Immune regulation following pediatric cardiac surgery - What goes up must come down

Abstract

The immune system is a dynamic system that is designed to respond rapidly to potential harmful stimuli. Following activation tight control mechanisms are in place to avoid collateral damage. Cardiac surgery is well known to induce an acute systemic inflammatory response and therefore, elective cardiac surgery creates an opportunity to study the inflammatory response in human in detail, from its initiation through the peak of inflammation up to recovery. So to restore the dynamic immunological equilibrium; ‘What goes up must come down’. In this thesis we illustrate how the immune system of children responds to two different aspects of pediatric cardiac surgery, both known to disturb the immunological equilibrium. In the first part of this thesis the immediate inflammatory response due to surgery is investigated with an emphasis on endogenous feedback mechanisms. In the second part of this thesis we investigate how the developing immune system copes with total thymectomy due to neonatal cardiac surgery. We describe two intrinsic regulatory mechanisms detectable immediately after the onset of the systemic inflammatory response due to pediatric cardiac surgery. First, monocytes exhibit a reduced responsiveness to toll like receptor stimulation. This reduced responsiveness is due to active regulation maintained predominantly through the IL-10/STAT3 pathway. Secondly, the regulatory transcription factor FOXP3 is upregulated in T cells. These FOXP3+ T cells remain unresponsive to TCR stimulation, like true FOXP3+ regulatory T cells (Treg), though show a reduced capacity to inhibit effector T cells. A reduced regulatory capacity of healthy Treg can be induced through exposure to plasma taken from patients after cardiac surgery. This implies a plasma mediated regulation of Treg during the peak of a systemic inflammatory response after pediatric cardiac surgery. Neonatal cardiac surgery often necessitates removal of the complete thymus to gain access to the surgical site. We studied the short and long term effects of neonatal thymectomy. In the first years after neonatal thymectomy, the immune system is unable to maintain naive T cell numbers. From approximately 5 years onwards we found evidence of renewed thymic activity. Although naive T cells subsequently return to normal healthy numbers, the effect of neonatal thymectomy on functionality of the T cell compartment requires further studies. The FOXP3+ Treg population is crucial for immune homeostasis in most inflammatory conditions. Peripheral proliferation of Treg cells counteracts the effect of loss of thymopoiesis, which illustrates the relative plasticity of the human immune system. However, changes in composition of the Treg population do warrant further investigation in the long-term functional effects of neonatal thymectomy following cardiac surgery.