Aspirin and the induction of tolerance by dendritic cells

Abstract

Tolerance is maintained by central and peripheral regulatory mechanisms and is essential to prevent autoimmunity. In the setting of solid organ or haematopoietic transplantation, the indirect pathway of allorecognition is a significant driver of chronic rejection. Chronic rejection proceeds despite effective immunosuppressive therapy, therefore achieving immunological tolerance to control the indirect pathway is a desirable goal. Tolerance induction may be achieved by vaccination with modified antigen presenting cells (APCs). Mature dendritic cells (DCs) are potent APCs, but immature DCs have been shown to have a reduced allo-stimulatory capacity and can be tolerogenic. Drug treatment has been shown to decrease the allo-stimulatory capacity of DC compared to immature DC. Dexamethasone and vitamin D3 have been established as having potent effects on dendritic cell immunogenicity.The effects of aspirin, a non-steroidal anti-inflammatory, on DCs have not previously been so extensively studied and here we will review the work which has been carried out using aspirin to induce tolerogenic DCs.We have examined the mechanisms of tolerance induction using human DCs and T cells. It has been possible to demonstrate that in aspirin treated, human DCs there is inhibition of the nuclear factor K-B (NFKB) signalling pathway, modified cytokine production, reduced expression of co-stimulatory molecules (CD40, CD80, and CD86) and increased expression of immunoglobulin-like transcript-3 (ILT3). The decreased expression of co-stimulatory molecules is maintained following cytokine or lipopolysaccharide (LPS) challenge. Drug treatment of DCs increases the expression of immunoglobulin-like transcript 3 (ILT3) when compared with immature DCs (iDCs), and these high levels of expression are maintained when the cells are challenged with a maturational stimulus. Aspirin also reduces the allo-stimulatory capacity of human DCs, and induces hypo-responsiveness and regulatory activity in responder T cells. These regulatory T-cells were CD4(+) CD25(+) FOXP3(+) and by studying CD25(-) or CD45RA populations, it was possible to determine that these regulatory T cells were generated de novo rather than requiring the expansion of naturally occurring Tregs. Aspirin continues therefore to be of interest with regard its wider effects on immune regulation, other than that mediated by direct inhibition of cyclo-oxygenase, in particular its ability to induce tolerogenic DCs at therapeutic concentrations in humans.