Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients

Zhou, Wendi; Longmate, Jeffrey; Lacey, Simon F.; Palmer, Joycelynne; Gallez-Hawkins, Ghislaine; Thao, Lia; Spielberger, Ricardo; Nakamura, Ryotaro; Forman, Stephen J.; Zaia, John A.; Diamond, Don J.

doi:10.1182/blood-2009-02-203307

Cited by 139 publications

(139 citation statements)

References 63 publications

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“…Nevertheless, the mere presence of these functional T-cell types was associated with lower levels of CMV replication within episodes of active CMV infection, and hence with a shorter duration of episodes. This is in line with previously published data (Lilleri et al, 2008;Muñoz-Cobo et al, 2012;Zhou et al, 2009), and further highlights the crucial role of adaptive T-cell immunity in the control of CMV viraemia in Allo-SCT recipients.…”

Section: Discussionsupporting

confidence: 81%

Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting

Giménez

Lobo

Muñoz-Cobo

et al. 2015

Journal of General Virology

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The role of cytomegalovirus (CMV)-specific polyfunctional CD8 + T-cells and that of antibodies neutralizing virus epithelial infection (AbNEI) in the control of CMV DNAemia were investigated in 39 CMV-seropositive allogeneic stem-cell transplant (Allo-SCT) recipients with (n524) or without (n515) CMV DNAemia. AbNEI levels were monitored prospectively by means of a neutralization assay employing retinal epithelial cells (ARPE-19) and the recombinant CMV strain BADrUL131-Y4. Quantification of CMV-specific polyfunctional CD8 + T-cells (expressing two or three of the following markers: IFN-cc, TNF-a and CD107a) in whole blood was performed by flow cytometry for intracellular cytokine staining. We found no differences in the dynamic pattern of AbNEI in patients with or without subsequent CMV DNAemia. Baseline and peak AbNEI titres were not predictive of the dynamics of CMV replication within episodes. No correlation was found between CMV DNA loads and AbNEI levels during episodes of CMV DNAemia (r50.09; 95 % confidence interval 20.52 to 0.64; P50.78). The detection of pp65/IE-1 CMV-specific polyfunctional CD8 + T-cells was associated with low-level virus replication within subsequent episodes of CMV DNAemia. Interestingly, the presence of AbNEI titres (inverse) .4.7 log 2 was predictive of the occurrence of CMV DNAemia (sensitivity, 83 %; specificity, 80 %). Our findings provide an insight to the role of humoral and cellular immunity in the control of CMV infection in an Allo-SCT setting.

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Section: Discussionsupporting

confidence: 81%

Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting

Giménez

Lobo

Muñoz-Cobo

et al. 2015

Journal of General Virology

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“…4 Furthermore, 60% of the cohort underwent myeloablative conditioning. Interestingly, our assertion that strategies that result in full donor chimerism might offer little antiviral protection in the context of R1/D2 transplants is supported by the clinical outcome data of these studies, 4,5 as well as by a smaller study that demonstrated persistence of recipient-derived CMV-specific T cells in T-deplete but not T-replete HSCT. 12 The latter study used an in vitro T-cell depletion strategy with Campath-1M plus complement, which results in depletion of mainly donor T cells while leaving recipient T cells intact.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 In high-risk cases in which the recipient is seropositive, this is likely to be the most prolonged when the donor is seronegative (D2), as immunity is then reliant on the development of a primary immune response. [3][4][5] After myeloablative conditioning, the establishment of protective immunity may be delayed still further by the incorporation of T-cell depletion strategies aimed at reducing the risk for graft-vs-host disease (GvHD).…”

Section: Introductionmentioning

confidence: 99%

CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

Sellar

Vargas

Henry

et al. 2015

Blood

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Key Points• CMV serostatus significantly influences chimerism levels after T-cell-depleted allogeneic transplantation.• CMV-specific T cells are exclusively of recipient origin after R1/D2 T-cell-depleted transplants and appear to provide protective immunity.Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R1)/seronegative donor (D2) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-celldepleted conditioning, recipient-derived CMV-specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R1/D2 and R1/seropositive donor patients. We show that in R1/D2 patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R1/D2 setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor-derived immunity. (Blood. 2015;125(4):731-739)

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“…Also, impaired function of regulatory T cells (e.g., through conditioning regimens or immunosuppression) could play a role (34). However, also transplantation of quiescent autoreactive T cells in the grafts could lead to subsequent activation and amplification of such cells in the absence of an effective immunosurveillance during transplantation (38,39). Because we did not detect any autoreactive T cells in donor samples, the first mechanism seems to be more likely.…”

Section: Discussionmentioning

confidence: 66%

Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft–host interaction

Mirza

Zierhut²,

Korn

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Graft-versus-host disease (GVHD) represents the major nonrelapse complication of allogeneic hematopoietic cell transplantation. Although rare, the CNS and the eye can be affected. In this study, manifestation in the retina as part of the CNS and T-cell epitopes recognized by the allogeneic T cells were evaluated. In 2 of 6 patients with posttransplantation retina diseases and 6 of 22 patients without ocular symptoms, antigen-specific T-cell responses against retina-specific epitopes were observed. No genetic differences between donor and recipient could be identified indicating T-cell activation against self-antigens (graft versus self). Transplantation of a preexisting immunity and cross-reactivity with ubiquitous epitopes was excluded in family donors and healthy individuals. In summary, an immunological reaction against retina cells represents a mechanism of graft-versus-host interaction following hematopoietic cell transplantation.

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Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients

Abstract: Reconstitution of cytomegalovirus (CMV)-specific CD8 ؉ T cells is essential to the control of CMV infection in CMV-

Cited by 139 publications

References 63 publications

Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting

Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting

CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

Graft versus self (GvS) against T-cell autoantigens is a mechanism of graft–host interaction

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