Influence of T cell depletion method on circulating γδ T cell reconstitution and potential role in the graft-versus-leukemia effect

Lamb, Lawrence S.; Gee, Adrian P.; Hazlett, Linda J.; Musk, Philip; Parrish, Rudolph S.; O’Hanlon, Terrance P.; Geier, Steven S.; Folk, R.S.; Harris, Willie G.; McPherson, Kirsty; Lee, C.; Henslee‐Downey, P. Jean

doi:10.1080/0032472031000141295

Cited by 57 publications

(71 citation statements)

References 19 publications

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“…Finally, data from our laboratory have shown no correlation between increased ␥␦ + T cells and the development of GVHD. 9,10 In summary, our clinical observations and preliminary data indicate that these cells may be useful in cellular immunotherapy against leukemia. We believe this to be the first report of proliferation, binding, and cytotoxicity of donor ␥␦ + T cells to recipient primary ALL.…”

Section: Discussionmentioning

confidence: 99%

“…9 We have also shown that enrichment of the marrow graft with ␥␦ + T cells favors an increase in these cells and therefore a decreased incidence of relapse. 10 Of interest, eight of eight patients in our series with a persistent increase in ␥␦ + T cells who were transplanted for acute lymphoblastic leukemia (ALL) are all alive and well at up to 6 years.…”

mentioning

confidence: 99%

“…These findings are consistent with data from our laboratory that show no correlation between increased ␥␦ + T cells and the development of GVHD. 9,10 In this study, we investigated the response of donorderived ␥␦ + T cells in response to recipient primary acute leukemic blasts in culture and to normal mononuclear cells (MNC) in the allogeneic mixed lymphocyte reaction (MLR). The observations lend further support to our clinical data and suggest ␥␦ + T cells as an effective immunotherapeutic approach for acute lymphoblastic leukemia, a disease that has historically been resistant to cell-based therapy following relapse.…”

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confidence: 99%

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Human γδ+ T lymphocytes have in vitro graft vs leukemia activity in the absence of an allogeneic response

Lamb

Musk

et al. 2001

Bone Marrow Transplant

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Summary:Refractory acute lymphoblastic leukemia (ALL) is often incurable, and relapse rates following allogeneic bone marrow transplantation (BMT) remain high. We have reported that patients who develop increased numbers of ␥␦ + T cells soon after BMT are significantly less likely to relapse. We now show in seven donor/recipient pairs that donor-derived V␦1 + CD4 − CD8 − ␥␦ + T cells are activated and proliferate in response to recipient primary ALL blasts. In addition, these cells have been shown to bind and lyse the recipient ALL blasts. Separately, ␥␦ + T cells proliferate poorly or not at all in mixed lymphocyte culture against HLA-mismatched unrelated stimulator cells. These observations suggest that allogeneic ␥␦ + T cells could be an effective immunotherapeutic strategy against refractory disease without the risk of graft-versus-host disease. Bone Marrow Transplantation (2001) 27, 601-606.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Human γδ+ T lymphocytes have in vitro graft vs leukemia activity in the absence of an allogeneic response

Lamb

Musk

et al. 2001

Bone Marrow Transplant

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“…Vδ1 γδ T cells have not yet been infused, but their presence has correlated with complete responses observed in patients with B-cell acute lymphoblastic leukemia after undergoing αβ T celldepleted allogeneic hematopoietic stem cell transplantation. [17][18][19][20] As both of these subpopulations of γδ T cells are associated with antitumor activity, but have not been combined for cell therapy, we sought a clinically appealing approach to propagate T cells that maintain a polyclonal TCRγδ repertoire.…”

Section: Introductionmentioning

confidence: 99%

Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor

et al. 2013

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Even though other γδ T-cell subsets exhibit antitumor activity, adoptive transfer of γδ Tcells is currently limited to one subset (expressing Vγ9Vδ2 T-cell receptor (TCR)) due to dependence on aminobisphosphonates as the only clinically appealing reagent for propagating γδ T cells. Therefore, we developed an approach to propagate polyclonal γδ T cells and rendered them bispecific through expression of a CD19-specific chimeric antigen receptor (CAR). Peripheral blood mononuclear cells (PBMC) were electroporated with Sleeping Beauty (SB) transposon and transposase to enforce expression of CAR in multiple γδ T-cell subsets. CAR(+)γδ T cells were expanded on CD19(+) artificial antigen-presenting cells (aAPC), which resulted in >10(9) CAR(+)γδ T cells from <10(6) total cells. Digital multiplex assay detected TCR mRNA coding for Vδ1, Vδ2, and Vδ3 with Vγ2, Vγ7, Vγ8, Vγ9, and Vγ10 alleles. Polyclonal CAR(+)γδ T cells were functional when TCRγδ and CAR were stimulated and displayed enhanced killing of CD19(+) tumor cell lines compared with CAR(neg)γδ T cells. CD19(+) leukemia xenografts in mice were reduced with CAR(+)γδ T cells compared with control mice. Since CAR, SB, and aAPC have been adapted for human application, clinical trials can now focus on the therapeutic potential of polyclonal γδ T cells.

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“…No other factor was found to be independently associated with improved DFS in these patients (4), and the two patients who relapsed did so only after the ␥␦ϩ T cell count returned to the normal range. Further studies have shown that enrichment of the marrow graft with ␥␦ T cells contributed to the later development of increased ␥␦ T cells (5). The ␥␦ T cells from these patients are predominately V␦1ϩ "normally" recovering patients and healthy donors show predominant expression of V␦2.…”

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Abstracts from the 17th Annual Meeting of the Clinical Cytometry Society

2002

Cytometry

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Assessment of the proliferative capacity of plasma cells (labelling index) is an important independent prognostic indicator in myeloma. A high labelling index (LI) is associated with bad prognosis or worsening of disease. Conversely, a low index corresponds to a good prognosis. Traditionally, the LI has been determined by a microscope immunofluorescent assay. In recent years, a modified method utilising flow cytometry has been developed. We studied the use of flow cytometry to determine LI in 30 patients with newly diagnosed or relapsed myeloma. Using a combination of CD38 PE and CD138 FITC, and propidium iodide to intercalate double stranded DNA, the DNA content of S phase cells (cycling cells) was calculated using Multicycle software (Phoenix Flow Systems, USA). A cut-off point of 4% was adopted as threshold for significant increase in the LI. Of the 30 patients, 23 (77%) had LI of greater than 4% while 7 (23%) had LI less than 4%. Adoption of flow cytometric method over the traditional manual slide method to determine LI should be encouraged and further studied. It is more objective and much easier to perform as the counting procedure is automated. Studies have found it to correlate well with slide based technique. Whole blood was collected from 7 healthy donors and 8 HIV-1 ϩ individuals (average absolute CD4ϩ T cell counts 875.77, SDϮ 446.61). Standard 4-color flow cytometry techniques were utilized, a total of 20,000 CD8ϩ T cells were acquired for tetramers and the percentage of tetramerϩCD57ϩ cells obtained; for cytokine intracellular assays 50.000 CD4ϩ T cells was collected and the percentage obtained reflected coexpression of IFN-␥ and CD69. Membrane marker acquisition of 40.000 cells was acquired.HIVϩ individuals showed significantly increased CD8ϩCD38ϩ expression and tetramers (Mann-Whitney U test, pϭ0.001; 0.002) in comparison to healthy subjects. HIVϩ individuals demonstrated significantly reduced Absolute CD4ϩ T cell counts pϭ0.004) and CD4ϩ/CD8ϩ ratio (Mann-Whitney U test, pϭ0.001) in comparison to controls. However, assessment of intracellular IFN-␥ in these subjects revealed no significant differences (Mann-Whitney U test, pϾ0.05) compared to controls.This study suggests the existence of homeostatic mechanisms in HIV disease that selectively preserve memory CD8ϩ T cell populations reactive towards ubiquitous pathogens. The preservation of reactive CMV responses may be at the expense of T cell memory to infrequently encountered infectious agents.

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Influence of T cell depletion method on circulating γδ T cell reconstitution and potential role in the graft-versus-leukemia effect

Cited by 57 publications

References 19 publications

Human γδ+ T lymphocytes have in vitro graft vs leukemia activity in the absence of an allogeneic response

Human γδ+ T lymphocytes have in vitro graft vs leukemia activity in the absence of an allogeneic response

Bispecific T-cells Expressing Polyclonal Repertoire of Endogenous γδ T-cell Receptors and Introduced CD19-specific Chimeric Antigen Receptor

Abstracts from the 17th Annual Meeting of the Clinical Cytometry Society

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