Cellular alloresponses for rejection-risk assessment after pediatric transplantation

Abstract

Current immune monitoring practices detect antidonor antibodies and antibody-mediated rejection, and are less suited for the detection of acute cellular rejection (ACR), the predominant form of rejection after transplantation. We review the use of mixed lymphocyte coculture-based assays that measure cellular alloresponses, for measurement of the risk of ACR after liver, intestine, and kidney transplantation. Flow cytometry enables the rapid measurement of cellular alloresponses using dilution of the intravital dye carboxyfluorescein succinimidyl ester within 72 h or of intracellular CD154 in alloantigen-specific T-cells or B-cells within 16 h. Assay output is personalized by expressing donor-induced alloresponse as a fraction of the third-party alloresponse for each patient. The resulting parameter called the immunoreactivity index indicates increased risk of rejection if donor-response exceeds third-party response. The rejection-risk threshold immunoreactivity index predicts or associates with ACR of liver, kidney, or intestine allografts with sensitivity and specificity of 75% or more. Lifelong assessment is facilitated by using 'surrogate' donor stimulators from normal human individuals in lieu of actual donor cells, without compromising rejection-risk assessment. Cellular alloresponses can measure the risk of ACR accurately in the clinic, so that immunosuppression may be managed safely and more effectively in individual patients.