The major histocompatibility complex: a model for understanding graft-versus-host disease

Abstract

Acute graft-versus-host disease (GVHD) afflicts as much as 80% of all patients who receive an unrelated donor hematopoietic cell transplant (HCT) for the treatment of blood disorders, even with optimal donor HLA matching and use of prophylactic immunosuppressive agents. Of patients who develop acute GVHD, many are at risk for chronic GVHD and bear the burden of considerable morbidity and lowered quality of life years after transplantation. The immunogenetic basis of GVHD has been the subject of intensive investigation, with the classic HLA genetic loci being the best-characterized determinants. Recent information on the major histocompatibility complex (MHC) region of chromosome 6 as an important source of untyped genetic variation has shed light on novel GVHD determinants. These data open new paradigms for understanding the genetic basis of GVHD.

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

“…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. 16 Reflecting distinct features of its polymorphism, HLA-DPB1 has been the first locus to be explored as a model for clinically permissive, that is, well tolerated, donor-recipient HLA mismatches.…”

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

“…[8][9][10] The greater GVHD incidence in HLA allele-matched (ie, unrelated) vs haplotype-matched (ie, sibling) HCT hints at the existence of intra-major histocompatibility complex (MHC)-encoded, yet HLA-A-, HLA-B-, HLA-C-, HLA-DRB1-, and HLA-DQB1-independent (and hence hitherto unidentified), histocompatibility loci. 11,12 Other than HLA-DPB1, [13][14][15][16][17] the most promising MHC-encoded candidate is the MHC class I chain-related gene A (MICA). MICA is a highly polymorphic nonconventional MHC class I molecule, with 105 alleles reported to date.…”

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

“…However, a double immunological barrier adds complexity, including host-versus-graft (graft rejection) and graftversus-host reactions. 5,6 Both barriers increase with the degree of disparities in major and minor histocompatibility antigens. Graft rejection is always associated with detrimental effects for the patient.…”

“…Graft rejection is always associated with detrimental effects for the patient. [5][6][7][8][9] In contrast, the graft-versus-host reactions present a Janus face. The detrimental part, graft-versus-host disease, remains the most important direct or indirect cause for nonrelapse mortality after allogeneic HSCT.…”

“…The detrimental part, graft-versus-host disease, remains the most important direct or indirect cause for nonrelapse mortality after allogeneic HSCT. 1,[5][6][7] The 'other face', the graft-versus-malignancy effect, is desired and may result in cure of the recipient. 10 HSCT presents also as role model of precision medicine: one individual donor is selected for one individual recipient based on genetic findings.…”