MMF-Driven Disruption of B-cell Populations as a Biomarker for Infection Risk in Solid Organ Transplant Recipients

Abstract

Solid-organ transplant recipients receive long-term immunosuppression to prevent graft rejection, thereby leading to increased risk of infection. We sought to identify biomarkers of infection risk in pediatric solid-organ transplant recipients to better predict risk of infection in this population. 75 kidney and 20 liver pediatric transplant patients were analyzed in a single-center registry study. Immunologic labs, including lymphocyte subsets, immunoglobulins, and vaccine titers, were collected at 6-month intervals as a part of standard-of-care. Number of infections and immunosuppressive regimens were recorded in corresponding intervals. The association between immune parameters and number of infections was determined via linear mixed-effects regression model. Association between medications and immune parameters was analyzed via 2-sample t-test.A higher ratio of naïve:memory B-cells was associated with increased risk of infection (β = 0.03, p < 0.001) with independent contributions from both the naïve B-cell percentage (β = 0.03, p = 0.02) and decreased memory B-cell percentage (β = –0.02, p = 0.005), the latter driven by class-switched memory B-cells (β = –0.03, p = 0.006). The β value indicates the increase in the absolute number of infections per 6-month time period for every unit increase in the immune variable by 1. No significant associations were found between number of infections and immunoglobulin levels or vaccine titers.Mycophenolate mofetil (MMF) was associated with increased naïve: memory B-cell ratio (Δ = 3.1, p = 0.008) driven by decreased memory B-cell percent (Δ = 10.3%, p < 0.0001), predominantly from the class-switched memory B cell component (Δ = 6.81%, p < 0.0001). In contrast, azathioprine was associated with decreased naïve:memory B-cell ratio (Δ = -5.1%, p < 0.0001) driven by increased memory B-cell percent (Δ = 15.0%, p <0.0001) from increased class-switched memory B-cells (Δ = 10.6% p < 0.0001). MMF was associated with 0.63 more total infections/year (Δ = 2.2, p = 0.03). Azathioprine and tacrolimus had no association with total infections/year.An increase in the naïve:memory B-cell ratio may indicate increased infection risk, with MMF as the culprit. The ratio of naïve:memory B-cells has potential as a biomarker to predict infection risk in solid-organ transplant recipients. [Display omitted] [Display omitted] [Display omitted]