Faculty Opinions recommendation of A Macrophage Colony-Stimulating-Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence.

PURPOSE: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein. PATIENTS AND METHODS: Sixty-four patients with HER-2/neu–overexpressing breast, ovarian, or non–small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled. RESULTS: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein–specific T-cell immunity (P = .03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. CONCLUSION: The majority of patients with HER-2/neu–overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

Download Full-text

Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.93.20.10972 ◽

1996 ◽

Vol 93 (20) ◽

pp. 10972-10977 ◽

Cited By ~ 174

Author(s):

L. W. Kwak ◽

H. A. Young ◽

R. W. Pennington ◽

S. D. Weeks

Keyword(s):

T Cell ◽

Cell Response ◽

T Cell Response ◽

Colony Stimulating Factor ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Download Full-text

Macrophage colony-stimulating factor (CSF-1) gene expression in human T- lymphocyte clones

Blood ◽

10.1182/blood.v77.4.780.780 ◽

1991 ◽

Vol 77 (4) ◽

pp. 780-786 ◽

Cited By ~ 16

Author(s):

MM Hallet ◽

V Praloran ◽

H Vie ◽

MA Peyrat ◽

G Wong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Phenotypic Diversity ◽

Calcium Ionophore ◽

Colony Stimulating Factor ◽

T Cell Clones ◽

Cell Clones ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract Macrophage colony stimulating factor (CSF-1) is one of several cytokines that control the differentiation, survival, and proliferation of monocytes and macrophages. A set of 11 human T-cell clones, chosen for their phenotypic diversity, were tested for their ability to express CSF-1 mRNA. After 5 hours of stimulation with phorbol myristate acetate (PMA) + calcium ionophore (Cal), all T-cell clones expressed a major 4-kb transcript, a less abundant 2-kb transcript, and several other minor species. This pattern of expression is typical for CSF-1 mRNAs. Furthermore, of the two alloreactive T-cell clones analyzed, only one showed a definitive message for CSF-1 on specific antigenic stimulation, but with delayed kinetics and less efficiency. Both conditions of stimulation induced the release of CSF-1 protein by T cells in the culture medium. Together, these findings demonstrate for the first time that normal T cells are able to produce CSF-1, previous reports being limited to two cases of tumoral cells of the T-cell lineage.

Download Full-text

NF-kappa B as inducible transcriptional activator of the granulocyte-macrophage colony-stimulating factor gene.

Molecular and Cellular Biology ◽

10.1128/mcb.10.3.1281 ◽

1990 ◽

Vol 10 (3) ◽

pp. 1281-1286 ◽

Cited By ~ 131

Author(s):

R Schreck ◽

P A Baeuerle

Keyword(s):

T Cells ◽

Transcription Factor ◽

T Cell ◽

Interleukin 2 ◽

Colony Stimulating Factor ◽

Nf Kappa B ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

The expression of the gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) is induced upon activation of T cells with phytohemagglutinin and active phorbolester and upon expression of tax1, a transactivating protein of the human T-cell leukemia virus type I. The same agents induce transcription from the interleukin-2 receptor alpha-chain and interleukin-2 genes, depending on promoter elements that bind the inducible transcription factor NF-kappa B (or an NF-kappa B-like factor). We therefore tested the possibility that the GM-CSF gene is also regulated by a cognate motif for the NF-kappa B transcription factor. A recent functional analysis by Miyatake et al. (S. Miyatake, M. Seiki, M. Yoshida, and K. Arai, Mol. Cell. Biol. 8:5581-5587, 1988) described a short promoter region in the GM-CSF gene that conferred strong inducibility by T-cell-activating signals and tax1, but no NF-kappa B-binding motifs were identified. Using electrophoretic mobility shift assays, we showed binding of purified human NF-kappa B and of the NF-kappa B activated in Jurkat T cells to an oligonucleotide comprising the GM-CSF promoter element responsible for mediating responsiveness to T-cell-activating signals and tax1. As shown by a methylation interference analysis and oligonucleotide competition experiments, purified NF-kappa B binds at positions -82 to -91 (GGGAACTACC) of the GM-CSF promoter sequence with an affinity similar to that with which it binds to the biologically functional kappa B motif in the beta interferon promoter (GGGAAATTCC). Two kappa B-like motifs at positions -98 to -108 of the GM-CSF promoter were also recognized but with much lower affinities. Our data provide strong evidence that the expression of the GM-CSF gene following T-cell activation is controlled by binding of the NF-kappa B transcription factor to a high-affinity binding site in the GM-CSF promoter.

Download Full-text

Enhanced expression of the granulocyte-macrophage colony stimulating factor gene in acute myelocytic leukemia cells following in vitro blast cell enrichment

Blood ◽

10.1182/blood.v72.4.1329.bloodjournal7241329 ◽

1988 ◽

Vol 72 (4) ◽

pp. 1329-1332 ◽

Cited By ~ 1

Author(s):

DC Kaufman ◽

MR Baer ◽

XZ Gao ◽

ZQ Wang ◽

HD Preisler

Keyword(s):

T Cell ◽

Leukemic Cells ◽

Acute Myelocytic Leukemia ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Myelocytic Leukemia ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Expression of the granulocyte-macrophage colony-stimulating factor (GM- CSF) gene in acute myelocytic leukemia (AML) was assayed by Northern blot analysis. GM-CSF messenger RNA (mRNA) was detected in the freshly obtained mononuclear cells of only one of 48 cases of AML, in contrast with recent reports that GM-CSF mRNA might be detected in half of the cases of AML when RNA is prepared from T-cell- and monocyte-depleted leukemic cells. We did find, however, that expression of the GM-CSF gene was detectable in five of ten cases after in vitro T-cell and monocyte depletion steps. Additional studies suggest that expression of GM-CSF in the bone marrow of the one positive case, rather than being autonomous, was under exogenous control, possibly by a paracrine factor secreted by marrow stromal cells. These studies emphasize the potential for altering in vivo patterns of gene expression by in vitro cell manipulation.

Download Full-text

Enhanced survival but reduced engraftment in murine recipients of recombinant granulocyte/macrophage colony-stimulating factor following transplantation of T-cell-depleted histoincompatible bone marrow

Blood ◽

10.1182/blood.v72.4.1148.1148 ◽

1988 ◽

Vol 72 (4) ◽

pp. 1148-1154 ◽

Cited By ~ 15

Author(s):

BR Blazar ◽

MB Widmer ◽

CC Soderling ◽

S Gillis ◽

DA Vallera

Keyword(s):

Bone Marrow ◽

T Cell ◽

Hematological Parameters ◽

Donor Cell ◽

Colony Stimulating Factor ◽

Murine Bone Marrow ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Abstract In vivo administration of murine recombinant granulocyte/macrophage colony stimulating factor (rGM-CSF) was evaluated for effects on survival and engraftment in an allogeneic murine bone marrow transplantation (BMT) model involving T-cell depletion of donor marrow. The model provides a high incidence of graft failure/rejection. Recipients of continuous subcutaneous infusions of rGM-CSF had a significant survival advantage when compared with untreated controls. However, a significantly lower incidence of donor cell engraftment was noted. Hematological parameters were not substantially affected. When rGM-CSF was administered intraperitoneally (IP), twice daily injections closely approximated the effects of continuous infusion on survival. Single IP injections were without significant effects on survival or engraftment. These results demonstrate that prolonged frequent in vivo exposure to rGM-CSF can significantly improve survival but significantly decreases donor cell repopulation in recipients of T-cell- depleted histoincompatible marrow grafts.

Download Full-text