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J Thorac Cardiovasc Surg 2002;123:803-809
© 2002 The American Association for Thoracic Surgery

Cardiothoracic Transplantation (TX)

Role of CD8⁺ lymphocytes in chronic rejection of transplanted hearts

From the Division of Cardiothoracic Surgery, Department of Surgery,^a Department of Microbiology, Immunology, and Molecular Genetics,^b and Department of Pathology and Laboratory Medicine,^c University of California, Los Angeles, UCLA Medical Center, Los Angeles, Calif.

Received for publication May 1, 2001. Revisions requested July 27, 2001; revisions received Aug 16, 2001. Accepted for publication Aug 31, 2001. Address for reprints: Abbas Ardehali, MD, UCLA Medical Center, Department of Surgery, Division of Cardiothoracic Surgery, CHS 62-246, 10833 LeConte Blvd, Los Angeles, CA 90095 (E-mail: aardehali{at}mednet.ucla.edu).

Background: The contribution of CD8⁺ lymphocytes to the pathogenesis of cardiac allograft vasculopathy, or chronic rejection in heart transplants, remains undefined. We used both major histocompatibility complex class I mismatched and major histocompatibility complex class II mismatched models of cardiac allograft vasculopathy to characterize the role of CD8⁺ lymphocytes in the development of cardiac allograft vasculopathy.
Methods: Donor hearts from B10.A mice were transplanted into B10.BR recipients (major histocompatibility complex class I mismatched). Donor hearts were harvested at 1, 7, 14, and 30 days after transplantation and (1) quantitated morphometrically for lesion development, (2) stained immunohistochemically, or (3) digested for isolation of graft-infiltrating cells. The cytotoxic phenotype of graft-infiltrating CD8⁺ lymphocytes was determined with flow cytometry. Intracellular cytokine staining of CD8⁺ and CD4⁺ lymphocytes for interleukin 2, interferon g, interleukin 4, and interleukin 10 was performed with 2-color flow cytometry. Finally, B6.C-H2^bm12 donor hearts were transplanted into either C57BL/6 wild-type (major histocompatibility complex class II mismatched) or CD8 -/- knockout recipients and examined for the development of cardiac allograft vasculopathy.
Results: In the major histocompatibility complex class I mismatched model, CD8⁺ lymphocytes were the predominant T-lymphocyte subset that infiltrated the allografts and demonstrated markers of activation. The intracellular cytokine-staining assay demonstrated that CD8⁺ lymphocytes were the primary sources of allograft interleukin 2 and interferon . Intimal lesions developed in the allografts by day 14 (12.0% ± 4.0%) and further increased by day 30 (44.0% ± 5.0%). In the major histocompatibility complex class II mismatched model, the donor hearts in the CD8 -/- knockout recipients had substantially less severe intimal lesions when compared with the donor hearts in wild-type recipients (19.0% ± 6.0% vs 50.0% ± 7.0%, respectively; P < .05).
Conclusions: In both major histocompatibility complex class I and II mismatched models, CD8⁺ lymphocytes contribute significantly to chronic rejection. The findings of this study suggest that control of chronic rejection requires interventions directed at CD8⁺ lymphocytes.

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