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J Thorac Cardiovasc Surg 1999;117:714-718
© 1999 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

SIROLIMUS (RAPAMYCIN) POTENTIATES CYCLOSPORINE IN PREVENTION OF ACUTE LUNG REJECTION

From the Division of Cardiothoracic Surgery, University of Southern California and Childrens Hospital Los Angeles, Los Angeles, Calif.

Supported by a grant to Dr Barr from the Heart and Lung Surgery Foundation, Los Angeles, Calif.

Received for publication Aug 7, 1998. Revisions requested Oct 30, 1998. Revisions received Nov 10, 1998. Accepted for publication Nov 11, 1998. Address for reprints: Mark L. Barr, MD, Division of Cardiothoracic Surgery, University of Southern California, 1510 San Pablo St, Los Angeles, CA 90033.

Background: Cyclosporine-based immunosuppressive regimens (INN: ciclosporin) in human lung transplantation continue to result in a high incidence of acute cellular rejection. We investigated the use of sirolimus, a macrolide with structural similarity to tacrolimus, as monotherapy and in combination with cyclosporine in a rodent lung transplant model.
Methods: Orthotopic left lung transplantation was performed in Lewis recipients from Brown-Norway donor rats with syngeneic Lewis-to-Lewis controls. Open biopsies were performed on postoperative day 7, and the severity of acute lung rejection was graded by a pathologist blinded to the protocol.
Results: All recipients survived despite the amount of acute rejection seen on examination of the biopsy tissue. Lewis-to-Lewis isografts demonstrated near normal pulmonary architecture. Allogeneic recipients receiving high-dose cyclosporine (25 mg/kg) monotherapy showed mild to moderate acute rejection with some perivascular focal interstitial infiltrates. Recipients receiving low-dose cyclosporine (5 mg/kg) monotherapy or low- or high-dose sirolimus (0.5 or 2.0 mg/kg, respectively) monotherapy demonstrated massive cellular infiltration leading to necrosis and infarction and could not be graded. However, the addition of low-dose sirolimus (0.5 mg/kg) to low-dose cyclosporine (5 mg/kg) demonstrated a significant potentiating immunosuppressive effect, and the addition of high-dose sirolimus (2.0 mg/kg) to low-dose cyclosporine (5.0 mg/kg) demonstrated an even greater effect, with rejection scores better than those obtained with high-dose cyclosporine monotherapy and similar to those obtained with isografts.
Conclusions: This study demonstrates that low-dose sirolimus has a cyclosporine-sparing effect and that a higher dose of sirolimus in combination with cyclosporine strongly protects lung allografts from acute cellular rejection. These results suggest that sirolimus may be indicated as an adjunct to current cyclosporine-based immunosuppressive regimens in clinical lung transplantation.