A Prospective, Randomized Study to Compare the Effect of Campath-1,Low Dose Sirolimus Versus Campath-1H, Low Dose CsA Both in Addition to Low Dose Mycophenolate Mofetil on Phenotypic and Functional Profiles of PBMCs in Kidney Transplant Recipients in a Steroid-Free Regimen

The last 40 years have been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term results. These findings were achieved mainly using the conventional triple-drug regimen with cyclosporine (CsA), azathioprine (or mycophenolate mofetil, MMF), and steroids. During the past 15 years, however, the superior immunosuppressive efficacy of CsA and the well-known toxicity of long-term steroid therapy have prompted trials of steroid withdrawal from renal allograft recipients at various intervals after transplantation, Few transplant centers have also adopted a steroid-free immunosuppressive regimen. Reported benefit of eliminating steroids from immunosuppressive regimens of CsA-treated renal transplant recipients have included improvement of hypertension, hyperlipidemia, glucose intolerance and, in children, acceleration of growth. Avoiding these steroid-related side effects would contribute to improve long-term outcome of the grafts. These and other benefits of steroid withdrawal or avoidance must be balanced against the associated risk of precipitating acute allograft rejection. Moreover, with the current immunosuppressive regimens, by 10 years approximately 50% of grafts will have been lost due mainly to chronic rejection or the side-effects of immunosuppressive therapy. Thus, the quest for therapies that might induce specific immune tolerance - ideally via short-term interventions that would target only the pathogenic immune response and leave the protective host immune response unimpaired - has provided a "holy grail" for transplant immunologists. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. Indeed, true tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function.

The humanized IgG monoclonal antibody Campath-1H with a unique target CD52 on T, B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for more than a month in kidney transplant recipients. Given its potent but safe effect of depleting T and B cells, Campath-1H has been hypothesized to provide enough immunosuppression that would allow maintenance therapy with low-dose CsA, and possibly reprogramming the immune system so to encourage tolerance processes. This has been formally tested in 31 patients undergoing first cadaver renal allograft. The results with a mean two year follow-up have been encouraging, 29 patients having good graft function without receiving maintenance steroids. Similar results have been achieved recently combining Campath-1H and full dose sirolimus in renal transplant recipients. Twenty-three out of 24 patients had good graft function 1 year post transplant. However, most patients were on a lipid-lowering agent to counteract the hyperlipidemic effect of sirolimus. It should be also considered that in both clinical trials acute rejection episodes early post transplant occurred in 20-25% of the patients. Thus, to reduce the risk of hyperlipidemia associated with the current full-dose of sirolimus, while minimizing the risk of rejection, a combination regimen of low dose sirolimus and low dose MMF is worth investigating.

Despite Campath-1H immunosuppressive regimens have been claimed to induce a condition of "almost tolerance", this has not been proved nor evidence of development of persistent regulatory immune responses long-term post transplant has been provided. Thus, characterizing phenotypically and functionally distinct subsets of T-regulatory cells possibly generated selectively in non-rejecting transplant recipients in Campath-1H-based immunosuppressive regimens may help to find new noninvasive markers of immune system activation to tailor immunosuppressive protocols.

Aims of the study

This prospective study in adult kidney transplant recipients is designed with the following aims: