title: An experimental model of acute humoral rejection of renal allografts associated with concomitant cellular rejection.
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 micromol/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.
authors.affiliation: Department of Pathology, The Ohio State University College of Medicine and Public Health, Columbus, OH 43210, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Bickerstaff
authors.forename: Ronald
authors.initials: R
authors.lastname: Pelletier
authors.forename: Jiao-Jing
authors.initials: JJ
authors.lastname: Wang
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Nadasdy
authors.forename: Nicholas
authors.initials: N
authors.lastname: DiPaola
authors.forename: Charles
authors.initials: C
authors.lastname: Orosz
authors.forename: Anjali
authors.initials: A
authors.lastname: Satoskar
authors.forename: Gregg
authors.initials: G
authors.lastname: Hadley
authors.forename: Tibor
authors.initials: T
authors.lastname: Nadasdy
mesh_terms: D000818:Animals; D015933:Complement C3d / Q000276:immunology; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007518:Isoantibodies / Q000097:blood* / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016038:Skin Transplantation / Q000473:pathology*
chemical_list: D007518:Isoantibodies; D015933:Complement C3d; D003404:Creatinine