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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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Tumour growth in congenic and immunocompromised mice. (A) Mice were implanted with subcutaneous Neuro-2a cells and after 5 days were conditioned and grafted with 5 × 106 whole bone marrow cells (BMCs). Immunocompetent mice were irradiated (700 rad) and immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice were conditioned with busulfan (2 × 25 μg g–1). (B) Tumour growth in allografted mice congenic to the tumour (H2Ka, n=19) and NOD/SCID mice (H2Kg7) grafted with whole BMCs from B6 (H2Kb, n=9) and A (H2Ka, n=7) donors.
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fig2: Tumour growth in congenic and immunocompromised mice. (A) Mice were implanted with subcutaneous Neuro-2a cells and after 5 days were conditioned and grafted with 5 × 106 whole bone marrow cells (BMCs). Immunocompetent mice were irradiated (700 rad) and immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice were conditioned with busulfan (2 × 25 μg g–1). (B) Tumour growth in allografted mice congenic to the tumour (H2Ka, n=19) and NOD/SCID mice (H2Kg7) grafted with whole BMCs from B6 (H2Kb, n=9) and A (H2Ka, n=7) donors.

Mentions: Tumour growth in congenic mice is limited as compared with immunocompromised mice, suggesting that Neuro-2a is submitted to immune surveillance in immunocompetent mice (Ash et al, 2009). Furthermore, transition to adaptive immunity by either syngeneic or allogeneic BMT suppressed tumour growth, suggesting that a state of immune activation is beneficial to GVH reactivity. To evaluate whether lymphopenia actually promotes GVT reactivity (Borrello et al, 2000; Hu et al, 2002), tumour growth in reconstituted NOD/SCID mice was compared with allogeneic transplants (Figure 2A): mice were implanted with subcutaneous tumours and after 5 days were conditioned and grafted with 5 × 106 allogeneic BMC. NOD/SCID mice were conditioned with busulfan, which is significantly less immunosuppressive as compared with total body irradiation (Askenasy and Farkas, 2003). Tumour growth was significantly suppressed by transplantation of allogeneic whole BMC from H2Ka and K2Kb donors into NOD/SCID mice (P<0.01, Figure 2B), consistent with avid repopulation of the lymphopenic organs. Notably, residual host immune cells are detected in lymphoid organs of allografted immunocompetent mice after myeloablative irradiation (Kaminitz et al, 2009), whereas in NOD/SCID mice the lymphoid organs were full donor (not shown). Therefore, both intrinsic lymphopenia in NOD/SCID mice and radiation-induced lymphodepletion facilitate GVT reactivity.


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)

Tumour growth in congenic and immunocompromised mice. (A) Mice were implanted with subcutaneous Neuro-2a cells and after 5 days were conditioned and grafted with 5 × 106 whole bone marrow cells (BMCs). Immunocompetent mice were irradiated (700 rad) and immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice were conditioned with busulfan (2 × 25 μg g–1). (B) Tumour growth in allografted mice congenic to the tumour (H2Ka, n=19) and NOD/SCID mice (H2Kg7) grafted with whole BMCs from B6 (H2Kb, n=9) and A (H2Ka, n=7) donors.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Tumour growth in congenic and immunocompromised mice. (A) Mice were implanted with subcutaneous Neuro-2a cells and after 5 days were conditioned and grafted with 5 × 106 whole bone marrow cells (BMCs). Immunocompetent mice were irradiated (700 rad) and immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice were conditioned with busulfan (2 × 25 μg g–1). (B) Tumour growth in allografted mice congenic to the tumour (H2Ka, n=19) and NOD/SCID mice (H2Kg7) grafted with whole BMCs from B6 (H2Kb, n=9) and A (H2Ka, n=7) donors.
Mentions: Tumour growth in congenic mice is limited as compared with immunocompromised mice, suggesting that Neuro-2a is submitted to immune surveillance in immunocompetent mice (Ash et al, 2009). Furthermore, transition to adaptive immunity by either syngeneic or allogeneic BMT suppressed tumour growth, suggesting that a state of immune activation is beneficial to GVH reactivity. To evaluate whether lymphopenia actually promotes GVT reactivity (Borrello et al, 2000; Hu et al, 2002), tumour growth in reconstituted NOD/SCID mice was compared with allogeneic transplants (Figure 2A): mice were implanted with subcutaneous tumours and after 5 days were conditioned and grafted with 5 × 106 allogeneic BMC. NOD/SCID mice were conditioned with busulfan, which is significantly less immunosuppressive as compared with total body irradiation (Askenasy and Farkas, 2003). Tumour growth was significantly suppressed by transplantation of allogeneic whole BMC from H2Ka and K2Kb donors into NOD/SCID mice (P<0.01, Figure 2B), consistent with avid repopulation of the lymphopenic organs. Notably, residual host immune cells are detected in lymphoid organs of allografted immunocompetent mice after myeloablative irradiation (Kaminitz et al, 2009), whereas in NOD/SCID mice the lymphoid organs were full donor (not shown). Therefore, both intrinsic lymphopenia in NOD/SCID mice and radiation-induced lymphodepletion facilitate GVT reactivity.

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