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.
The two important issues affecting recipients of solid organ transplants and of importance to immunologists are (i) sensitization of the recipient to HLA antigens and the resultant humoral immune response leading to the development of anti-HLA antibodies; and ii) development of robust assays for early detection of humoral rejection post-transplant. Evidence from several studies clearly indicates that presence of circulating anti-HLA antibodies especially donor specific leads to early graft loss and high titres of DSA may even lead to hyperacute or accelerated acute rejection. Long-term graft survival too is adversely affected by the presence of either pre- or post-transplant DSA. HLA matching status of the recipient - donor pair - is an important factor in the modulation of humoral response following transplantation and in a way affects de novo development of DSA. Data collected over the past decade clearly indicate significantly lower level of DSAs in optimally matched donor-recipient pairs. HLA mismatches especially those on HLA-DR and HLA-C loci have wider implications on post-transplant graft survival. The presence of circulating anti-HLA antibodies leads to endothelial damage in the newly grafted organ through complement dependent or independent pathways. Although detection of C4d deposition in renal biopsies serves as an important indicator of humoral rejection, its absence does not preclude the presence of DSAs and humoral rejection, and hence, it cannot be relied upon in every case. The emergence of epitope-based screening for anti-HLA antibodies on Luminex platform with high degree of sensitivity has revolutionized the screening for anti-HLA antibodies and DSAs. Studies indicate that humoral response to non-HLA antigens might also have a detrimental effect on allograft survival. High titres of such circulating antibodies may even lead to hyperacute rejection. Pre-emptive testing of solid organ recipients, especially kidney transplant recipients for anti-HLA and non-HLA antibodies and aggressive post-transplant monitoring of allograft function to detect DSAs using Luminex-based tests, is highly recommended.
The detection and characterization of anti-HLA antibodies and the clinical impact of their appearance following renal transplantation are areas of immense interest. In particular, de novo development of donor-specific antibodies (DSA) has been associated with acute and chronic antibody-mediated graft rejection (AMR). Recently, methods for antibody detection have evolved remarkably from conventional cell-based assays to advanced solid phase systems. These systems have revolutionized the art of defining clinically relevant antibodies that are directed toward a renal graft. While anti-HLA DSAs have been widely associated with poor graft survival, the role of non-HLA antibodies, particularly those directed against endothelial cells, is beginning to be realized. Appreciation of the mechanisms underlying T cell recognition of alloantigens has generated great interest in the use of synthetic peptides to prevent graft rejection. Hopefully, continued progress in unraveling the molecular mechanisms of graft rejection and posttransplant monitoring of antibodies using highly sensitive testing systems will prove beneficial to immunological risk assessment and early prediction of renal allograft failure.
Besides the overriding influence of anti-HLA antibodies on the overall graft survival, immune response to non-HLA antigens has become a subject of substantial interest in recent years. The much-needed impetus towards understanding the relevance of non-HLA antibodies has come from multicentric analysis involving a large cohort of renal allograft recipients and published under the aegis of the Collaborative Transplant Study (CTS). 1 Subsequently, several investigators have highlighted an important role of non-HLA antibodies not only in kidney transplants, but also in those involving other organs such as heart and lung. 2-7 Major histocompatibility complex class I chain-related molecule A (MICA), the most notable
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