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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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Dendritic cells (DCs) enhance GVT reactivity. (A) Tumour size on day 28 after transplantation of allogeneic T-cell-depleted bone marrow cells (TCD-BMCs), subcutaneous inoculation of tumour-pulsed DC on day +7 and intravenous adoptive transfer of F1 splenocytes (spln.). (B) Complete regression of established tumours (>60 mm3) expressed as percentage of the experimental groups (numbers are given for each experimental group).
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fig6: Dendritic cells (DCs) enhance GVT reactivity. (A) Tumour size on day 28 after transplantation of allogeneic T-cell-depleted bone marrow cells (TCD-BMCs), subcutaneous inoculation of tumour-pulsed DC on day +7 and intravenous adoptive transfer of F1 splenocytes (spln.). (B) Complete regression of established tumours (>60 mm3) expressed as percentage of the experimental groups (numbers are given for each experimental group).

Mentions: The relative efficacy of the various protocols was determined by tumour size at the experimental end point and eradication of established tumours (>60 mm3). Although tumour-pulsed DC suppressed the growth of Neuro-2a cells under all conditions (P<0.01, Figure 6A), adoptive transfer of F1 splenocytes alone had no significant impact. The only additive effect was obtained by joint administration of F1 splenocytes and DCNeuro2a on day +7 (P<0.01 vs DC alone, P<0.001 vs F1 splenocytes alone). Consistently, the profile of complete regression of tumours exceeding 60 mm3 mirrored the variations in tumour size (Figure 6B), reinforcing the validity of growth measurements. Notably, the experimental conditions were designed to maximise differences between the various experimental conditions by generating relatively large tumours. Therefore, the important component towards induction of effective GVT constitutes of donor DC infusion, which elicits potent reactions able to cause complete regression of established tumours.


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)

Dendritic cells (DCs) enhance GVT reactivity. (A) Tumour size on day 28 after transplantation of allogeneic T-cell-depleted bone marrow cells (TCD-BMCs), subcutaneous inoculation of tumour-pulsed DC on day +7 and intravenous adoptive transfer of F1 splenocytes (spln.). (B) Complete regression of established tumours (>60 mm3) expressed as percentage of the experimental groups (numbers are given for each experimental group).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Dendritic cells (DCs) enhance GVT reactivity. (A) Tumour size on day 28 after transplantation of allogeneic T-cell-depleted bone marrow cells (TCD-BMCs), subcutaneous inoculation of tumour-pulsed DC on day +7 and intravenous adoptive transfer of F1 splenocytes (spln.). (B) Complete regression of established tumours (>60 mm3) expressed as percentage of the experimental groups (numbers are given for each experimental group).
Mentions: The relative efficacy of the various protocols was determined by tumour size at the experimental end point and eradication of established tumours (>60 mm3). Although tumour-pulsed DC suppressed the growth of Neuro-2a cells under all conditions (P<0.01, Figure 6A), adoptive transfer of F1 splenocytes alone had no significant impact. The only additive effect was obtained by joint administration of F1 splenocytes and DCNeuro2a on day +7 (P<0.01 vs DC alone, P<0.001 vs F1 splenocytes alone). Consistently, the profile of complete regression of tumours exceeding 60 mm3 mirrored the variations in tumour size (Figure 6B), reinforcing the validity of growth measurements. Notably, the experimental conditions were designed to maximise differences between the various experimental conditions by generating relatively large tumours. Therefore, the important component towards induction of effective GVT constitutes of donor DC infusion, which elicits potent reactions able to cause complete regression of established tumours.

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