Published online before print June 26, 2008

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2008.070391v1 173/2/347    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bickerstaff, A. Articles by Nadasdy, T. PubMed PubMed Citation Articles by Bickerstaff, A. Articles by Nadasdy, T.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070391

Accepted for publication May 13, 2008.

Article

An Experimental Model of Acute Humoral Rejection of Renal Allografts Associated with Concomitant Cellular Rejection

Alice Bickerstaff^*, Ronald Pelletier^*, Jiao-Jing Wang^*, Gyongyi Nadasdy, Nicholas DiPaola^*, Charles Orosz^*, Anjali Satoskar, Gregg Hadley^*, and Tibor Nadasdy^@

From the Departments of Surgery,* Pathology, and Molecular Virology, Immunology, and Medical Genetics, The Ohio State University College of Medicine and Public Health, Columbus, Ohio

^@ To whom correspondence should be addressed. E-mail: tibor.nadasdy{at}osumc.edu.

	Abstract

Acute humoral rejection (AHR), which occurs in up to 8% of kidney transplant recipients, is a significant cause of renal allograft dysfunction and loss. More efficacious treatment modalities are needed to eliminate or curtail alloantibody production and its deleterious effects on the kidney. The availability of animal models mimicking human AHR is essential to understand its pathophysiology and develop new treatment strategies. Using a mouse kidney transplant model, we demonstrate that presensitization of recipients with donor skin grafts results in rejection of subsequent renal allografts. All presensitized mice developed renal failure 8.6 ± 4.3 days after engraftment, with serum creatinine values near 100 µmol/dl. Graft histology revealed mild, diffuse, interstitial, mononuclear cell infiltrates; prominent peritubular capillary inflammatory cell margination; patchy interstitial hemorrhage; interstitial edema; and focal glomerular fibrin deposition. Complement (C3d) deposition was diffuse and prominent in peritubular capillaries. Serum analysis demonstrated high levels of circulating alloantibodies with broad cross-reactivity to many MHC haplotypes. The clinical setting and histological findings of our model strongly resemble AHR, which is frequently associated with cellular rejection, a situation commonly encountered in human renal allograft recipients. This animal model provides a valuable tool to study the pathogenesis of AHR, its relationship to cellular alloimmunity, its contribution to graft injury, and the effects of various potential therapeutic interventions.