Natural killer cell activity following T‐cell depleted allogeneic bone marrow transplantation

Rooney, Cliona M.; Wimperis, J. Z.; Brenner, Malcolm K.; Patterson, J.; Hoffbrand, A. V.; Prentice, HG

doi:10.1111/j.1365-2141.1986.tb02952.x

Cited by 64 publications

(14 citation statements)

References 23 publications

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“…37,38 In infant recipients who were partially immunized, the sustained production of antibody to specific vaccine antigen may be related not only to the helper effects by the thymus-dependent regeneration of CD4 ϩ T lymphocytes, but also by the relatively large numbers of NK cells found in these infants (Figure 3a). 39,40 This study has several limitations. First, the size of the cohort and the duration of follow-up are limited.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

Leung

Pitts

Burnette

et al. 2001

Bone Marrow Transplant

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Summary:The objective of this study is to investigate the outcome of children 24 months of age or younger (infants) at the time of allogeneic bone marrow transplantation (BMT) for acute leukemia or myelodysplasia. We analyzed the survival rate, prognostic factors, incidences of late sequelae, and immune reconstitution in 22 infants who underwent allogeneic BMT. The 5-year event-free survival estimate was 45.5% (95% confidence interval (CI), 24.4% to 63.3%). Six patients died of transplant-related complications and six died of disease relapse. Remission status at the time of BMT was the most important prognostic factor (P ‫؍‬ 0.005): no patient who received a transplant while their disease was not in remission survived, whereas the 5-year survival estimate for infants who underwent BMT during remission was 56% (95% CI, 31% to 75%). Long-term outcomes in the 10 infant survivors were compared with those of 10 older controls matched for diagnosis, disease status at the time of BMT, calendar year at the time of BMT, and source of stem cells. Immune function 1 year after transplantation and the incidences and spectra of late sequelae were similar for both groups during a median of 3.5 years (range, 1.5 to 7.2 years) of follow-up. Bone Marrow Transplantation (2001) 27, 717-722. Keywords: allogeneic transplantation; infant leukemia; myelodysplastic syndrome; late sequelaeThe incidences of lymphoid and myeloid leukemias in infants are approximately equal. Acute lymphoblastic leukemia (ALL) in infants accounts for 2.5% to 5% of all cases of childhood ALL, and acute myeloid leukemia (AML) in infants accounts for 6% to 14% of all cases of childhood AML. 1 The frequent presence of poor prognostic factors such as 11q23/MLL rearrangement in ALL and a high leukocyte count at the time of diagnosis of AML results in an overall long-term survival of only approxiCorrespondence: WH Leung,

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Section: Discussionmentioning

confidence: 99%

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

Leung

Pitts

Burnette

et al. 2001

Bone Marrow Transplant

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“…HSB-2 cells were used because LCL targets are more sensitive to lymphokine-activate killer (LAK)-than natural killer (NK)-mediated lysis, and this cell line has previously been shown to be an excellent target for LAK cells. 15 Assay plates were incubated for 6 hours at 37°C, 5% CO 2 , and 100 L supernatant was harvested and counted using a Packard Cobra Gamma Counter (Packard Instrument Company, Downer's Grove, IL). The percentage of specific lysis was calculated as follows: ([cpm released experimental Ϫ cpm spontaneous]/[cpm total lysis Ϫ cpm spontaneous]) ϫ 100%.…”

Section: Proliferation and Cytotoxicity Assaysmentioning

confidence: 99%

Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses

Amrolia

Muccioli-Casadei

Yvon

et al. 2003

Blood

137

133

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Poor immune reconstitution after haploidentical stem cell transplantation results in a high mortality from viral infections and relapse. One approach to overcome this problem is to selectively deplete the graft of alloreactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient peripheral blood mononuclear cells (PBMCs), and this can result in graft versus host disease (GVHD). We have refined this approach using recipient Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as stimulators to activate donor alloreactive T cells. Our studies demonstrate that allodepletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCLs more consistently depleted in vitro alloreactivity than stimulation with host PBMCs, as assessed in primary mixed lymphocyte reactions (MLRs). Allodepletion using this approach specifically abrogates cytotoxic T-cell responses against host LCLs. In interferon-␥ (IFN-␥) enzymelinked immunospot (ELISPOT) assays, antiviral responses to adenovirus and cytomegalovirus (CMV) were preserved following allodepletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T cells is unaffected by allodepletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the nonshared haplotype. Finally, we studied whether allodepletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLA-A2-PR1 tetramer analysis, we found that the frequency of T cells recognizing the PR1 epitope of proteinase 3 was not significantly different in allodepleted and unmanipulated PBMCs from patients with chronic myeloid leukemia (CML) undergoing transplantation. Based on these data, we have embarked on a phase 1 clinical trial of addback of allo-LCL-depleted donor T cells in the haplo-identical setting.

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“…However, this virus has been associated with several human malignancies, including Burkitt's lymphoma (BL), Hodgkin's disease and nasopharyngeal carcinoma (Henle et al, 1966;Gunven et al, 1970;Henle and Henle, 1973a, b). Moreover, EBV is implicated in disorders related to immunodeficiency, such as post-transplantation lymphoproliferative disorders and AIDS-related lymphomas (Purtilo, 1980;Ciobanu and Wiernik, 1986;Rooney et al, 1986;Thomas and Crawford, 1989).…”

Section: Introductionmentioning

confidence: 99%

Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cells

et al. 2009

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The Epstein-Barr virus (EBV) is carried by more than 90% of the adult world population and has been implicated in several human malignancies. Its ability to induce unlimited in vitro proliferation of B cells is frequently used to generate lymphoblastoid cell lines (LCLs). In this study, we have investigated the evolution of two LCLs up to 25 weeks after EBV infection. LCLs were karyotyped once a month by spectral karyotyping (SKY). LCLs but not mitogen-activated B cells showed evidence of DNA damage and DNA damage response within the first 2 weeks. After 4 weeks, the former, but not the latter, showed a high level of non-clonal structural aberrations, mainly deletions, fragments, dicentric chromosomes and unbalanced translocations. Genomic instability decreased thereafter over time. Nonrandom aneuploidy 12 weeks after infection showed clonal evolution in culture. After 25 weeks post-infection, most cells exhibited karyotypic stability. Chromosomal aberrations were compatible with telomere dysfunction, although in the absence of telomere shortening. The telomere capping protein TRF2 was partially displaced from telomeres in EBV-infected cells, suggesting an EBVmediated uncapping problem. In conclusion, this study suggests that DNA damage and telomere dysfunction contribute to EBV-related chromosomal instability in early LCLs.

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Natural killer cell activity following T‐cell depleted allogeneic bone marrow transplantation

Cited by 64 publications

References 23 publications

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome

Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses

Chromosomal rearrangements after ex vivo Epstein–Barr virus (EBV) infection of human B cells

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