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Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment
Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
Division of Clinical Immunology and Transfusion Medicine, University Hospital, Uppsala, Sweden.
Division of Microbiology, University Hospital, Uppsala, Sweden. (L Engstrand)
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2003 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 132, no 1, p. 96-104Article in journal (Refereed) Published
Abstract [en]

The availability of tetrameric complexes of HLA class I molecules folded with immunodominant peptides makes it possible to utilize flow cytometry for rapid and highly specific visualization of virus specific CD8+ T cells. An alternate technique is to incubate whole blood with specific antigens and to subsequently detect and characterize responding T cells (e.g. by performing intracellular staining of interferon-gamma). By using an HLA-A2 tetramer construct folded with the same immunodominant CMV-peptide as that used for peptide pulsing, we monitored both the presence and functional capacity of CMV-specific CD8+ T cells. In addition T cell activation was assayed by determination of CD38 and CD69 expression. Twelve organ transplant patients and 31 healthy blood donors with latent CMV infection were investigated using CMV pp65 tetramer staining and intracellular staining of interferon-gamma after CMV pp65 peptide pulsing or CMV lysate pulsing. CMV-specific T cells were detected in similar absolute numbers as well as frequencies of T cells in the two groups investigated. However, the CMV-specific CD8+ T cells in immunosuppressed individuals showed a decreased functional response to the CMV-peptide, as evidenced by reduced interferon-gamma production when compared to healthy blood donors (19%; 42%, P < 0·005). In addition, CD38 expression was markedly higher in immunosuppressed patients compared to healthy blood donors (24%; 6%, P < 0·005). In a case report we demonstrate that reactivation of CMV can occur in an immunosuppressed patient with high number of CMV-specific T cells, but without functional capacity. Hence, these findings reflect impaired activation of cytotoxic T cells controlling latent CMV infection in immunosuppressed patients.

Place, publisher, year, edition, pages
2003. Vol. 132, no 1, p. 96-104
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90463DOI: 10.1046/j.1365-2249.2003.02098.xPubMedID: 12653843OAI: oai:DiVA.org:uu-90463DiVA, id: diva2:162824
Available from: 2003-05-16 Created: 2003-05-16 Last updated: 2018-02-28Bibliographically approved
In thesis
1. Cellular Immune Responses to Allografts and Cytomegalovirus
Open this publication in new window or tab >>Cellular Immune Responses to Allografts and Cytomegalovirus
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Today the immunosuppressive treatment is kept to a level were the incidence of acute rejection is below 20% within the first year after transplantation. As a consequence, a group of transplanted patients is over-immunosuppressed and at risk for infections. There is therefore an urgent need for tools which are able to determine the cellular immune response after organ transplantation. This knowledge would facilitate the task of prospectively opimize the immunosuppressive treatment and identify patients at risk of developing rejection episodes or infections.

To address this issue, a rat-kidney transplantation model for acute rejection was developed to study immune responses to allografts. Infiltrating lymphocytes were analysed using an in vitro culture system which allowed cells to propagate from the biopsies to culture medium. The numbers of outgrowing cells were correlated with morphological and immunohistochemical signs of rejection. When immunosuppressive treatment was administered for 2 and four days after acute rejection, histology did not reveal any improvement, however cellular propagation was reduced by 50 and 75%, respectively. Using the tissue culture technique in human transplanted kidney grafts, which was originally developed for the animal model, the number of propagated cells measured was profoundly higher in grafts with acute cellular rejection than from grafts in other groups. In some cases the number of propagated cells was better correlated with the clinical outcome than the diagnosis made by morphological evaluation. To determine immune responses to cytomegalovirus (CMV), we utilised Human Leukocyte Antigen (HLA) tetramer staining and stimulation of T cells with viral antigens. Both of these techniques independently detected CMV specific T cells in immunosuppressed and healthy individuals with latent or active infection. Although the frequency of CMV specific T cells did not differ between groups, there was a functional impairment in immunosuppressed patients as evidenced by reduced interferon-gamma production. In conclusion, these techniques can be used to determine the cellular immune response to allografts and cytomegalovirus and prove valuable for the optimization of immunosuppressive protocols and antiviral treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. p. 100
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1269
Keywords
Immunology, Transplantation, Rejection, Monitoring, Flow Cytometry, MHC, Tetramer, CMV, infection, Immunologi
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-3441 (URN)91-554-5652-9 (ISBN)
Public defence
2003-06-06, Fåhraeussalen, C5, Rudbecklaboratoriet, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-05-16 Created: 2003-05-16 Last updated: 2018-01-13Bibliographically 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. p. 65
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 321
Keywords
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: 2018-01-13Bibliographically approved

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Lidehäll, Anna KarinTötterman, Thomas H.Herrmann, BjörnEriksson, Britt-MarieKorsgren, Olle

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