Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling.
BACKGROUND
The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment.


METHODS
We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles.


RESULTS
We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001).


CONCLUSIONS
Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection.
Sarwal
Minnie
M
Department of Pediatrics, Stanford University, Stanford, Calif, USA. msarwal@stanford.edu
Chua
Mei-Sze
MS
Kambham
Neeraja
N
Hsieh
Szu-Chuan
SC
Satterwhite
Thomas
T
Masek
Marilyn
M
Salvatierra
Oscar
O
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D018951:Antigens, CD20 / Q000032:analysis; D001402:B-Lymphocytes / Q000276:immunology; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004351:Drug Resistance / Q000276:immunology; D015870:Gene Expression; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D005938:Glucocorticoids / Q000627:therapeutic use; D006084:Graft Rejection / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007668:Kidney / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D013601:T-Lymphocytes; D014184:Transplantation, Homologous
D018951:Antigens, CD20; D005938:Glucocorticoids