Antibodies to Angiotensin II Type 1 Receptor and Endothelin Type A Receptor are associated with Cytokine Production Enriched for Type 2 Immune Response and Antibody Production in Pediatric Kidney Transplant Recipients

Activating antibodies to angiotensin II type 1 receptor (AT1R) and endothelin type A receptor (ETAR) have been associated with rejection, allograft loss, decline in allograft function, and development of human leukocyte antigen donor-specific antibodies in kidney transplantation. Understanding immune dysregulation and inflammatory signatures associated with these antibodies is important for generating targeted investigations of pathogenesis. We investigated a panel of 38 cytokines in a multicenter cohort of 133 pediatric kidney transplant recipients with 1 to 2 years of follow up to further elucidate AT1R and ETAR-Ab-associated inflammatory signatures. Pretransplant and posttransplant blood samples (n = 483) were tested for AT1R-Ab, ETAR-Ab, and 38 cytokines. The relationship between AT1R and/or ETAR-Ab positivity and cytokine elevations were evaluated accounting for demographic and clinical factors. AT1R and/or ETAR-Ab positivity was associated with elevations in 33 of the 38 cytokines, with some elevations resolving or intensifying on posttransplant vs pretransplant samples. Interrogation of these data using z-score comparisons and principal component analyses revealed a strong signal for interleukin (IL)-9, IL-13, IL-5, IL-4, IL-6, lymphotoxin α, and granulocyte-macrophage colony-stimulating factor-cytokines involved with antibody formation and type 2 immune responses. The relationship of this signal to transplant outcomes and impact of adjunctive receptor blockade requires additional investigation.