Thoracic transplantation
Monocyte chemoattractant protein-1 levels in bronchoalveolar lavage fluid of lung-transplanted patients treated with tacrolimus as rescue treatment for refractory acute rejection

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Abstract

Background

Cytokines are important mediators of the complex process of extravasation and influx of peripheral mononuclear cells into a site of graft injury, an action that may be affected by the immunosuppressive regimen. The aim of this study was to compare the effect of different immunosuppressive regimens on cytokine expression in the grafted lung.

Methods

We analyzed the cytokine profiles in broncho-alveolar lavage fluid (BAL-F) from 18 lung transplanted patients undergoing a shift from a cyclosporine- to a tacrolimus-based triple therapy regimen due to refractory acute rejection.

Results

Three months after the conversion to tacrolimus, BAL-F levels of interleukin 8 (IL8), IL18, IL12 and IL10 were not significantly different than those measured before conversion. In contrast, monocyte chemoattractant protein-1 (MCP-1) levels showed a significant and sustained decrease in BAL-F during tacrolimus therapy. In addition the levels of gamma interferon (IFN-γ) in the BAL-F were decreased albeit not significantly.

Conclusion

These findings suggest that the clinical and functional stabilization of patients observed after conversion to a tacrolimus based regimen, may be due, at least in part, to the induced down-regulation of MCP-1 production.

Section snippets

Patients

Tacrolimus has been used at our institution for rescue treatment of nonresponsive acute lung rejection since May 1994. All patients who were alive 1 month after transplant were considered candidates for conversion to tacrolimus if they had persistent biopsy-proven AR despite treatment with a methylprednisolone bolus.

Overall, 29 lung recipients were converted from a CsA- to a tacrolimus-based immunosuppressive regimen because of refractory biopsy-proven AR. The 18 patients selected for this

Results

On the basis of a previously reported preliminary study showing encouraging clinical, immunologic, and functional results, 29 patients were converted from CsA to tacrolimus because of RAR. Eighteen of these patients were selected for the present cytokine study on the basis of the length of the follow-up and the availability of serial pre- and postconversion BAL-F samples. All patients had been on the CsA regimen for a median of 6.8 (3.7 to 8.2; 25th to 75th percentile) months after transplant.

Discussion

Future development of immunosuppressive therapy for organ transplantation must be aimed at tailoring therapy to the individual patient’s reactivity, while inducing graft acceptance by modulating the local inflammatory and immune reaction.10 However, the difficulties encountered in understanding and monitoring graft reactivity in humans hamper the understanding of these events, particularly in the field of lung transplantation. In fact, few data are presently available concerning the

References (22)

  • M. Reynaud-Gaubert et al.

    J Heart Lung Transplant

    (2002)
  • P. Vitulo et al.

    J Heart Lung Transplant

    (2002)
  • B.L. Colvin et al.

    Transplantation

    (2002)
  • Y. Sekine et al.

    Am J Respir Cell Mol Biol

    (2000)
  • A. Boehler et al.

    Am J Respir Crit Care Med

    (1999)
  • J.A. Belperio et al.

    J Clin Invest

    (2001)
  • S.A. Yousem et al.

    J Heart Lung Transplant

    (1996)
  • Am J Respir Crit Care Med

    (1995)
  • A.H. Tiroke et al.

    Clin Transplant

    (1999)
  • J. Massicot-Fisher et al.

    Transplantation

    (2001)
  • J. Scholma et al.

    Am J Respir Crit Care Med

    (2000)
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    Supported by Grant 070rfm/00/01, Ministero della Sanità.

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