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CMV-specific T-cell immunity, viral load, and clinical outcome in seropositive renal transplant recipients: a pilot study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. (Olle Korsgren)
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2010 (English)In: Clinical Transplantation, ISSN 0902-0063, E-ISSN 1399-0012, Vol. 24, no 3, 401-409 p.Article in journal (Refereed) Published
Abstract [en]

Background: 

Cytomegalovirus (CMV) infection is still the leading opportunistic infection following solid organ transplantation. The aim of this prospective study of renal transplant recipients was to evaluate the dynamics of CMV-specific T-cells, viral load, and clinical symptoms of CMV infection.

Methods: 

Levels of tetramer-selected CD8+ T-cells (TetraCD8), CMV-specific interferon-γ producing CD8+ T-cells (IFNγCD8), and CD4+ T-cells (IFNγCD4), measured using major histocompatibility complex-tetramer and cytokine flow cytometry techniques, and CMV DNA were monitored monthly in 17 CMV-seropositive patients up to one yr (median 12 months, range 3–12) after transplantation and correlated to clinical outcome.

Results: 

CMV DNAemia was detected in 94% of the patients, but only one patient developed CMV disease. CMV DNAemia >1 million copies/mL was seen in asymptomatic patients. CMV-specific T-cells decreased rapidly after transplantation. TetraCD8 and IFNγCD8 regenerated within three months, whereas IFNγCD4 recovery was impaired up to one yr after transplantation. The proportion of IFNγCD4 at two months post-transplantation as compared with baseline, correlated strongly with the magnitude of the CMV DNAemia.

Conclusions: 

Monitoring the reduction of IFNγCD4 compared with baseline during the first months after transplantation could be considered in predicting risk for high-grade CMV DNAemia and in deciding strategic approaches for pre-emptive and prophylactic therapy.

Place, publisher, year, edition, pages
2010. Vol. 24, no 3, 401-409 p.
Keyword [en]
CMV, CMV DNAemia, CMV-specific immunity, Renal transplantation, Tetramer
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97643DOI: 10.1111/j.1399-0012.2009.00976.xISI: 000278307500018PubMedID: 19222507OAI: oai:DiVA.org:uu-97643DiVA: diva2:172664
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Cytomegalovirus Infection in Immunocompetent and Renal Transplant Patients: Clinical Aspects and T-cell Specific Immunity
Open this publication in new window or tab >>Cytomegalovirus Infection in Immunocompetent and Renal Transplant Patients: Clinical Aspects and T-cell Specific Immunity
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cytomegalovirus (CMV) is a β-herpesvirus that, after primary infection, establishes a life-long persistence in the human host. Up to 90% of humans are infected with CMV, that is kept under control by CMV-specific CD8+ and CD4+ T cells. In patients with an impaired cellular immunity, however, CMV infections can be life-threatening. Thus, it is vital to identify risk factors and target high-risk patients. In this thesis we have evaluated low-dose valacyclovir prophylaxis in renal transplant patients and studied CMV-specific T cell immunity in healthy and renal transplant patients.

In renal transplant patients, the CMV serostatus of both the recipient (R) and the donor (D) has a major impact on the risk of developing CMV disease. In the high-risk D+/R- population, >50% are likely to develop CMV disease in the absence of prophylaxis and/or pre-emptive therapy. We have used low-dose valacyclovir prophylaxis for high-risk renal transplant patients, and graft and patient survival up to 5 years after transplantation was comparable to data reported for other prophylactic protocols. The incidence of CMV disease and graft rejection during the first year after transplantation was also comparable to that achieved with other protocols, and without the adverse effects reported for other therapies.

In the D+/R+ population, with a 15-35% risk of developing CMV disease, it is important to identify those individuals that are subject to a higher risk because of risk factors other than CMV serostatus. We therefore measured several immunologic parameters in renal transplant patients and in immunocompetent individuals with latent and primary CMV infection. In patients with a primary symptomatic CMV infection, CMV-specific CD8+ T cells peaked within a month after onset of symptoms but declined rapidly. In renal transplant patients, we found that the reduction in IFNγ-producing CMV-specific CD4+ T cells at 2 months post-transplantation may predict high-grade CMV DNAemia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 386
Keyword
Cytomegalovirus, renal transplantation, cellular immunity, valacyclovir, mismatched, prophylaxis, tetramer, CD4 T cells, CD8 T cells
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-9324 (URN)978-91-554-7309-9 (ISBN)
Public defence
2008-11-29, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2010-12-28Bibliographically approved
2. Cellular Immune Responses to Cytomegalovirus
Open this publication in new window or tab >>Cellular Immune Responses to Cytomegalovirus
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cytomegalovirus (CMV) is a widespread infection affecting 50-90% of the human population. A typical silent primary infection is followed by life-long persistence in the host under control by virus-specific CD8 (“killer”) and CD4 (“helper”) T cells. Although harmless in most people, CMV may cause disease and sequelae in patients with deficient cellular immunity, such as AIDS patients, recipients of organ transplants and children who have acquired the virus before birth. In this thesis we have characterized the cellular immunity to CMV in immunocompetent subjects, in patients receiving transplants and in infants.

In healthy individuals with latent CMV, the frequencies of CMV-specific CD8 T cells varied considerably between the donors. Within the same individual, the changes over time were usually small. In patients with primary, symptomatic CMV infection, the frequencies of CMV-specific CD8 T cells peaked within the first month after the appearance of symptoms. The frequencies then declined to levels similar to those in latently infected CMV carriers. The CD4 T-cell function followed the same pattern, but with lower peak values.

Immunosuppressed renal transplant patients with latent CMV had CMV-specific CD4 cell function similar to healthy controls. The frequencies of CMV-specific CD8 T cells were also comparable, but their function was impaired. When renal transplant recipients were investigated longitudinally, we found that their CMV-specific T cells decreased rapidly after transplantation. Whereas the frequencies and function of CD8 T cells rebounded within 3 months, CD4 T-cell recovery was impaired during the entire first year after transplantation.

Finally, the frequencies and function of CMV-specific T-cells were investigated in children with congenital and postnatal CMV. CMV-specific CD8 T cells could be detected in even the youngest children, suggesting that these cells can develop early in life. In contrast, CMV specific CD4 T cells were low or absent in the youngest children but increased slowly with age.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 321
Keyword
Cytomegalovirus, cellular immunology, infection, immune responses, congenital infection, CD4 T cells, CD8 T cells, immunosuppressed
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-8578 (URN)978-91-554-7132-3 (ISBN)
Public defence
2008-04-11, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-20 Created: 2008-03-20 Last updated: 2010-12-28Bibliographically approved

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Sund, FredrikLidehäll, Anna KarinTötterman, Thomas H.Korsgren, OlleEriksson, Britt-Marie

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