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J Thorac Cardiovasc Surg 2005;130:1167-1174
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Selective cyclooxygenase 2 inhibitor induces indefinite survival of fully allogeneic cardiac grafts and generates CD4⁺ regulatory cells

^a Department of Surgery of Nihon University School of Medicine, Tokyo, Japan
^b Teikyo University, Tokyo, Japan
^c Keio University School of Medicine, Tokyo, Japan

Received for publication January 17, 2005; revisions received May 15, 2005; accepted for publication June 20, 2005.

^_* Address for reprints: Nozomu Shirasugi, MD, Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan (Email: nozomujs{at}med.teikyo-u.ac.jp).

BACKGROUND: Selective inhibition of cyclooxygenase 2 has been reported to have not only anti-inflammatory effects but also effects on the immune response. We investigated ability of a cyclooxygenase 2 inhibitor to inhibit alloimmune response in a murine cardiac transplantation model.

METHODS: CBA (H2^k) mice underwent transplantation of C57BL/10 (H2^b) hearts. On the day of transplantation, the recipients received either no treatment or single administration of aspirin (a cyclooxygenase 1 and 2 inhibitor) or the selective cyclooxygenase 2 inhibitor NS-398. Naive CBA mice (secondary recipients) underwent adoptive transfer of splenocytes from treated mice with long-surviving grafts (primary recipients) to determine whether regulatory cells developed after NS-398 treatment. Histologic, cell-proliferation, and cytokine studies were also performed.

RESULTS: Untreated CBA mice rejected C57BL/10 cardiac grafts acutely (median survival time, 8 days). The majority of recipients given aspirin rejected their grafts within 20 days (median survival time, 11 days). In mice given NS-398, the majority of the grafts survived indefinitely (median survival time, >100 days). Secondary CBA recipients given CD4⁺ splenocytes from primary CBA recipients treated with NS-398 also had indefinite survival of C57BL/10 hearts (median survival time, >60 days). Graft acceptance and proliferative hyporesponsiveness were also confirmed by the histologic and cell-proliferation studies, respectively. Production of interleukin 4 and 10 from splenocytes of the recipients treated with NS-398 were significantly higher than that from untreated recipients.

CONCLUSIONS: In our model administration of cyclooxygenase 2 inhibitor induced indefinite survival of fully mismatched cardiac grafts and generated CD4⁺ regulatory cells. Cyclooxygenase 2 inhibitor could warrant consideration for use as an immunomodulating agent in clinical transplantation.