Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies

Abstract

Introduction Angiotensin II type 1 receptor antibody (AT1R-Ab), is a non–human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients. Methods Blood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated. Results AT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant. Conclusions This profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab–mediated allograft injury in kidney transplantation.

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

“…We have previously shown AT1R-Ab to be associated with elevations in IL-8, TNF-a, IL-1b, IFN-g, IL-17, and IL-6 in patient blood samples. 33,37 The findings in this analysis are consistent with our previous data, but provide additional insight into the potential role of ETAR-Ab in enhancing these relationships. For all cytokines, the addition of ETAR-Ab increased the magnitude of the association between AT1R-Ab and elevations in each cytokine.…”

“…[46][47][48][49][50][51] Differences between the antibody groups evaluated by Kruskal-Wallis test were noted for IL-8 in the patient-level analysis (P ¼ 0.010, n ¼ 64; Table 2 and Supplementary Table S3), but not for TNF-a, IFN-g, IL-1b, IL-6, and IL-17 ( Supplementary Table S3). In the sample-level analysis, consistent with our previous data, 37 all blood samples with AT1R-Ab (AT1R-Ab alone and both AT1R-Ab and ETAR-Ab) had higher levels of all cytokines tested (n ¼ 260; Supplementary Table S4). Comparisons between the 3 groups of samples by antibody status were significant for all cytokines except IL-17.…”

“…Studies to assess the role of receptor expression, epitope specificity, antibody kinetics, and antibody subclass in differentiating among phenotypes of transplant patients with ETAR-Ab and AT1R-Ab may be informative. It is noteworthy that our previous work showed elevations in cytokines associated with AT1R-Ab, 33,37 and this analysis has added that IL-8, in particular, may increase above the level of AT1R-Ab alone in patients who also develop ETAR-Ab. Based on this and the timing of antibody development, we hypothesize that the development of ETAR-Ab may be a form of progression that occurs in some kidney transplant patients with AT1R-Ab.…”

“…33 Importantly, AT1R-Ab has been associated with vascular inflammation, decline in estimated glomerular filtration rate (eGFR), and allograft loss 33,34 in this vulnerable population. AT1R-Ab has also been associated with elevations in tumor necrosis factor-a (TNF-a), interferon-g (IFN-g), interleukin (IL)-8, IL-1b, IL-6, and IL-17 in pediatric kidney transplant recipients, 33,37 further supporting an association between vascular inflammation and autoantibody formation.…”

Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation

“…Transplanted grafts may be injured in a similar manner. Elevated inflammatory cytokines have been reported in pediatric renal recipients who were positive for AT1R-AA but not DSA (24). AT1R activation could promote proliferation of smooth muscle cells and collagen synthesis in fibroblasts (20).…”