Non-hematopoietic minor histocompatibility antigen (mHag)

Non-hematopoietic minor histocompatibility antigens (mHags) are peptides derived from intracellular proteins that contain genetic polymorphisms, such as single nucleotide polymorphisms (SNPs), which differ between a transplant donor and recipient [Spierings, 2014, Tissue Antigens]. These peptides are processed and presented by Human Leukocyte Antigen (HLA) molecules on the surface of non-hematopoietic cells, including those in the skin, liver, and gastrointestinal tract [Bleakley & Riddell, 2004, Nat Rev Cancer]. In allogeneic hematopoietic stem cell transplantation, donor T cells may recognize these recipient-specific peptides as foreign, initiating a targeted immune attack against the host's healthy tissues. This process is the primary driver of Graft-versus-Host Disease (GVHD), a severe and potentially fatal complication of transplantation [Goulmy, 1997, Curr Opin Immunol]. Unlike mHags restricted to the hematopoietic system, which can facilitate the beneficial Graft-versus-Leukemia (GVL) effect, non-hematopoietic mHags are generally considered undesirable targets because their recognition leads to systemic toxicity rather than tumor clearance [Griffioen et al., 2016, Blood]. Current therapeutic research focuses on identifying these antigens to better match donors or to develop strategies that selectively deplete or inhibit T cells reactive to these tissue-specific targets while sparing those that provide anti-tumor immunity.

Other names

Minor histocompatibility antigenmHagMiHATissue-specific minor histocompatibility antigenNon-hematopoietic MiHARecipient-specific minor histocompatibility antigen

Donor-derived T-cell receptors (TCRs) recognize polymorphic peptides (mHags) presented by recipient HLA molecules on non-hematopoietic tissues, leading to T-cell activation, cytokine release, and direct cytotoxic destruction of host cells [Griffioen et al., 2016, Blood; Goulmy, 1997, Curr Opin Immunol].