A clinical research consortium sponsored by NIAID and JDRF
Knechtle SJ, Sollinger HW, Jankowska-Gan E, Burlingham WJ, Bloom DJ
Department of Surgery, Division of Transplantation, University of Wisconsin, Madison, WI
Rationale: In order to assess the ability of immune cell depletion by alemtuzumab in combination with a limited course of tacrolimus and rapamycin therapy following renal transplantation to promote immunologic tolerance, a pilot study sponsored by the Immune Tolerance Network is being conducted in 10 patients at this center. All donor-recipient combinations have at least 3 out of 6 HLA matches. One 0-mismatched deceased donor recipient has been entered. HLA-identical living-related donor-recipient combinations were excluded.
Methods: Patients received 3 doses of alemtuzumab (Campath-1H, 30 mg IV) on days 0, 1, and 2 and were started on tacrolimus and sirolimus on day 1 post-transplant. Tacrolimus was discontinued after 60 days and sirolimus continued until at least 1 year. Patients were monitored by 1 year protocol biopsy, cytokine kinetics assay (CK), CFSE MLR, trans-vivo DTH assay, and flow cytometry of immune cells in addition to clinical parameters.
Results: To date all 10 patients have been transplanted and have excellent graft function, and 2 patients have reached 1-year follow-up. Seven patients are being treated with sirolimus monotherapy and 3 patients have not yet reached the 2-month follow-up. There have been no rejection episodes. Tacrolimus in the first month has ranged between 5-10 ng/ml and sirolimus levels between 6-12 ng/ml. Protocol biopsies at 1 year in the first two patients have shown no evidence of rejection and Luminex testing for alloantibody have shown no evidence of alloantibody. The first patient is specifically non-responsive to donor antigen according to the CK assay, and DTH at 6 and 12 months show that this patient has a regulated and suppressed response to donor antigen. This patient is being gradually weaned from sirolimus to evaluate for clinical evidence of tolerance.
Conclusions: In contrast to an earlier pilot study with Campath-1H, this protocol to date has been free from acute rejection or antibody development. The CK and DTH assays suggest in vitro evidence of donor-specific unresponsiveness and immune regulation. These preliminary results are encouraging in that all rejection has been avoided using a steroid-free regimen relying on sirolimus and short-term calcineurin-inhibitor use.
