The Pharmaceutical Journal
Vol 268 No 7201 p815-816
8 June 2002

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American Transplant Congress 2002

New strategies in immunosuppression

To judge from the data presented at the American Transplant Congress, the textbooks are about to be rewritten on the subject of immunosuppression for transplantation. In the past, nearly all renal transplant centres have used a standard immunosuppression regimen of ciclosporin, azathioprine and prednisolone for every transplant recipient, resulting in over-immunosuppression in some patients, and under-immunosuppression in others. However, the advent of the newer anti-rejection agents has enabled centres to investigate novel combinations of drugs in an attempt to tailor the immunosuppression regimen to the individual patient, thus maximising the clinical efficacy of the drugs used, but at the same time minimising the adverse effects.

Creeping creatinine

With newer immunosuppression agents, acute graft rejection is much easier both to prevent and treat. Most renal transplant centres now quote one-year graft survival rates of 85 to 90 per cent. However, the most common cause of late graft loss after renal transplantation is chronic allograft dysfunction (CAD) and, at a time when the gap between organ donations and the number of patients waiting for transplants in the UK is growing, the prevention of chronic graft loss continues to present a major challenge to transplant clinicians. CAD is characterised by a progressively increasing serum creatinine over time (creeping creatinine) with concomitant histological changes. One of the factors contributing to this process is the thought to be the toxicity associated with long-term use of calcineurin inhibitors, and hence many strategies now being investigated involve minimising the dose of, or complete withdrawal of these drugs from immunosuppressive regimens.

The results of one such study was presented by Dr Chris Dudley on behalf of the MMF Creeping Creatinine Study Group. The study involved 143 patients who were at least six months post-transplant, with progressively rising serum creatinines in the range 100–400mmol/L, who were randomised such that 70 remained on a ciclosporin-based regimen, while 73 were commenced on mycophenolate mofetil (Cellcept) and their ciclosporin withdrawn. Follow-up at six months revealed that renal function had stabilised or improved in 58 per cent of the patients in the mycophenolate group compared with only 28 per cent of patients in the ciclosporin group. In addition, it was noted that diastolic blood pressure decreased by an average of 10mmHg and serum cholesterol was also reduced in the mycophenolate group.

Dr Henri Kreis, on behalf of the Rapamune Maintenance Regimen Study Group, presented the two-year data of a European multicentre study also looking at the withdrawal of calcineurin inhibitors. A total of 525 patients were given ciclosporin, sirolimus (Rapamune) and prednisolone at the time of transplantation. At three months, they were randomised either to remain on triple therapy, or to have the ciclosporin withdrawn, and the sirolimus dose increased accordingly. At two years, there was no statistically significant difference between the two groups in terms of graft and patient survival, and the incidence of post-randomisation acute rejection. However, both the systolic blood pressure (134 vs 141mmHg), and serum creatinine (134 vs 165mmol/L) were significantly lower in the group which had ciclosporin withdrawn. There was no difference in serum LDL-cholesterol or triglycerides between the two groups, although HDL-cholesterol was significantly higher in the sirolimus group. Hence it has been shown by these and many other studies that calcineurin inhibitors can be withdrawn with preservation of renal function, either in the early post-transplant phase, or later on in cases of chronic allograft nephropathy without risk of acute rejection.

One major problem associated with maintenence immunosuppression is the development of post-transplant diabetes mellitus. Data from the United States indicate an incidence of 8.3 per cent at three months post transplantation, and 22.3 per cent at three years. One strategy to try to minimise this risk is to wean patients off steroids. This has been tried previously, but was found to be associated with a significantly increased risk of acute rejection. However, several new immunosuppression regimens have been investigated, including low-dose tacrolimus plus sirolimus, low-dose tacrolimus with mycophenolate, or low-dose ciclosporin plus mycophenolate, all with either daclizumab (Zenapax) or basiliximab (Simulect) induction therapy, and the results indicate that steroids may be safely withdrawn, either at seven days, or at three months post transplantation, without significant risk of acute rejection.

As well as looking at using drugs currently in clinical use in novel ways, there was also a wealth of information on new drugs under development. Dr Mark Abel, of Edmonton, Canada, discussed ISA 247, a novel calcineurin inhibitor from Isotechnika, which does not appear to exhibit the nephrotoxicity associated with ciclosporin and tacrolimus (Prograf). In Phase I trials, it has been shown to have two to three times the ability of ciclosporin to inhibit calcineurin activity. Phase II trials are currently underway in the US and Canada for renal transplantation, rheumatoid arthritis and psoriasis. One such trial involves patients at least six months post-renal transplant, on a ciclosporin-based immunosuppression regimen. Half the patients are randomised to remain on ciclosporin, the other half switch to ISA 247. To date, there are no documented rejection episodes in the ISA 247 group, and no serious adverse events, specifically, no significant changes in serum creatinine.

Perhaps of greater interest is FTY 720, an endothelial differentiator gene receptor agonist being developed by Novartis. Dr Barry Kahan, University of Texas, Houston, described how this novel immunosuppressive agent enhances the lymphocyte migratory response to homing cytokines, and hence reduces the number of T- and B-cells in peripheral blood. It also inhibits T-cell infiltration into inflamed tissues and transplanted organs. Interestingly, there appears to be no effect on memory cells, and so should not impair acquired immunity to infection. It is currently undergoing trials in combination with ciclosporin and prednisolone for de novo renal transplants, and with everolimus (Certican, a new cousin of sirolimus) and steroids in cases of delayed graft function, with promising results. It has been noted that there is a substantial reduction in both serum cholesterol and triglycerides when FTY 720 is added to ciclosporin and prednisolone, but these levels return to above baseline when the FTY 720 is discontinued. This suggests that the drug can alter lipid metabolism independently of any effects of ciclosporin.

Immunodepletion

One final treatment strategy that generated much interest is that of immunodepletion. Campath-1H (a humanised anti-CD52 monoclonal antibody) has been shown to allow renal transplantation with a significant reduction in maintenance immunosuppression. Dr Steven Hoffman, Bethesda, Maryland, described how its use markedly depletes T-cells and modestly depletes monocytes. It has been found that renal transplant recipients given Campath-1H as induction therapy typically experience a reversible acute rejection episode within the first month after transplantation, although these rejections differ both immunologically and histologically from the typical T-cell mediated episodes seen in patients on standard triple immunosuppression. However, Campath-1H induction followed by sirolimus monotherapy as maintenance immunosuppression is yielding promising results.

Taking this approach one stage further, early data have suggested that the Campath-1H rejection episodes are initiated by monocyte infiltration associated with a high intragraft TNFa titre. In one small study, 15 patients underwent perioperative Campath-1H therapy (0.3mg/kg x four doses) followed by the humanised anti-TNFamonoclonal antibody, Infliximab (3mg/kg x three doses), then maintenance immunosuppression of sirolimus initiated 18 to 108 days after the infliximab. After six to 22 months of follow-up, there have been no graft losses to rejection, and 14 out of the 15 patients remain alive, well and rejection-free.

As our understanding of the immune system increases, so we are able to use more sophisticated strategies to optimise graft function and prevent rejection. Our ultimate goal in transplantation has long been the ability to induce immunotolerance to grafts by pharmacological and immunological manipulation. The day when we can finally achieve this may not be so far away.