Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

Abstract

Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion are effective treatment modalities for various hematological malignancies. Their therapeutic effect, the graft-versus-tumor (GvT) effect, is based mainly on an alloimmune response of donor T cells directed at tumor cells, in which differences in the expression of minor histocompatibility Ags (mHags) on the cells of the patient and donor have a crucial role. However, these differences are also responsible for induction of sometimes detrimental GvHD. As relapse and development of GvHD pose major threats for a large proportion of allotransplanted patients, additional therapeutic strategies are required. To augment the GvT response without increasing the risk of GvHD, specific mHagdirected immunotherapeutic strategies have been developed. Over the past years, much effort has been put into the identification of therapeutically relevant mHags to enable these strategies for a substantial proportion of patients. Currently, the concept of mHag-directed immunotherapy is tested in clinical trials on feasibility, safety and efficacy. In this review, we will summarize the recent developments in mHag identification and the clinical data on mHag-specific immune responses and mHag-directed therapies in patients with hematological malignancies. Finally, we will outline the current challenges and future prospectives in the field.

Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response

“…In the past decade, increasing numbers of MiHAs have been characterized mainly due to the application of whole-genome association scanning (WGAs) (22). We identified multiple MiHAs by WGAs and demonstrated in several patients that at least 3 to 8 different HLA class I-restricted MiHAs were targeted by donor CD8 T cells after HLA-matched alloSCT and DLI (23)(24)(25).…”

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.…”

Mechanisms underlying human genetic diversity: consequence for antigraft antibody responses

“…Oostvogels et al . recently reviewed current identification strategies for mHAs in the Journal of Bone Marrow Transplantation .…”