaine et al, 2001). The molecular basis for such a strong T cell response has not been understood.…”