H60: A Unique Murine Hematopoietic Cell-Restricted Minor Histocompatibility Antigen for Graft-versus-Leukemia Effect

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for many types of hematological malignancies. Matching of donor and recipient for the major histocompatibility complex (MHC) improves the HSCT reconstitution, but donor-derived T cells reactive to non-MHC encoded minor histocompatibility antigens (MiHAs) can induce graft-versus-host disease (GVHD) while also being needed for graft-versus-leukemia (GVL) effects. MiHAs are allelically variant self-peptides presented conventionally on MHC molecules, but are alloantigenic in transplantation settings. Immunodominant MiHAs are most strongly associated with GVHD and GVL. There is need for mouse paradigms to understand these contradictory effects. H60 is a highly immunodominant mouse MiHA with hematopoietic cell-restricted expression. Immunodominance of H60 is tightly associated with its allelic nature (presence vs. absence of the transcripts), and the qualitative (TCR diversity) and quantitative (frequency) traits of the reactive T cells. The identity as a hematopoietic cell-restricted antigen (HRA) of H60 assists the appearance of the immunodominace in allo-HSCT circumstances, and generation of GVL effects without induction of serious GVHD after adoptive T cell transfer. Also it allows the low avidity T cells to escape thymic negative selection and exert GVL effect in the periphery, which is a previously unevaluated finding related to HRAs. In this review, we describe the molecular features and immunobiology in detail through which H60 selectively exerts its potent GVL effect. We further describe how lessons learned can be extrapolated to human allo-HCST.

Shared Graft Versus Leukemia Minor Histocompatibility Antigens in DISCOVeRY-BMT

“…Using mass spectrometry, we validated a total of 24 novel GvL mHAs, an increase from the 13 GvL mHAs that have been discovered since Els Goulmy et al reported the first discovered GvL mHA, HA-1, in 1983 1,25,28,[30][31][32][33] . The 16 novel GvL mHAs found for HLA-A*02:01 together cover 98.8% of HLA-A*02:01-positive patients in the DISCOVeRY-BMT dataset, the three for HLA-B*35:01 cover 60.7% of HLA-B*35-:01-positive DISCOVeRY-BMT patients, and the five for HLA-C*07:02 cover 78.9% of HLA-C*07:02-positive DISCOVeRY-BMT patients.…”

“…The copyright holder for this preprint this version posted August 15, 2022. ; https://doi.org/10.1101/2022.08.12.503667 doi: bioRxiv preprint cell responses against them will lead to GvL effects without GvHD. Approximately 55 mHAs have been reported to date, including 13 validated GvL mHAs, and clinical trials of mHA-targeted cellular immunotherapies and vaccines have been performed [25][26][27][28][29][30][31][32][33] .…”

“…GvL mHAs are defined as mHAs that are only expressed in hematopoietic tissue, so T cell responses against them will lead to GvL effects without GvHD. Approximately 55 mHAs have been reported to date, including 13 validated GvL mHAs, and clinical trials of mHA-targeted cellular immunotherapies and vaccines have been performed [25][26][27][28][29][30][31][32][33] .…”

Granulocytic myeloid-derived suppressor cells to prevent and treat murine immune-mediated bone marrow failure

“… 8 The immunogenicity of the B6⇒C.B10 LN cell infusion model arises from mismatch at multiple minor H antigens, H60 being dominant. 52 , 53 , 54 , 55 Immune disparity between B6 and C.B10 mice also involves other minor antigens such as H4, H7, H13, and H28. 56 The attenuation of marrow failure by infusion of male G-MDSCs into female C.B10 BMF recipients showed that G-MDSC immunosuppression could overcome Y antigen disparity.…”