Rejection and regulation: a tight balance

Achieving allograft tolerance is the holy grail of transplantation. However, tolerance and rejection are two extreme ends of a scale that can be tipped in either direction. We review the novel effector and regulatory mechanisms involved and factors that tip the balance in favor of rejection or regulation.

It is increasingly recognized that established T-cell phenotypes could change their commitments. New data point to the plasticity of Th17 cells in vivo with a reciprocal balance of Th17 cells and regulatory T cells (Tregs) driven by the local cytokine environment. Treg-cell profiles have been linked to acute and chronic allograft outcomes, and emerging data also indicate a novel role of a regulatory B-cell population. Current research efforts are looking into factors that tip the balance toward allograft tolerance by targeting cytokines, novel costimulatory pathways such as T-cell immunoglobulin mucin molecules, and components of innate immunity, particularly dendritic cells.

The balance of effector and regulatory mechanisms contributing to allograft outcome is very complex. It is likely that targeting multiple pathways will be required to achieve tolerance. Further studies are warranted to define this balance and identify optimal combination of therapeutic interventions.