Sensitive detection of human cytomegalovirus peptide–specific cytotoxic T-lymphocyte responses by interferon-γ–enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation

Hebart, Holger; Daginik, Senay; Stevanović, Stefan; Grigoleit, Ulrich; Dobler, Andrea; Baur, Manuela; Rauser, Georg; Sinzger, Christian; Jahn, Gerhard; Loeffler, Juergen; Kanz, Lothar; Rammensee, Hans‐Georg; Einsele, Hermann

doi:10.1182/blood.v99.10.3830

Cited by 148 publications

(111 citation statements)

References 35 publications

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“…Indeed the CMV-specific CD4 þ and CD8 þ T-cell responses both represented 10% of their respective T-cell repertoire. Such extreme immunodominance of CMV in the post transplant period has been observed in other studies 28 and may reflect the observation of CMV latency and reactivation in myeloid DCs. 32 The CMV-specific CD4 þ T-cell immune response is unusual in that the great majority of the population is comprised of cytotoxic CD4 cells, a minority population within the CD4 þ T-cell repertoire.…”

Section: Discussionmentioning

confidence: 74%

“…In HSCT, several studies have demonstrated the importance of both the CD4 þ and CD8 þ CMV-specific T cells in protection from CMV reactivation. 27,28 More recently, Lilleri proposed that an absolute CD4 and CD8 count of 1 and 3 cells/ml, respectively, may be valuable in protection from recurrent CMV reactivation in young HSCT patients. 14 Our data shows a clear association between reconstitution of the CD4 þ CMV-specific T-cell immune response within the first 50 days and protection against CMV reactivation.…”

Section: Discussionmentioning

confidence: 99%

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Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

Pourgheysari

Piper

McLarnon

et al. 2008

Bone Marrow Transplant

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Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4 þ and CD8 þ components of the CMVspecific immune response in protection from reactivation is unclear. The CMV-specific CD4 þ and CD8 þ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4 þ and CD8 þ responses, respectively. A deficient CMVspecific CD4 þ T-cell immune response within the first 30-50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4 þ and CD8 þ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4 þ T cells correlated with CMV-specific CD8 þ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4 þ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4 þ immune response is useful in managing viral reactivation following HSCT.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

Pourgheysari

Piper

McLarnon

et al. 2008

Bone Marrow Transplant

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“…The MUC1 protein sequence was screened with HLA class I binding algorithms provided by the SYFPEITHI software as described earlier 15,16, and new MUC1 peptides binding to HLA-A*6801, HLA-B*0702 and HLA-B*4402 were predicted. The peptides (Table 2) were synthesized using standard fluorenylmethoxycarbonyl chemistry on an automated peptide synthesizer (432A; Applied Biosystems, Weiterstadt, Germany).…”

Section: Peptidesmentioning

confidence: 99%

CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT

Kapp

Stevanović

Fick

et al. 2009

Bone Marrow Transplant

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The GVL effect following allo-SCT is one of the most prominent examples showing the ability of the immune system to eliminate malignant hematological diseases. Tumor-associated Ags (TAA), for instance WT1 and proteinase-3, have been proposed as targets for T cells to establish a GVL effect. Here, we examined an additional TAA (MUC1) as a possible T-cell target of GVL-related immune responses. We have defined new peptide epitopes from the MUC1 Ag to broaden patients' screening and to expand the repertoire of immunologic monitoring as well as for therapeutic approaches in the future. Twenty-eight patients after allo-SCT have been screened for T-cell responses toward TAA (proteinase-3, WT1, MUC1). We could detect a significant relationship between relapse and the absence of a TAA-specific T-cell response, whereby only 2/13 (15%) patients with TAA-specific CTL relapsed, in contrast to 9/15 (60%) patients without TAA-specific CTL responses (Po0.05). In conclusion, CD8 þ T-cell responses directed to TAA might contribute to the GVL effect. These observations highlight both the importance and the potential of immunotherapeutic approaches after allo-SCT.

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“…Analysis of T cell response in transplanted patients who did not develop HCMV disease showed contrasting results. Indeed, high frequencies of IE1-but not pp65-speciWc CD8+ T cells were found protective in one case [29] whereas, rising numbers of pp65-speciWc T cells correlated with immune reconstitution in another case [30]. Interestingly, all patients protected by IE1-specifc T cells were HCMV-seropositive before transplantation suggesting that viral reactivation was responsible for expansion of CTL against IE1 which is produced in large amounts in the IE phase.…”

Section: Role Of Cross-presentation To Bypass Viral Subversion and Inmentioning

confidence: 98%

Interplay between human cytomegalovirus and dendritic cells in T cell activation

Martin

Mandron

Davrinche

2008

Med Microbiol Immunol

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Control of human cytomegalovirus (HCMV) infection and prevention of associated diseases in immunocompetent hosts are ensured mainly by CD8+ T cells, in spite of numerous viral tricks to impair antigen presentation and activation of T cells. At sites of primary infection, dendritic cells (DCs) are in the forefront to ensure capture of viral antigens and their capacity to bypass the eVects of viral immunoevasins is crucial in moulding CD8+ T cell repertoire. In HCMV-seropositive donors, the spectrum of CD8+ T cells speciWcities was shown to include immediate-early (IE), early (E) and late (L) gene products, a surprising Wnding if we consider that expression of immunoevasins could paralyse infected DCs from the IE phase of infection. In the present report, we suggest that uninfected dendritic cells could acquire HCMV-antigens derived from input virus or neosynthesis, either in soluble forms or in association with infected dead cells resulting from death-ligand-mediated apoptosis and necrosis. Activation of naïve CD8+ T cells could then occur in lymph nodes through cross-presentation by antigen-loaded DCs, providing an explanation for shape and size of the memory compartment.

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Sensitive detection of human cytomegalovirus peptide–specific cytotoxic T-lymphocyte responses by interferon-γ–enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation

Abstract: Reconstitution of human cytomegalovirus (HCMV)-specific cytotoxic T lymphocytes (CTLs),

Cited by 148 publications

References 35 publications

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT

CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT

Interplay between human cytomegalovirus and dendritic cells in T cell activation

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