Early loss of renal transcripts in kidney allografts: relationship to the development of histologic lesions and alloimmune effector mechanisms.
We sought to understand the epithelial response to the T-cell mediated inflammatory process in kidney allograft rejection. Using microarrays, we studied transcriptome changes of kidney parenchymal cells and their relationship to the development of pathologic lesions such as tubulitis in mouse kidney allografts and isografts. Inflammatory infiltrate in allografts developed by day 5, but tubulitis first appeared at day 7 and was severe by day 21. Using microarrays, we selected 70 solute carrier transcripts with high renal parenchymal expression and known epithelial function. Transcript expression was reduced early in isografts and allografts, followed by progressive loss in allografts and recovery in isografts. The expression pattern of day 21 allografts developed progressively from the time of engraftment and was established before histologic lesions. These changes are probably functionally significant: selected proteins showed decreased immunostaining at days 7 and 21. Allospecific loss of transcripts was dependent on T cells but independent of perforin, granzymes A/B, CD103, or B cells. Weighted sum decomposition revealed multiple components of the epithelial response with allospecific changes from day 1. We conclude that loss of renal transcripts indicates an early stage of T-cell mediated alloimmune injury that later progresses to pathologic lesions such as tubulitis.
Einecke
G
G
Division of Nephrology and Transplantation Immunology, University of Alberta, Edmonton, Canada. gunilla.einecke@ualberta.ca
Broderick
G
G
Sis
B
B
Halloran
P F
PF
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology*; D006084:Graft Rejection / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000502:physiology; D039001:Integrin alpha Chains / Q000235:genetics / Q000502:physiology; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology* / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D015703:Antigens, CD; D002352:Carrier Proteins; D039001:Integrin alpha Chains; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C091367:alpha E integrins; D054353:Perforin; D053804:Granzymes