High frequency of Epstein–Barr virus (EBV) lymphoblastoid cell line-reactive lymphocytes in cord blood: evaluation of cytolytic activity and IL-2 production

Moretta, Antonia; Comoli, Patrizia; Montagna, Daniela; Gasparoni, Antonella; Percivalle, Elena; Carena, Ilaria; Revello, Maria Grazia; Gerna, Giuseppe; Mingrat, G.; Locatelli, Franco; Rondini, G; Maccario, Rita

doi:10.1111/j.1365-2249.1997.258-ce1131.x

Cited by 30 publications

(28 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, a persistence of this unique pattern of cord blood cytolytic response towards NIMA after the perinatal period could possibly explain why recipients of renal transplants from a HLA-haploidentical NIMA-disparate sibling enjoy a longer graft survival than patients given the kidney from a donor diverse for NIPA. 29 In keeping with previously published data demonstrating that autologous EBV-LCL are able to elicit in CBMC a strong innate immunological response mediated by both NK cells and CD4 + T lymphocytes, 43 our present data demonstrate that a similar preferential expansion of NK subsets can also be observed after activation with allogeneic EBV-LCL, and confirm evidence on the strong functional capacity of cord blood NK cells, when activated by some viral stimuli. 43 It has been reported that in humans EBV-specific immune responses may generate a CTL-mediated crossreaction with alloantigens, 44 this explains the clinical association between herpesvirus infections and GVHD.…”

Section: Discussionsupporting

confidence: 92%

“…29 In keeping with previously published data demonstrating that autologous EBV-LCL are able to elicit in CBMC a strong innate immunological response mediated by both NK cells and CD4 + T lymphocytes, 43 our present data demonstrate that a similar preferential expansion of NK subsets can also be observed after activation with allogeneic EBV-LCL, and confirm evidence on the strong functional capacity of cord blood NK cells, when activated by some viral stimuli. 43 It has been reported that in humans EBV-specific immune responses may generate a CTL-mediated crossreaction with alloantigens, 44 this explains the clinical association between herpesvirus infections and GVHD. The preferential early activation of NK cord blood cells, instead of CTL, in response to some viral infections, similar to that observed after NIMA challenge, may also contribute to the low incidence and severity of GVHD in CBT recipients.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Characterisation of CTL directed towards non-inherited maternal alloantigens in human cord blood

Moretta

Locatelli

Mingrat

et al. 1999

Bone Marrow Transplant

Self Cite

View full text Add to dashboard Cite

Summary:Allogeneic cord blood transplantation (CBT), especially from unrelated donors, is being increasingly used for treating paediatric patients with both malignant and nonmalignant disorders. Recent clinical and experimental evidence suggests that human cord blood mononuclear cells (CBMC) may acquire in utero a state of tolerance towards non-inherited maternal antigens (NIMA). In order to better define this phenomenon, we measured, by means of a limiting dilution assay (LDA), the frequency of NIMA-specific CTL precursors ( Over the past decade, allogeneic cord blood transplantation (CBT) from both related and unrelated donors has been used increasingly for the treatment of paediatric patients with both malignant and non-malignant disorders. 1-4 Previously published results demonstrate that, at least when the donor is a compatible relative, CBT recipients experience a

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Characterisation of CTL directed towards non-inherited maternal alloantigens in human cord blood

Moretta

Locatelli

Mingrat

et al. 1999

Bone Marrow Transplant

Self Cite

View full text Add to dashboard Cite

show abstract

“…The effector cells from the seronegative adults are true CTL, showing clear evidence of MHC restriction and target cell specificity. Several investigators have previously reported that LCL can enhance NK or LAK activity in EBV-seronegative donors, and apparent EBVspecific cytotoxic activity obtained from seronegative donors has often not been clearly differentiated from NK-or LAK-mediated activity (17,33,35). We observed a similar phenomenon in three of our seronegative children from whom cytolytic T cell lines were elicited using the standard protocol.…”

Section: Discussionsupporting

confidence: 75%

“…EBV-specific CTL can be reactivated from EBV-seropositive individuals by stimulation of peripheral blood T cells with autologous irradiated EBV-transformed lymphoblastoid B cell lines (LCL) (11,16). Although LCL are potent APCs, they seem incapable of inducing a primary immune response to EBV in vitro (11)(12)(13)(14)(15)(16)(17). This has been a major problem for the high-risk seronegative recipients of EBV-seropositive organ grafts, who are the individuals most at risk (8).…”

mentioning

confidence: 99%

Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals

Savoldo

Cubbage

Durett

et al. 2002

The Journal of Immunology

104

View full text Add to dashboard Cite

Adoptive immunotherapy with EBV-specific CTL (EBV-CTL) effectively prevents and treats EBV-driven lymphoproliferation in immunocompromised hosts. EBV-seronegative solid organ transplant recipients are at high risk of EBV-driven lymphoproliferation because they lack EBV-specific memory T cells. For the same reason, standard techniques for generating EBV-CTL in vitro from EBV-naive individuals are unsuccessful. To overcome this problem, we compared several methods of expanding EBV-CTL from seronegative adults and children. First, the standard protocol, using EBV-transformed lymphoblastoid B cell lines (LCL) as the source of APC, was compared with protocols using EBV-Ag-loaded dendritic cells as APC. Surprisingly, the standard protocol effectively generated CTL from all seronegative adults. The additional finding of EBV-DNA in the peripheral blood of three of these four adults suggested that some individuals may develop cellular, but not humoral, immune responses to EBV. By contrast, LCL failed to reactivate EBV-CTL from any of the six EBV-seronegative children. EBV-Ag-loaded dendritic cells could expand EBV-CTL, but only in a minority of children. However, the selective expansion of CD25-expressing T cells, 9–11 days after activation with LCL alone, proved to be a simple and reliable method for generating EBV-CTL from all seronegative children. The majority of these CTL were CD4+ (71 ± 26%) and demonstrated HLA class II-restricted, EBV-specific killing. Our results suggest that a negative EBV serology does not accurately identify EBV-negative individuals. In addition, our method for selecting EBV-specific CTL from naive individuals by precursor cell enrichment may be applicable to the immunotherapy of cancer patients with a low frequency of tumor- or virus-specific CTL.

show abstract

“…35 Briefly, fresh PBMC or cells recovered from primary MLC were seeded in a final volume of 200 l in 96-well round-bottom microplates. Decreasing numbers of responder cells (10 4 , 5 ϫ 10 3 , 2.5 ϫ 10 3 , 1.25 ϫ 10 3 , 0.6 ϫ 10 3 ) were stimulated with 10 4 autologous irradiated (7000 rads) B-LCL.…”

Section: Limiting Dilution Assay For Evaluation Of Cmv-and Ebvspecifimentioning

confidence: 99%

Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses

Comoli

Locatelli

Moretta

et al. 2001

Bone Marrow Transplant

Self Cite

View full text Add to dashboard Cite

Summary:The success of allogeneic hematopoietic stem cell transplantation from HLA-disparate donors depends on the development of new strategies for graft-versus-host disease prevention able to target specifically donor antihost alloreactivity, while preserving GVL and antiviral immune surveillance. Recent experimental and clinical work has shown the feasibility of an approach based on induction of anergy to host alloantigens through blockade of B7/CD28 costimulatory signal in donor T cells, but data on the impact of this strategy on the recovery of the immune system are still lacking. We devised an ex vivo method for induction of host alloantigen-specific unresponsiveness based on treatment with the B7/CD28 blocking agent CTLA4-Ig associated with CsA. We then proceeded to assess the maintenance of an effective immune response towards viral pathogens and tumor cells after CTLA4-Ig/CsA treatment, by measuring the frequency of CTL precursors directed against CMVand EBV-infected targets, and against autologous leukemic blasts. We demonstrated that (1) CTLA4-Ig and CsA can act synergistically in inducing a state of unresponsiveness to alloantigens; (2) the number of leukemia-reactive, EBV-specific and CMV-specific CTLp is not impaired by CTLA4-Ig/CsA treatment. Our data provide the first direct in vitro evidence that it is possible to preserve antiviral and antileukemia effector cells after blockade of CD28/B7 interaction during MLR. Bone Marrow Transplantation (2001) 27, 1263-1273. Keywords: T lymphocytes; anergy; infectious immunityvirus; tumour immunity; transplantation Allogeneic hematopoietic stem cell transplantation (HSCT) offers the chance of a cure to patients with hematological and immunological disorders. Unfortunately, no more than two-thirds of patients eligible for this procedure have an HLA-matched donor, either related or unrelated. Attempts to augment the size of the donor pool by transplanting unmanipulated hematopoietic progenitors from HLA-haploidentical related or mismatched unrelated donors resulted in a considerable increase in the incidence and severity of GVHD. 1,2 The feasibility of HSCT from HLA-haploidentical related or mismatched unrelated donors, achieved through GVHD prevention by means of T cell depletion prior to infusion of stem cells, was first demonstrated in pediatric patients transplanted for primary immunodeficiencies, 3 and more recently confirmed in both adult and pediatric patients given HSCT for malignancy. 4,5 Notwithstanding the remarkable improvements in the achievement of engraftment without GVHD, infections and leukemia relapse are still a major complication of the delayed immune recovery experienced by patients given T cell-depleted HSCT from HLA-partially matched donors. 4,5 The development of new approaches to T cell manipulation aimed at selective induction of unresponsiveness 6-10 or depletion of alloreactive T cells, 11-13 could allow prevention of GVHD, while drastically reducing the risk of infection and leukemia relapse by accelerating immunological recovery a...

show abstract

High frequency of Epstein–Barr virus (EBV) lymphoblastoid cell line-reactive lymphocytes in cord blood: evaluation of cytolytic activity and IL-2 production

Cited by 30 publications

References 36 publications

Characterisation of CTL directed towards non-inherited maternal alloantigens in human cord blood

Characterisation of CTL directed towards non-inherited maternal alloantigens in human cord blood

Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals

Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses

Contact Info

Product

Resources

About