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 mol/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.

Key Role for CD4 T Cells During Mixed Antibody-Mediated Rejection of Renal Allografts

“…We have previously described a mouse model of mixed AMR in which B6 hosts are primed to DBA/2 alloantigens with a DBA/2 skin allograft 14 to 21 days prior to receiving a DBA/2 renal allograft (11). As shown in Figure S1, identical results were obtained with recipients primed to donor alloantigens at times ranging from 11–91 days prior to kidney transplantation, indicating that the time of renal transplantation relative to the priming stage was not critical.…”

Sequential analysis of donor-specific antibodies and pathological findings in acute antibody-mediated rejection in a rat renal transplantation model

“…These results indicated that DSA-producing cells should be presensitized in AAMR. Bickerstaff et al 21 reported that depletion of pre-sensitized CD8 ± T cells had no effect on AAMR model of mouse renal transplantation. However, further studies are required to evaluate which type of presensitized cell is indispensable to AAMR.…”

“…and many of the inflammatory cells are in the PTCs but those cells are not infiltrating tubules at the time of AAMR in mouse renal transplantation model 21. …”

Allogeneic Stimulation Causes Transcriptional Reactivation of Latent Murine Cytomegalovirus

“…What is not directly addressed by the current study is the question of whether CMV reactivation contributes to rejection. In our model, allograft survival (~10–11 days, not shown) was not shorter than historical controls (15), but it is important to note that this model is biased toward rapid rejection, so CMV reactivation may have inadequate time to contribute to this process, particularly because reactivation appears to occur after the rejection episode. Interestingly, using a model of induced cardiac allograft tolerance (without ongoing immunosuppression), we have recently shown that cardiac allograft acceptance is disrupted when recipients are latently infected with CMV, and this disruption is associated with MCMV reactivation (16).…”