Whilst conventional general immunosuppressive agents are superbly effective in preventing rejection responses, they can also suppress the development of regulatory responses. Historically, various therapeutic regimens have been devised which purportedly favour regulatory processes, although none has been satisfactorily shown to be “pro-tolerogenic”. In this regard, current opinion advocates the use of lymphocyte-depleting induction therapies, avoidance of CNIs and prolonged steroid treatment, the use of mTOR inhibitors and a relatively gradual weaning of maintenance therapy (1,2). This approach runs contrary, in almost every respect, to the previous fashion of initiating treatment with minimal immunosuppression and then weaning maintenance therapy rapidly; indeed, it has even been suggested that early immunological activation is essential to induce later immunoregulatory processes (3,4). Evidence in favour of either general approach is not overwhelming and needs to be urgently readdressed because, with the advent of novel agents intended to promote tolerance to allografts, including cell-based therapies, an optimised tolerance-promoting immunosuppressive protocol must be defined. In this project, comparisons will be drawn between liver transplant recipients treated according to a standard protocol and patients treated with a bottom-up regimen based on the delayed introduction of either CsA or Everolimus. Patient outcomes will be assessed clinically and in terms of their immunological profile, defined by marker analyses and functional assays. Emphasis will be placed on serial examination of patients in the early time-period after transplantation on the hypothesis that bottom-up, as opposed to top-down, immunosuppression promotes the early expansion of regulatory cell types. One future perspective of this project, beyond the immediate funding period, is the establishment of a clinical protocol for liver transplant patients that could be used as a suitable platform for testing novel, cell-based immunosuppressive therapies.
