Differential Immunogenicity and Clinical Relevance of Kidney Compartment Specific Antigens after Renal Transplantation

Li Li¹, Tara Sigdel¹, Matthew Vitalone¹, Sang Ho Lee¹, Minnie Sarwal¹.

¹Pediatric Department, Stanford University, Stanford, CA, USA.

To evaluate the pathogenic role of non-HLA antibodies after organ transplantation, 81 unique serum samples from renal transplant patients without interval acute rejection, were analyzed by protein array technology, validated by ELISA and the results correlated with clinical parameters. Integrative genomic analysis was conducted to ascertain if particular kidney compartment specific antigens had differential clinical relevance with time post-transplantation or post-transplant graft function. Expression of target proteins of interest in renal tissue was confirmed by immunohistochemical (IHC) analysis.

There was a significant association of de novo non-HLA antibodies with time post-transplantation (n=1,785) and decline in graft function over the subsequent year (n=105). There was an enrichment of immunogenic antigens in the renal cortex (p=0.01) with post-transplant time, and for glomerular specific targets (p=0.02) with decline in graft function. Two target non-HLA antibodies with very strong correlation in each category (AGT and SPDYA), were validated by customized ELISA assays in independent patient sera and their localization in the kidney confirmed by immunohistochemistry. In addition, 12 overlapping targets between the 2 data-sets correlated with both time posttransplant and transplant functional decline. About 2/3 of these targets are highly expressed in endothelial cells, monocytes and T cells. Three of the antibodies have corresponding antigenic epitopes which provide key targets for modulation by three currently used immunosuppressive agents, namely, RPTOR which is regulated by Rapamycin; TRMU which is regulated by Azathioprine; and ITPRIP which is regulated by Mycophenolate Mofetil.

In conclusion, defined profiles of these non-HLA antibodies to renal cortical proteins develop with increasing length of engraftment, and may reflect the increasing recognition of altered localization or exposure of renal tubular and interstitial proteins, affected by advancing chronic non-mmune graft injury. The panel of non-HLA antibodies to glomerular targets is most interesting, as these corresponding antigenic targets may be important pathways in functional graft injury and could provide novel targets for drug design.