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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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Kinetics of spleen reconstitution after bone marrow transplantation (BMT) and immunomodulation. (A) Percent recovery of spleen cellularity at 4 weeks after allogeneic BMT (allo-BMT) (H2Kb → H2Ka), infusion of F1 splenocytes (spln.) and tumour-pulsed dendritic cells (DCs) normalised against naïve C57/BL (B6) donors (n=5–6 for each point). (B) Fractional distribution of CD4+ and CD8+ T cells in the spleens of allografted mice in the various experimental protocols. (C) Dynamics of splenic cellularity in allografted mice and with adoptive transfer of F1 splenocytes on days 0 and +7 as a function of time elapsing from transplantation.
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fig5: Kinetics of spleen reconstitution after bone marrow transplantation (BMT) and immunomodulation. (A) Percent recovery of spleen cellularity at 4 weeks after allogeneic BMT (allo-BMT) (H2Kb → H2Ka), infusion of F1 splenocytes (spln.) and tumour-pulsed dendritic cells (DCs) normalised against naïve C57/BL (B6) donors (n=5–6 for each point). (B) Fractional distribution of CD4+ and CD8+ T cells in the spleens of allografted mice in the various experimental protocols. (C) Dynamics of splenic cellularity in allografted mice and with adoptive transfer of F1 splenocytes on days 0 and +7 as a function of time elapsing from transplantation.

Mentions: Reduced proliferation of splenocytes in recipients of F1 lymphocytes might be attributed either to the timing of adoptive transfer or variable interactions with the DC. These possibilities were analysed by monitoring the immune profiles of the reconstituted mice. Quantitatively, spleen cellularity at the experimental end point of 4 weeks was reduced by F1 lymphocyte infusion (day 0) and was apparently unaffected by F1 lymphocyte infusion on day +7 (Figure 5A). Qualitatively, minor differences in splenic T-cell subsets were observed under the different treatment protocols (Figure 5B), with a trend of reduced T-cell fraction in mice infused with DCNeuro2a. As F1 lymphocytes are not detected in the lymphoid organs of recipients at 4 weeks after transplantation (Ash et al, 2009), transient engraftment might modulate lymphoid reconstitution by cells derived from the bone marrow. Administration of F1 splenocytes on day 0 resulted in transient rise in spleen cellularity that subsided during the third week, whereas infusion of F1 splenocytes on day +7 caused a more sustained rise in spleen cellularity (Figure 5C). These differences correlate with the slower growth rates of tumours attained by F1 lymphocyte infusion on day +7 as compared with day 0, showing that the kinetics of lymphoid reconstitution are important to maximise the maturing effect of DC.


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)

Kinetics of spleen reconstitution after bone marrow transplantation (BMT) and immunomodulation. (A) Percent recovery of spleen cellularity at 4 weeks after allogeneic BMT (allo-BMT) (H2Kb → H2Ka), infusion of F1 splenocytes (spln.) and tumour-pulsed dendritic cells (DCs) normalised against naïve C57/BL (B6) donors (n=5–6 for each point). (B) Fractional distribution of CD4+ and CD8+ T cells in the spleens of allografted mice in the various experimental protocols. (C) Dynamics of splenic cellularity in allografted mice and with adoptive transfer of F1 splenocytes on days 0 and +7 as a function of time elapsing from transplantation.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Kinetics of spleen reconstitution after bone marrow transplantation (BMT) and immunomodulation. (A) Percent recovery of spleen cellularity at 4 weeks after allogeneic BMT (allo-BMT) (H2Kb → H2Ka), infusion of F1 splenocytes (spln.) and tumour-pulsed dendritic cells (DCs) normalised against naïve C57/BL (B6) donors (n=5–6 for each point). (B) Fractional distribution of CD4+ and CD8+ T cells in the spleens of allografted mice in the various experimental protocols. (C) Dynamics of splenic cellularity in allografted mice and with adoptive transfer of F1 splenocytes on days 0 and +7 as a function of time elapsing from transplantation.
Mentions: Reduced proliferation of splenocytes in recipients of F1 lymphocytes might be attributed either to the timing of adoptive transfer or variable interactions with the DC. These possibilities were analysed by monitoring the immune profiles of the reconstituted mice. Quantitatively, spleen cellularity at the experimental end point of 4 weeks was reduced by F1 lymphocyte infusion (day 0) and was apparently unaffected by F1 lymphocyte infusion on day +7 (Figure 5A). Qualitatively, minor differences in splenic T-cell subsets were observed under the different treatment protocols (Figure 5B), with a trend of reduced T-cell fraction in mice infused with DCNeuro2a. As F1 lymphocytes are not detected in the lymphoid organs of recipients at 4 weeks after transplantation (Ash et al, 2009), transient engraftment might modulate lymphoid reconstitution by cells derived from the bone marrow. Administration of F1 splenocytes on day 0 resulted in transient rise in spleen cellularity that subsided during the third week, whereas infusion of F1 splenocytes on day +7 caused a more sustained rise in spleen cellularity (Figure 5C). These differences correlate with the slower growth rates of tumours attained by F1 lymphocyte infusion on day +7 as compared with day 0, showing that the kinetics of lymphoid reconstitution are important to maximise the maturing effect of DC.

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