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Immunomodulation with dendritic cells and donor lymphocyte infusion converge to induce graft vs neuroblastoma reactions without GVHD after allogeneic bone marrow transplantation.

Ash S, Stein J, Askenasy N, Yaniv I - Br. J. Cancer (2010)

Bottom Line: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice.Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DC(Neuro2a) and lymphocytes devoid of graft vs host (GVH) activity (H2K(a/b)).In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Israel.

ABSTRACT

Background: Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT.

Methods: Mice bearing congenic (H2K(a)) Neuro-2a tumours were grafted with allogeneic (H2K(b)) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DC(Neuro2a)) were inoculated (on day +7) in conjunction with donor (H2K(b)) and haploidentical (H2K(a/b)) lymphocytes.

Results: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DC(Neuro2a) and lymphocytes devoid of graft vs host (GVH) activity (H2K(a/b)). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

Conclusions: The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours.

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Neuro-2a cells elicit immune reactions. (A) C57/BL mice (H2Kb) were immunised with two intravenous injections of 3 × 106 Neuro-2a (H2Ka) or A20 cells (H2Kd) at 3-day intervals and cytolytic responses were evaluated after 3 days. (B) Target Neuro-2a (n=6) and A20 cells (n=5) were exposed to lymphocytes from respectively immunised mice at various target/effector ratios to determine lysis according to lactate dehydrogenase (LDH) release. Data represent means±s.d.
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fig1: Neuro-2a cells elicit immune reactions. (A) C57/BL mice (H2Kb) were immunised with two intravenous injections of 3 × 106 Neuro-2a (H2Ka) or A20 cells (H2Kd) at 3-day intervals and cytolytic responses were evaluated after 3 days. (B) Target Neuro-2a (n=6) and A20 cells (n=5) were exposed to lymphocytes from respectively immunised mice at various target/effector ratios to determine lysis according to lactate dehydrogenase (LDH) release. Data represent means±s.d.

Mentions: The Neuro-2a cell line is considered to be particularly low immunogenic, as a general feature of human NB. To determine the relative efficacy of tumour antigen presentation by Neuro-2a cells, cytolytic responses were compared with the murine A20 lymphoma cell line. B6 mice (H2Kb) were immunised twice at 3-day interval, and lymphocytes were co-incubated with target cells (Figure 1A). Neuro-2a cells (H2Ka) were gradually killed at decreasing target/effector ratios and were comparable to lysis of A20 (H2Kd, Figure 1B), with significant difference only at the lowest target/effector ratio (P<0.05). Therefore, the Neuro-2a cell line elicits effective immune responses comparable to an immunogenic cell line (Asavaroengchai et al, 2002, 2004).


Immunomodulation with dendritic cells and donor lymphocyte infusion converge to induce graft vs neuroblastoma reactions without GVHD after allogeneic bone marrow transplantation.

Ash S, Stein J, Askenasy N, Yaniv I - Br. J. Cancer (2010)

Neuro-2a cells elicit immune reactions. (A) C57/BL mice (H2Kb) were immunised with two intravenous injections of 3 × 106 Neuro-2a (H2Ka) or A20 cells (H2Kd) at 3-day intervals and cytolytic responses were evaluated after 3 days. (B) Target Neuro-2a (n=6) and A20 cells (n=5) were exposed to lymphocytes from respectively immunised mice at various target/effector ratios to determine lysis according to lactate dehydrogenase (LDH) release. Data represent means±s.d.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990575&req=5

fig1: Neuro-2a cells elicit immune reactions. (A) C57/BL mice (H2Kb) were immunised with two intravenous injections of 3 × 106 Neuro-2a (H2Ka) or A20 cells (H2Kd) at 3-day intervals and cytolytic responses were evaluated after 3 days. (B) Target Neuro-2a (n=6) and A20 cells (n=5) were exposed to lymphocytes from respectively immunised mice at various target/effector ratios to determine lysis according to lactate dehydrogenase (LDH) release. Data represent means±s.d.
Mentions: The Neuro-2a cell line is considered to be particularly low immunogenic, as a general feature of human NB. To determine the relative efficacy of tumour antigen presentation by Neuro-2a cells, cytolytic responses were compared with the murine A20 lymphoma cell line. B6 mice (H2Kb) were immunised twice at 3-day interval, and lymphocytes were co-incubated with target cells (Figure 1A). Neuro-2a cells (H2Ka) were gradually killed at decreasing target/effector ratios and were comparable to lysis of A20 (H2Kd, Figure 1B), with significant difference only at the lowest target/effector ratio (P<0.05). Therefore, the Neuro-2a cell line elicits effective immune responses comparable to an immunogenic cell line (Asavaroengchai et al, 2002, 2004).

Bottom Line: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice.Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DC(Neuro2a) and lymphocytes devoid of graft vs host (GVH) activity (H2K(a/b)).In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva 49202, Israel.

ABSTRACT

Background: Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT.

Methods: Mice bearing congenic (H2K(a)) Neuro-2a tumours were grafted with allogeneic (H2K(b)) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DC(Neuro2a)) were inoculated (on day +7) in conjunction with donor (H2K(b)) and haploidentical (H2K(a/b)) lymphocytes.

Results: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DC(Neuro2a) and lymphocytes devoid of graft vs host (GVH) activity (H2K(a/b)). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT.

Conclusions: The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours.

Show MeSH
Related in: MedlinePlus