Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses

Abstract

Immune regulatory pathways involving the newly discovered T regulatory (Treg) and Th17 cells are amongst the principal targets of immunosuppressive agents employed in transplant recipients and key mediators of host inflammatory responses in fungal infections. These novel signaling pathways, in concert with or independent of Th1/Th2 responses, have potentially important implications for yielding valuable insights into the pathogenesis of immune reconstitution syndrome (IRS) in transplant recipients, for aiding the diagnosis of this entity, and for achieving a balance of immune responses that enhance host immunity while curbing unfettered inflammation in IRS.

Figure 1

Schematic diagram depicting T-cell differentiation. Depending upon the cytokine milieu i.e., IL-12, TGF-β plus IL-6, TGF-β or IL-4, the naive or precursor T helper cells (Th0) develop into Th1, Th17, Treg or Th2 cells, respectively via expression of their specific transcription factors T-Bet, retinoid orphan receptor (RoR)γT, foxhead box protein (FoxP3), and GATA binding protein (GATA-3), respectively. IFN-γ and IL-17, the signature cytokines of Th1 and Th17 cells mediate proinflammatory responses whereas TGF-β, IL-10 and IL-4 production by Tregs and Th2 cells mediate anti inflammatory responses.

Figure 2

Proposed model of immune responses leading to immune reconstitution syndrome in transplant recipients with invasive fungal infections.