Published Online
on October 2, 2006

A more recent version of this article appeared on October 10, 2006

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Submitted on December 10, 2005
Revised on June 19, 2006
Accepted on July 13, 2006

T-Cell Immunity to Subclinical Cytomegalovirus Infection Reduces Cardiac Allograft Disease

Wenwei Tu MD, PhD, Luciano Potena MD, PhD, Pamela Stepick-Biek MS, Lanxiang Liu BS, Kira Y. Dionis BS, Helen Luikart RN, MS, William F. Fearon MD, Tyson H. Holmes PhD, Clifford Chin MD, John P. Cooke MD, PhD, Hannah A. Valantine MD, Edward S. Mocarski PhD, and David B. Lewis MD^*

From the Departments of Pediatrics (W.T., P.S.-B., L.L., K.Y.D., C.C., D.B.L.), Cardiovascular Medicine (L.P., H.L., W.F.F., J.P.C., H.A.V.), Health Research and Policy (T.H.H.), and Microbiology and Immunology (E.S.M.), and the Program in Immunology (D.B.L.), Stanford University School of Medicine, Stanford, Calif.

^* To whom correspondence should be addressed. E-mail: dblewis{at}stanford.edu.

Background--Asymptomatic cytomegalovirus (CMV) replication is frequent after cardiac transplantation in recipients with pretransplantation CMV infection. How subclinical viral replication influences cardiac allograft disease remains poorly understood, as does the importance of T-cell immunity in controlling such replication.

Methods and Results--Thirty-nine cardiac recipients who were pretransplantation CMV antibody positive were longitudinally studied for circulating CMV-specific CD4 and CD8 T-cell responses, CMV viral load in blood neutrophils, and allograft rejection during the first posttransplantation year. Nineteen of these recipients were also analyzed for changes of coronary artery intimal, lumen, and whole-vessel area. All recipients received early prophylactic therapy with ganciclovir. No recipients developed overt CMV disease. Those with detectable levels of CMV-specific CD4 T cells in the first month after transplantation were significantly protected from high mean and peak posttransplantation viral load (P<0.05), acute rejection (P<0.005), and loss of allograft coronary artery lumen (P<0.05) and of whole-vessel area (P<0.05) compared with those who lacked this immune response. The losses of lumen and vessel area were both significantly correlated with the time after transplantation at which a CD4 T-cell response was first detected (P<0.05) and with the cumulative graft rejection score (P<0.05).

Conclusions--The early control of subclinical CMV replication after transplantation by T-cell immunity may limit cardiac allograft rejection and vascular disease. Interventions to increase T-cell immunity might be clinically useful in limiting these adverse viral effects.

Key words: atherosclerosis • immune system • lymphocytes • rejection • transplantation • viruses

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