Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo

McGoldrick, Suzanne; Bleakley, Marie; Guerrero, Abraham; Turtle, Cameron J.; Yamamoto, Tori N.; Pereira, Shalini; Delaney, Colleen; Riddell, Stanley R.

doi:10.1182/blood-2012-09-453720

Cited by 38 publications

(30 citation statements)

References 38 publications

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“…The findings are consistent with the demonstration that donor-derived CMV-specific immune responses are primed within 7 to 8 weeks of transplantation in R1/D2 HSCT, where the donor graft is either conventional G-CSF-mobilized peripheral blood stem cells or umbilical cord blood. 19 One notable difference, however, was that CMV-specific T cells failed to proliferate sufficiently in vivo to provide protective immunity early after transplantation in the prior study, whereas this was clearly not the case after DLI. It is possible that the difference relates to CD4 deficiency, immunosuppressive drugs, or other environmental factors that are either absent or present at earlier points after HSCT.…”

Section: Discussionmentioning

confidence: 57%

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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Section: Discussionmentioning

confidence: 57%

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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“…41 Similarly, McGoldrick et al were able to detect IFN-g 1 CMV-specific CD4 1 and CD8 1 T cells of UCB origin after in vitro stimulation in the majority of seropositive patients in the first 56 days after transplantation. 64 These findings suggest that both CD8…”

Section: Clinically Prognostic Value Of Thymopoietic Recovery After Ucbtmentioning

confidence: 72%

“…However, the UCBderived CD8 1 CMV-specific T cells remain at low numbers and fail to control CMV reactivation in the early posttransplant period. 64 The functional deficiency of CMV-specific CD8 1 T cells may be explained by the profound paucity of CD4 1 T helper cells after UCBT, 41,64 which are imperative for the development of a functional CD8…”

Section: Clinically Prognostic Value Of Thymopoietic Recovery After Ucbtmentioning

confidence: 99%

The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation

Politikos

Boussiotis

2014

Blood

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Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells for patients without HLA-matched adult donors. UCB contains a low number of nucleated cells and mostly naive T cells, resulting in prolonged time to engraftment and lack of transferred T-cell memory. Although the first phase of T-cell reconstitution after UCB transplantation (UCBT) depends on peripheral expansion of transferred T cells, permanent T-cell reconstitution is mediated via a central mechanism, which depends on de novo production of naive T lymphocytes by the recipient’s thymus from donor-derived lymphoid-myeloid progenitors (LMPs). Thymopoiesis can be assessed by quantification of recent thymic emigrants, T-cell receptor excision circle levels, and T-cell receptor repertoire diversity. These assays are valuable tools for monitoring posttransplantation thymic recovery, but more importantly they have shown the significant prognostic value of thymic reconstitution for clinical outcomes after UCBT, including opportunistic infections, disease relapse, and overall survival. Strategies to improve thymic entry and differentiation of LMPs and to accelerate recovery of the thymic stromal microenvironment may improve thymic lymphopoiesis. Here, we discuss the mechanisms and clinical implications of thymic recovery and new approaches to improve reconstitution of the T-cell repertoire after UCBT.

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“…It is critical to look at CMV reactivation outcomes in CBHCT specifically as CBHCT is unique. CB T cells are naïve and there is no transfer of protective memory T cells 19 ; therefore, CB is considered inherently seronegative and CB transplant is associated with a high incidence of CMV reactivation in the seropositive recipient. CBHCT also tends to be associated with less acute and chronic GVHD given the degree of mismatch, yet a powerful graft versus leukemia effect remains 20–22 .…”

Section: Introductionmentioning

confidence: 99%

Impact of early CMV reactivation in cord blood stem cell recipients in the current era

Ramanathan

Teira

Battiwalla

et al. 2016

Bone Marrow Transplant

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Several studies have reported an association between cytomegalovirus (CMV) reactivation and a decreased incidence of relapse for acute myeloid leukemia (AML) after adult donor allogeneic hematopoietic cell transplantation (HCT). Limited data, however, are available on the impact of CMV reactivation on relapse after cord blood stem cell (CB) transplantation. The unique combination of higher incidence of CMV reactivation in the seropositive recipient and lower incidence of graft versus host disease (GvHD) in CB HCT allows for a valuable design to analyze the impact of CMV reactivation. Data from 1684 patients transplanted with cord blood (CB) between 2003 and 2010 for AML and acute lymphoblastic leukemia (ALL) were analyzed. The median time to CMV reactivation was 34 days (range: 2 – 287). CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) amongst both AML and ALL CB recipients [Reactivation, AML: RR 1.41 (1.07–1.85); ALL: 1.60 (1.14 – 2.23); Serology, AML: RR 1.39 (1.05 – 1.85), ALL: RR 1.61 (1.18 – 2.19)]. For patients with ALL, but not those with AML, this yielded inferior overall survival (p<0.005). Risk of relapse was not impacted by CMV reactivation or positive CMV serostatus for either disease.

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Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo

Abstract: Key Points Priming of CMV-specific CD4+ and CD8+ T cells occurs as early as day 42 in patients undergoing UCBT. Lack of CMV control in UCBT patients could be related to low absolute frequency of T cells and lack of in vivo expansion of T cells.

Cited by 38 publications

References 38 publications

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

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

The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation

Impact of early CMV reactivation in cord blood stem cell recipients in the current era

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