Synergistic interaction between interleukin-12 and steel factor in support of proliferation of murine lymphohematopoietic progenitors in culture

We have investigated the effects of interleukin (IL)-12 (natural killer cell stimulatory factor/cytotoxic lymphocyte maturation factor) on the proliferation of murine myeloid and lymphohematopoietic progenitors in methylcellulose culture. In the presence of erythropoietin (Ep), IL-12 alone failed to support colony formation by mononuclear and enriched marrow cells of normal mice. Steel factor (SF) alone supported primarily formation of granulocyte/macrophage (GM) colony formation. However, the combination of the two cytokines yielded a significant number of multilineage colonies. When tested on marrow cells from 5- fluorouracil (5-FU)-treated mice, the combination of IL-12 and SF, but not the single factors, was effective in support of formation of various types of colonies. Approximately 25% of these colonies yielded pre-B-cell colonies when replated in secondary culture containing SF and IL-7, indicating that IL-12 can interact with SF in supporting the development of primitive lymphohematopoietic progenitors. These results demonstrate that IL-12, a cytokine believed to be involved in the development of cell-mediated immune responses, has a wider range of activity, including committed myeloid and multipotent lymphohematopoietic progenitors.

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Synergistic interaction between interleukin-12 and steel factor in support of proliferation of murine lymphohematopoietic progenitors in culture

Blood ◽

10.1182/blood.v83.1.92.92 ◽

1994 ◽

Vol 83 (1) ◽

pp. 92-98 ◽

Cited By ~ 58

Author(s):

F Hirayama ◽

N Katayama ◽

S Neben ◽

D Donaldson ◽

EB Nickbarg ◽

...

Keyword(s):

Immune Responses ◽

Colony Formation ◽

Killer Cell ◽

Interleukin 12 ◽

Cytotoxic Lymphocyte ◽

Steel Factor ◽

Maturation Factor ◽

Secondary Culture ◽

Stimulatory Factor ◽

Marrow Cells

Abstract We have investigated the effects of interleukin (IL)-12 (natural killer cell stimulatory factor/cytotoxic lymphocyte maturation factor) on the proliferation of murine myeloid and lymphohematopoietic progenitors in methylcellulose culture. In the presence of erythropoietin (Ep), IL-12 alone failed to support colony formation by mononuclear and enriched marrow cells of normal mice. Steel factor (SF) alone supported primarily formation of granulocyte/macrophage (GM) colony formation. However, the combination of the two cytokines yielded a significant number of multilineage colonies. When tested on marrow cells from 5- fluorouracil (5-FU)-treated mice, the combination of IL-12 and SF, but not the single factors, was effective in support of formation of various types of colonies. Approximately 25% of these colonies yielded pre-B-cell colonies when replated in secondary culture containing SF and IL-7, indicating that IL-12 can interact with SF in supporting the development of primitive lymphohematopoietic progenitors. These results demonstrate that IL-12, a cytokine believed to be involved in the development of cell-mediated immune responses, has a wider range of activity, including committed myeloid and multipotent lymphohematopoietic progenitors.

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Cooperation of Natural Killer Cell Stimulatory Factor/Interleukin-12 with Other Stimuli in the Induction of Cytokines and Cytotoxic Cell-Associated Molecules in Human T and NK Cells

Cellular Immunology ◽

10.1006/cimm.1994.1192 ◽

1994 ◽

Vol 156 (2) ◽

pp. 480-492 ◽

Cited By ~ 98

Author(s):

Miguel Aste-Amezaga ◽

Annalisa D'Andrea ◽

Marek Kubin ◽

Giorgio Trinchieri

Keyword(s):

Natural Killer Cell ◽

Nk Cells ◽

Natural Killer ◽

Killer Cell ◽

Interleukin 12 ◽

Cytotoxic Cell ◽

Stimulatory Factor

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Human Alveolar Macrophages Augment Natural Killer Cell Stimulatory Factor (Interleukin-12)-inducible Killer Activity from Autologous Blood Lymphocytes

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1995.tb02991.x ◽

1995 ◽

Vol 86 (1) ◽

pp. 81-87 ◽

Cited By ~ 5

Author(s):

Takashi Haku ◽

Saburo Sone ◽

Roustem Nabioullin ◽

Takeshi Ogura

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Alveolar Macrophages ◽

Autologous Blood ◽

Killer Cell ◽

Interleukin 12 ◽

Killer Activity ◽

Blood Lymphocytes ◽

Human Alveolar Macrophages ◽

Stimulatory Factor

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Natural killer cell stimulatory factor (NKSF) or interleukin-12 is a key regulator of immune response and inflammation

Progress in Growth Factor Research ◽

10.1016/0955-2235(92)90016-b ◽

1992 ◽

Vol 4 (4) ◽

pp. 355-368 ◽

Cited By ~ 105

Author(s):

Giorgio Trinchieri ◽

Maria Wysocka ◽

Annalisa D'Andrea ◽

Manthrasalam Rengaraju ◽

Miguel Aste-Amezaga ◽

...

Keyword(s):

Immune Response ◽

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Interleukin 12 ◽

Stimulatory Factor

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Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells

European Journal of Immunology ◽

10.1002/eji.1830230814 ◽

1993 ◽

Vol 23 (8) ◽

pp. 1826-1830 ◽

Cited By ~ 89

Author(s):

Jihed Chehimi ◽

Nicholas M. Valiante ◽

Annalisa D'Andrea ◽

Manthrasalam Rengaraju ◽

Zenaida Rosado ◽

...

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Killer Cell ◽

Interleukin 12 ◽

Enhancing Effect ◽

Infected Cells ◽

Stimulatory Factor

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Induction Mechanism of Human Blood CD8+T Cell Proliferation and Cytotoxicity by Natural Killer Cell Stimulatory Factor (Interleukin-12)

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1994.tb02958.x ◽

1994 ◽

Vol 85 (8) ◽

pp. 853-861 ◽

Cited By ~ 12

Author(s):

Roustem Nabioullin ◽

Saburo Sone ◽

Akihiko Nil ◽

Takashi Haku ◽

Takeshi Ogura

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Natural Killer Cell ◽

Human Blood ◽

Killer Cell ◽

Cd8 T Cell ◽

T Cell Proliferation ◽

Interleukin 12 ◽

Induction Mechanism ◽

Stimulatory Factor

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Cytotoxic lymphocyte maturation factor (interleukin 12) is a synergistic growth factor for hematopoietic stem cells.

Journal of Experimental Medicine ◽

10.1084/jem.178.2.413 ◽

1993 ◽

Vol 178 (2) ◽

pp. 413-418 ◽

Cited By ~ 74

Author(s):

S E Jacobsen ◽

O P Veiby ◽

E B Smeland

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Growth Factor ◽

Hematopoietic Stem Cells ◽

Progenitor Cells ◽

Synergistic Effects ◽

Interleukin 12 ◽

Cytotoxic Lymphocyte ◽

Hematopoietic Stem ◽

Maturation Factor

The recently cloned cytotoxic lymphocyte maturation factor (interleukin 12 [IL-12]) has been described as a growth factor for mature lymphocytes. The present study investigated whether purified recombinant murine IL-12 (rMuIL-12) also could affect the proliferation of primitive bone marrow progenitor cells. Using a population of Lin-Sca-1+ murine bone marrow stem cells, we now demonstrate that IL-12 is a potent synergistic factor for primitive hematopoietic stem cells. The synergy of IL-12 was observed in single-cell cloning assays, demonstrating that its effects are directly mediated. Specifically, IL-12 enhanced stem cell factor-induced myelopoiesis of Lin-Sca-1+ cells sevenfold, and synergized with colony-stimulating factors (CSFs) to induce proliferation of Lin-Sca-1+ stem cells. IL-12 increased the number of responding progenitor cells as well as the size of the colonies formed. IL-12 also increased colony formation of high proliferative potential colony-forming cells with multiple CSF combinations. The effects of IL-12 were concentration dependent with a 50% effective dose of 2-20 and 20-200 ng/ml, resulting in maximum stimulation. Furthermore, a neutralizing anti-IL-12 antibody blocked the synergistic effects of rMuIL-12. In addition, IL-12 was found to have synergistic effects on more committed bone marrow progenitors as well. Our results therefore suggest that in addition to being a potent lymphopoietic stimulator, IL-12 is a regulator of the growth of hematopoietic stem cells and their myeloid progeny.

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Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1387 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1387-1398 ◽

Cited By ~ 744

Author(s):

A D'Andrea ◽

M Rengaraju ◽

N M Valiante ◽

J Chehimi ◽

M Kubin ◽

...

Keyword(s):

Cell Lines ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Killer Cell ◽

Interleukin 12 ◽

Lymphoblastoid Cell Lines ◽

Peripheral Blood Mononuclear ◽

Ifn Gamma ◽

Blood Mononuclear Cells ◽

Stimulatory Factor

Natural killer cell stimulatory factor (NKSF), or interleukin 12 (IL-12), is a 70-kD heterodimeric cytokine composed of two covalently linked chains, p40 and p35. NKSF/IL-12 has multiple effects on T and NK cells and was originally identified and purified from the supernatant fluid of Epstein-Barr virus (EBV)-transformed human B lymphoblastoid cell lines. We have produced a panel of monoclonal antibodies against both chains of NKSF/IL-12. Some of these antibodies have neutralizing activity, and several combinations of them have been used to establish sensitive radioimmunoassays detecting the free p40 chain, the free p35 chain, or the p70 heterodimer. Using these reagents, we have determined that most EBV-transformed human B lymphoblastoid cell lines constitutively produce low levels of the p70 heterodimer and an excess of the free p40 chain, whereas Burkitt lymphoma-derived, T, myeloid, and many solid tumor-derived cell lines produce neither. Production of both p40 and p70 is increased several-fold upon stimulation of the EBV-transformed cell lines with phorbol diesters. The ability of supernatant fluids from unstimulated and phorbol diester-stimulated cell lines to induce interferon gamma (IFN-gamma) production from T and NK cells, one of the effects of NKSF/IL-12, parallels the levels of production of the p70 heterodimer, known to be the biologically active form of NKSF/IL-12. Staphylococcus aureus Cowan I strain (SAC) and other stimuli induce accumulation of p40 mRNA and production of both p40 and p70 by peripheral blood mononuclear cells (PBMC). The producer cells appear to include both adherent cells and nonadherent lymphocytes, possibly B cells. The supernatant fluids from SAC-stimulated PBMC mediate the typical functions of NKSF/IL-12 (i.e., IFN-gamma induction, mitogenic effects on T/NK blasts, enhancement of NK cell cytotoxicity) at concentrations of p70 similar to those at which recombinant NKSF/IL-12 mediates the same functions. Moreover, these activities are significantly inhibited by anti-NKSF/IL-12 antibodies. The neutralizing anti-NKSF/IL-12 antibodies also inhibit 85% of the IFN-gamma production in response to SAC, an NKSF/IL-12 inducer, and approximately 50% of the IFN-gamma production in response to non-NKSF/IL-12-inducers such as IL-2, phytohemagglutinin, and anti-CD3 antibodies. These results indicate that induced or constitutively produced NKSF/IL-12 has a major role in facilitating IFN-gamma production by peripheral blood lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

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Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

Nature Communications ◽

10.1038/s41467-021-21497-6 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Cheng-Tao Jiang ◽

Kai-Ge Chen ◽

An Liu ◽

Hua Huang ◽

Ya-Nan Fan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Noncovalent Interactions ◽

Killer Cell ◽

Antibody Immobilization ◽

Effector Cells ◽

Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

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