The first real major breakthrough that laid the basis of 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 Luminex platform with increasing degree of sensitivity and specificity. The latter have been of immense value for accurate identification of donor specific HLA antibodies in broadly reactive alloantisera, and to guide donor selection and kidney paired exchange programs through virtual crossmatching, and to serve as excellent tools for initiating pretransplant desensitization and post transplant antbody monitoring. Consensus is still evolving on the routine employment of all these methods in donor selection strategies, either stand-alone or in combination along with an understanding of the clinical relevance of antibodies detected by each of them.
The immunoassays based on Luminex platform and flow cytometric beads are however unable to discriminate complement fixing from non-complement fixing 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 with an intent to monitor high dose IVIG desensitization promises to be a surrogate complement fixing assay retaining the exquisite sensitivity and specificity of the Luminex platform. Currently, information obtained from these assays is at best preliminary and much needs to be done to standardize technologies and set a consensus ‘MFI cut off’ for antibodies to be taken in to account.
Besides the overriding influence of anti-HLA antibodies on the overall 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 the renal transplantation. 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. 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 molecule 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 immunosuppressive role of sMICA during allo transplantation as shown recently for heart transplantation. There is a need to address the dynamic relationship between sMICA with renal allograft rejection and/or tolerance.
The first real major breakthrough that laid the basis of 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 Luminex platform with increasing degree of sensitivity and specificity. The latter have been of immense value for accurate identification of donor specific HLA antibodies in broadly reactive alloantisera, and to guide donor selection and kidney paired exchange programs through virtual crossmatching, and to serve as excellent tools for initiating pretransplant desensitization and post transplant antbody monitoring. Consensus is still evolving on the routine employment of all these methods in donor selection strategies, either stand-alone or in combination along with an understanding of the clinical relevance of antibodies detected by each of them.
The immunoassays based on Luminex platform and flow cytometric beads are however unable to discriminate complement fixing from non-complement fixing 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 with an intent to monitor high dose IVIG desensitization promises to be a surrogate complement fixing assay retaining the exquisite sensitivity and specificity of the Luminex platform. Currently, information obtained from these assays is at best preliminary and much needs to be done to standardize technologies and set a consensus ‘MFI cut off’ for antibodies to be taken in to account.
Besides the overriding influence of anti-HLA antibodies on the overall 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 the renal transplantation. 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. 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 molecule 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 immunosuppressive role of sMICA during allo transplantation as shown recently for heart transplantation. There is a need to address the dynamic relationship between sMICA with renal allograft rejection and/or tolerance.
