Major Histocompatibility Complex Class I Chain-Related A (MICA) Molecules: Relevance in Solid Organ Transplantation

Abstract

An ever growing number of reports on graft rejection and/or failure even with good HLA matches have highlighted an important role of non-HLA antigens in influencing allograft immunity. The list of non-HLA antigens that have been implicated in graft rejection in different types of organ transplantation has already grown long. Of these, the Major Histocompatibility Complex class I chain-related molecule A (MICA) is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in the kidney transplantation. Humoral response to MICA antigens has repeatedly been associated with lower graft survival and an increased risk of acute and chronic rejection following kidney and liver transplantation with few studies showing conflicting results. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, a definitive consensus on this relationship has not been arrived yet. Furthermore, only a few studies have dealt with the impact of MICA donor-specific antibodies as compared to those that are not donor specific on graft outcome. In addition to the membrane bound form, a soluble isoform of MICA (sMICA), which has the potential to engage the natural killer cell-activating receptor NKG2D resulting in endocytosis and degradation of receptor–ligand interaction complex leading to suppression of NKG2D-mediated host innate immunity, has been a subject of intense discussion. Most studies on sMICA have been directed toward understanding their influence on tumor growth, with limited literature focusing its role in transplant biology. Furthermore, a unique dimorphism (methionine to valine) at position 129 in the α2 domain categorizes MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor depending on whether they have methionine or valine at this position. Although the implications of MICA 129 dimorphism have been highlighted in hematopoietic stem cell transplantation, its role in solid organ transplantation is yet to be explored. This review summarizes the currently available information on MICA antibodies, soluble MICA, and MICA-129 dimorphism in a setting of solid organ transplantation.

Efficient Killing of Murine Pluripotent Stem Cells by Natural Killer (NK) Cells Requires Activation by Cytokines and Partly Depends on the Activating NK Receptor NKG2D

“…The system of NKG2D and NKG2D ligands has been shown to be highly important for tumor immunity ( 58 ). It also affects the outcome of hematopoietic stem cell transplantation ( 59 – 62 ) and solid organ transplantation ( 63 , 64 ). NKG2D has also been reported to be involved in the rejection of neural progenitor cells by NK cells ( 65 ).…”

Prognostic value of MICA/B in cancers: a systematic review and meta-analysis

“…This complex induces a conformational change, enabling proteolytic cleavage of MICA by a disintegrin and metalloproteinase (ADAM) proteins [ 13 ]. Then, the interaction of sMICA/B with NKG2D results in the endocytosis and degradation of receptor-ligand complexes and also suppresses NKG2D-mediated host cancer rejection [ 14 , 15 ]. Therefore, MICA/B and sMICA/B, reflecting the cancer cell centric biological behavior and tumor immune surveillance status, could be a potential prognostic biomarker of cancer patients.…”

Novel insights into non‐HLA alloimmunity in kidney transplantation

“…MICA antigens are highly polymorphic and have been extensively studied in kidney transplantation. Alloantibodies against mismatched MICA antigens were associated with acute rejection episodes and reduced 1‐year graft survival in initial publications, but a retrospective analysis in a large European cohort of 779 kidney transplant recipients did not show an independent association with four‐year death‐censored graft survival . The understanding of pathophysiology of MICA is incomplete, and testing has not been implemented in clinical routine.…”