A new and clinically relevant murine model of solid - organ transplant aspergillosis

Since the pioneering experiments of Peter Medawar in the 1950s, immunosuppressive drugs have been used to inhibit the immune rejection of organ transplants in man (Medawar, 1958). Although early approaches were based upon cortisone and azathioprine, the discovery of the calcineurin inhibitor cyclosporin A in the 1970s was a major breakthrough that enabled transplantation to become an established therapy (Green and Allison, 1978). In the subsequent four decades, organ transplantation has emerged as an effective treatment for end-stage organ failure, as well as for diseases such as type 1 diabetes mellitus (Watson and Dark, 2012). In the USA there were more than 28,000 organ transplants in 2008 (http://www.srtr.org/) with this number increasing every year. The macrolide calcineurin inhibitor tacrolimus (FK506) was licensed for use in transplantation by the FDA in 1994, and it has now replaced cyclosporin A as the first-line calcineurin inhibitor in solid organ transplantation because of improved outcomes (Moore and Lord, 1994; Watson and Dark, 2012). FK506 binds to FKBP12 in T cells and this complex mediates calcineurin inhibition, and also blocks T cell signal transduction via NFAT and interleukin-2 (IL2) transcription (Tamura et al., 1994). Thus, the major mechanism of action of FK506 is to inhibit T-cell-dependent transplant rejection. However, recent studies have also demonstrated that calcineurin negatively regulates the Toll-like receptor signalling pathway (Kang et al., 2007) that is required for innate C-type lectin signalling (Greenblatt et al., 2010). These observations suggest a more widespread effect of calcineurin inhibitors on both innate as well as adaptive immune responses. Organ transplant recipients are at an increased risk of a number of different bacterial, viral and opportunistic fungal infections (Fishman, 2011). There is a clear association between calcineurin inhibitors and the opportunistic infections cytomegalovirus, hepatitis C, BK virus and invasive fungal pathogens (Kotton and Fishman, 2005; Fishman, 2007; Pappas et al., 2010). Comprehensive surveillance data from the US TRANSNET registry shows that solid organ transplant patients have an overall risk of 3.1% per annum for proven or probable IFIs, and that this risk continues for at least 3 years post-transplantation (Pappas et al., 2010). The overall mortality from IFIs in these patients is ~40%. The primary