2010 - TTS International Congress


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CMV Infection

90.7 - Development of primary CMV-specific T-cell responses in D+/R- transplant recipients during valganciclovir prophylaxis

Presenter: Corinna, La Rosa, DUARTE, United States
Authors: La Rosa C., Limaye A., Krishnan A., Blumstein G., Diamond D.

DEVELOPMENT OF PRIMARY CMV-SPECIFIC T-CELL RESPONSES IN D+/R- TRANSPLANT RECIPIENTS DURING VALGANCICLOVIR PROPHYLAXIS

CMV INFECTION

C. La rosa1, A.P. Limaye2, A. Krishnan1, G. Blumstein1, D.J. Diamond1
1Virology, CITY OF HOPE, DUARTE/UNITED STATES OF AMERICA, 2, University of Washington Medical Center, Seattle/UNITED STATES OF AMERICA

Body: Introduction Universal antiviral prophylaxis is the leading strategy in the United States to reduce the risk of invasive cytomegalovirus infection, in high risk D+/R- solid organ transplant (SOT) recipients. Emerging data suggest that antiviral agents do not facilitate immune priming and may delay CMV immunity in transplant (Tx) recipients. Since cellular immune responses are of high importance in initiating and maintaining immunity against primary CMV infections, we investigated levels and phenotype of primary CMV specific CD4+ and CD8+ T-cell responses, developed during valganciclovir (VAL) prophylaxis, in D+/R- liver and kidney Tx patients. Methods Thirty D+/R- liver (13) and kidney (17) Tx recipients have been consented and enrolled in a continuing longitudinal study, in which we report on as an interim analysis. Patients received induction therapy, maintenance immunosuppression, and 3-6 month prophylaxis with VAL. Clinical parameters and CMV-specific immune-monitoring were assessed bi-weekly, until 7.5 months post-transplant. Plasma was evaluated by quantitative real time PCR for viral load. PBMC were stimulated with peptide libraries specific for immunodominant pp65 and IE1 CMV antigens. Using FACS analyses, the CD137 activation marker and PD-1 inhibitory signaling were measured on CMV-specific T-cells, to assess the level of immune-competence/dysregulation in the cohort. Results During VAL prophylaxis, 8 out of 14 tested recipients showed detectable levels of CMV-specific T-cells. The highest frequency (6 out of 8 recipients) and levels of antigen activated T cells were found to be pp65 specific CD8+ (Figure: UPN 17 upper panel), followed by pp65 specific CD4+ T cells. The IE1 specific CD8+ and CD4+ T-cells were less prominent. PD-1 levels on CMV-specific T-cells remained generally elevated throughout the period of prophylactic VAL therapy. One patient required additional VAL administration for CMV viraemia, detected at 2 months post-transplant. Interestingly, even during the treatment with enhanced VAL dosage, the patient was able to mount sustained primary CMV-specific T-cell responses, which declined as viraemia resolved (Figure: UPN 15 lower panel). Conclusion Antiviral agents have proved successful for prevention of CMV disease in high risk SOT recipients, though prophylaxis has been shown to interfere with immunity. The preliminary data from our study suggest that during VAL therapy CMV infection may occur in D+/R- transplant recipients, and a primary CMV-specific T-cell response can be promptly detected. However, PD-1 up-regulation measured on CMV-specific T-cells from this D+/R- cohort is indicative of a state of immune impairment, which may lead to uncontrolled viraemia or clinical symptoms, once the prophylaxis is suspended. Our ongoing longitudinal investigation focuses in characterizing cellular immunity dysfunction and its role in disease progression of D+ /R- recipients during primary CMV infection.

Disclosure: All authors have declared no conflicts of interest.


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