Minor histocompatibility antigens: past, present, and future

Abstract

Minor histocompatibility (H) antigens are key molecules driving allo-immune responses in both graft-versus-host-disease (GvHD) and in graft-versus-leukemia (GvL) reactivity in human leukocyte antigen (HLA)-matched hematopoietic stem-cell transplantation (HSCT). Dissection of the dual function of minor H antigens became evident through their different modes of tissue and cell expression, i.e. hematopoietic system-restricted or broad. Broadly expressed minor H antigens can cause both GvHD and GvL effects, while hematopoietic system-restricted minor H antigens are more prone to induce GvL responses. This phenomenon renders the latter group of minor H antigens as curative tools for HSCT-based immunotherapy of hematological malignancies and disorders, in which minor H antigen-specific responses are enhanced in order to eradicate the malignant cells. This article describes the immunogenetics of minor H antigens and methods that have been developed to identify them. Moreover, it summarizes the clinical relevance of minor H antigens in transplantation, with special regards to allogeneic HSCT and solid-organ transplantation.

Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells

“…These could include non-classical histocompatibility Ags that can be detected by NK cell receptors such as Qa-1, RAE-1, or Clr-b (32,33). Other possibilities include SIRPa (a polymorphic membrane protein expressed by monocytes, DCs, macrophages and neurons) (47) or a wide range of minor histocompatibility Ags that have been identified throughout the genome (48,49). Protease inhibition by serpins can influence coagulation and inflammation, so it could be surmised that polymorphisms among serpins may affect early responses.…”

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…Furthermore, and in accordance with a rather restricted expression pattern for the MICA glycoprotein, it is perhaps not surprising that MICA mismatches are associated with limited (and not extensive; ie, multiorgan) chronic GVHD (supplemental Table 3). Alternatively, MICA can act as a minor histocompatibility locus (ie, be a source of polymorphic antigenic peptides presented by cognate and/or donor classical MHC molecules, similar to H60 and H-Y in mouse or H-Y and HA-1 in man 42 ), and hence participate in GVHD pathophysiology through its contribution to alloreactivity. Although this second possibility is theoretically feasible 43 (and, interestingly, there is a peculiar precedent for this: the murine minor histocompatibility locus, H60, encodes an MHC-I-like structure that is a NKG2D ligand 43,44 ), we much favor the first option, especially given that both NK and gd T are considered important effector cells that mediate GVL reactivity within the first weeks after transplantation.…”

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…9,10 These target structures are fundamentally different in allo-HCT from HLA-matched sibling and unrelated donors (UDs), which are often erroneously considered as a single entity ("HLA-matched" HCT). However, in sibling HCT the targets of T-cell alloreactivity are almost exclusively minor histocompatibility antigens (mHAgs), [11][12][13] whereas most HLAmatched UDs additionally present mismatches for the HLA-DP antigens encoded in the major histocompatibility complex (MHC). 14,15 The latter can elicit direct alloreactive T-cell responses with important implications for both GVHD and GVL.…”

“…9,[11][12][13] Allorecognition of mHAgs is mediated by conventional self-HLA-restricted, foreign peptide-specific T cells whose repertoire is shaped by positive and negative selection in the thymus. 21,22 Because allogeneic mHAgs are not expressed by thymic antigen-presenting cells (APCs) of self-origin, alloreactive T cells specific for mHAgs occur almost exclusively in the naive T-cell repertoire.…”