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Identifying Compartment-Specific Non-HLA Targets After Renal Transplantation by Integrating Transcriptome and ‘‘Antibodyome’’ Measures

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Identifying Compartment-Specific Non-HLA Targets After Renal Transplantation by Integrating Transcriptome and ‘‘Antibodyome’’ Measures Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and ‘‘antibodyome’’ measures Li Lia, Persis Wadiab, Rong Chenc, Neeraja Kambhamd, Maarten Naesensa, Tara K. Sigdela, David B. Miklosb, Minnie M. Sarwala,1, and Atul J. Buttea,c,1 aDepartment of Pediatrics, Blood and Marrow Transplantation Division, Departments of bMedicine and dPathology, and cCenter for Biomedical Informatics Research, Stanford University, 300 Pasteur Drive, Stanford, CA 94304 Communicated by Mark M. Davis, Stanford University School of Medicine, Stanford, CA, January 27, 2009 (received for review May 22, 2008) We have conducted an integrative genomics analysis of serological antigens, may be associated with chronic renal allograft histological responses to non-HLA targets after renal transplantation, with the injury (11). Antibodies against Agrin, the most abundant heparin aim of identifying the tissue specificity and types of immunogenic sulfate proteoglycan present in the glomerular basal membrane, non-HLA antigenic targets after transplantation. Posttransplant have been implicated in transplant glomerulopathy (12), and ago- antibody responses were measured by paired comparative analysis nistic antibodies against the Angiotensin II type 1 receptor of pretransplant and posttransplant serum samples from 18 pedi- (AT1R-AA) were described in renal allograft recipients with severe atric renal transplant recipients, measured against 5,056 unique vascular types of rejection and malignant hypertension (13). protein targets on the ProtoArray platform. The specificity of It is expected that there are many more unidentified non-HLA antibody responses were measured against gene expression levels non-ABO immune antigens that might evoke specific antibody specific to the kidney, and 2 other randomly selected organs (heart responses after renal transplantation (8). However, without target and pancreas), by integrated genomics, employing the mapping of antigen identification, antibody screening for specificity is near transcription and ProtoArray platform measures, using AILUN. The impossible. The advent of high-density protein microarrays has likelihood of posttransplant non-HLA targets being recognized made screening for serum antibodies against thousands of human preferentially in any of 7 microdissected kidney compartments was proteins more efficient, as seen in recent publications in autoim- also examined. In addition to HLA targets, non-HLA immune mune disease (14) and cancer (15). responses, including anti-MICA antibodies, were detected against Here, we use protein arrays to query de novo or augmented kidney compartment-specific antigens, with highest posttrans- postkidney transplantation antibody responses against a selection of plant recognition for renal pelvis and cortex specific antigens. The HLA and non-HLA targets in 18 transplant recipients. We are able compartment specificity of selected antibodies was confirmed by to simultaneously interrogate posttransplant antibody responses to IHC. In conclusion, this study provides an immunogenic and ana- Ͼ5,000 individual human proteins, but for these antibody responses tomic roadmap of the most likely non-HLA antigens that can to be clinically relevant, it would be important to interrogate if they generate serological responses after renal transplantation. Corre- are directed against the transplanted kidney. Second, if kidney lation of the most significant non-HLA antibody responses with specific antigens are preferentially recognized after transplantation, transplant health and dysfunction are currently underway. are some kidney compartments more immunogenic than the oth- ers? To address these questions, tissue-specific and microdissected integrative genomics ͉ kidney compartment ͉ kidney transplantation ͉ kidney compartment-specific gene expression raw data were down- non-HLA antigen loaded from the public domain [e.g., SYMATLAS (http:// symatlas.gnf.org/SymAtlas)], and gene identifiers from cDNA and espite advances in immunosuppressive therapies and the re- Affymetrix platforms were mapped to their corresponding protein Dsultant reduction in the incidence of acute rejection, declining identifiers on the ProtoArray platform. Our hypothesis was that graft function remains a paramount clinical concern, because kidney alloantigens can elicit de novo or augmented antibody recent studies have shown no benefit of the reduction of acute recognition after kidney transplantation. Microdissected normal rejection incidence on graft life expectancy (1). This may relate to kidney compartment-specific lists of expressed genes, were cross- the heterogeneity of the acute rejection injury (2) (3), but there is mapped to protein identifiers on the ProtoArray platform, to extensive evidence that antibodies recognizing and engaging with determine whether antigens in a specific kidney compartment were donor antigens also play a key role in renal allograft outcomes (4). being targeted after transplantation. Antibodies recognizing HLA molecules (major histocompatibil- ity antigens) are the most important group of antibodies for renal Results transplantation. HLA antibodies can be present before transplan- Identification of de Novo Non-HLA Non-ABO Antibody Formation After tation, because of prior exposure to nonself HLA molecules (after Renal Transplantation. The formation of de novo antibodies after pregnancy, blood transfusion or prior allo-transplantation), or can renal transplantation was assessed by comparing 18 posttransplant be produced de novo after transplantation (5). Donor-specific anti-HLA alloantibodies can initiate rejection through comple- ment-mediated and antibody-dependent, cell-mediated cytotoxic- Author contributions: D.B.M., M.M.S., and A.J.B. designed research; L.L., P.W., N.K., M.M.S., ity (6, 7). In contrast to these ‘‘major’’ histocompatibility antibodies, and A.J.B. performed research; T.K.S., D.B.M., M.M.S., and A.J.B. contributed new reagents/ analytic tools; L.L., R.C., M.N., M.M.S., and A.J.B. analyzed data; and L.L., M.M.S., and A.J.B. ‘‘minor’’ non-HLA antigens have been implicated in renal allograft wrote the paper. outcome, and likely have a much stronger role in clinical trans- The authors declare no conflict of interest. plantation than previously thought (8). Antibodies against MICA ϭ Data deposition: The data reported in this paper have been deposited in the Gene (MICA MHC class I polypeptide-related sequence A), a locus Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE10452). related to HLA determining a polymorphic series of antigens 1To whom correspondence may be addressed. E-mail: [email protected] or similar to HLA, have been associated with decreased graft survival [email protected]. (9, 10). Duffy [a chemokine receptor, the Duffy antigen-receptor This article contains supporting information online at www.pnas.org/cgi/content/full/ for chemokines (DARC)], and Kidd polymorphic blood group 0900563106/DCSupplemental. 4148–4153 ͉ PNAS ͉ March 17, 2009 ͉ vol. 106 ͉ no. 11 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0900563106 Downloaded by guest on September 24, 2021 Table 1. Frequency of compartment-specific humoral-antibodies and P value of enrichment across different kidney compartments at multiple ProtoArray thresholds Inner Inner Outer Outer Papillary Glomeruli Cortex Medulla Cortex Medulla Pelvis Tip ProtoArray threshold No. P No. P No. P No. P No. P No. P No. P 50 1 0.26 5 0.07 0 0.89 5 0.18 0 0.68 8 0.11 2 0.28 100 4 0.20 6 0.16 0 0.79 6 0.10 0 0.46 17 0.04 5 0.17 150 5 0.16 7 0.15 1 0.70 7 0.02 1 0.37 26 0.01 6 0.16 200 8 0.14 8 0.10 1 0.62 11 0.03 1 0.34 33 0.01 8 0.14 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 1,300 48 0.04 57 0.01 3 0.27 104 0.02 9 0.15 156 0.04 57 0.07 1,350 50 0.04 58 0.01 3 0.27 106 0.02 9 0.14 161 0.04 58 0.07 1,400 54 0.05 61 0.01 3 0.27 112 0.02 10 0.15 167 0.04 62 0.06 1,409 54 0.05 61 0.01 3 0.27 112 0.02 10 0.15 169 0.04 62 0.06 Data are shown for a single representative patient (ID ϭ 15). serum samples with 18 paired pretransplant serum samples. Of the graft outcomes (9, 10), was at a higher level after transplantation in 5,056 proteins present on the ProtoArray, an average of 61% (range 72% of patients in this study. There was no correlation between the across patients 21–96%) had an increased signal after transplanta- mean intensity of posttransplant antibody responses and HLA tion. A complete list of all 5,056 antigens has been deposited in the match or mismatch grades. Gene Expression Omnibus (GEO) (16). Integrative cDNA-Protein Microarray Analysis for Compartment-Spe- Mapping Genes That Are Specifically Expressed in Different Compart- cific Immunogenicity. A list of proteins against which each patient ments of Normal Kidney. We obtained from the Stanford Microarray developed significant antibody responses was generated for each Database (http://med.stanford.edu/jhiggins/Normal࿝Kidney/ patient, across a variety of possible threshold levels of immune download.shtml) a previously reported cDNA microarray gene response signal intensities. Each list was then tested to see whether expression dataset, in which 34 samples were obtained from 7 these antigens were significantly over-enriched by their correspond- different renal compartments of normal kidneys: glomerular (n ϭ ing genes, expressed in any particular individual renal compartment 4), inner cortex (n ϭ 5), outer cortex (n ϭ 5), inner medulla (n ϭ from the microarray dataset (17), by using the hypergeometric 5), outer medulla (n ϭ 5), pelvis (n ϭ 5) and papillary tip samples distribution (Table 1). If there was no renal compartment-specific (17). Raw data were downloaded and genes significant for each posttransplant antibody targeting, then over-enrichment of compartment selected by SAM (18), using an FDR Յ5%. Probes, compartment-specific antigens would not be expected as the sig- SCIENCES specific to each kidney compartment, were retained in our analysis nificance threshold of ProtoArray signals were reduced.
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