Antibody Repertoire and Graft Outcome Following Solid Organ Transplantation

The first real major breakthrough that laid the basis of HLA antibody detection in the field of solid organ transplantation, came with the introduction of the complement dependent cytotoxicity (CDC) test in 1964 by Terasaki and McClelland. Since then, methods for antibody detection have evolved remarkably from conventional cell-based assays to the current advanced solid phase systems on the Luminex platform, with increasing degree of sensitivity and specificity. The latter have been indispensable for more accurate identification of donor specific HLA antibodies in broadly reactive allo antisera, and to guide donor selection and kidney paired exchange programs through virtual crossmatching, in addition to serving as excellent tools for initiating pre-transplant desensitization and post- transplant antibody monitoring. Consensus is evolving on the optimal routine employment of these methods in donor selection strategies along with an understanding of the clinical relevance of antibodies detected by each of them. The immunoassays based on the Luminex platform and flow cytometric beads are however unable to discriminate complement fixing from non-complement fixing HLA antibodies. This is important because the former are considered clinically more pertinent in the peri-transplant period. The C1q assay which is a modification of the solid phase assay based on Luminex single antigen beads, which can be used effectively to monitor high dose IVIG desensitization is essentially a surrogate complement fixing assay, retaining the exquisite sensitivity and specificity of the Luminex platform. Currently, information obtained from these assays is preliminary and much needs to be done to standardize technologies and set a consensus ‘MFI cut off’ for antibody positivity. Besides the overriding influence of anti-HLA antibodies on overall solid organ graft survival, immune response to non-HLA antigens has become a topic of substantial interest in recent years. An ever expanding list of non-HLA antigens has been implicated in graft rejection for various organs, of which the most noted are the Major Histocompatibility Complex class I chain-related molecule A (MICA), Vimentin, Myosin, Angiotensin II type 1 receptor (AT1R), Tubulin and Collagen. MICA is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in renal transplantation. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, to date a definitive consensus on this relationship has not been agreed. Because MICA molecules are not expressed constitutively on immunocompetent cells such as T and B lymphocytes, it is of utmost importance to address the impact of MICA donor specific antibodies (DSA) as compared to those that are non- donor specific (NDSA) on graft outcome. The soluble isoform of MICA molecule (sMICA) that is derived from the proteolytic shedding of membrane bound molecules has the potential to engage the NK-cell activating receptor NKG2D and down-regulate its expression. Consequent to the interaction of NKG2D by sMICA, the receptor ligand complex is endocytosed and degraded and thus suppresses NKG2D mediated lysis of the target by NK cells. Thus interaction between NKG2D and sMICA leads to expansion of immunosuppressive/anergic T cells thereby resulting in suppression of NKG2D mediated host innate immunity. These concept support the possible involvement of an immunosuppressive role for sMICA during allotransplantation as shown recently for heart transplantation. This research topic focuses on the clinical utility of investigating the complete antibody repertoire in solid organ transplantation