Immune cell transcriptome datasets reveal novel leukocyte subset–specific genes and genes associated with allergic processes

The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.

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“…In human blood, only monocytes have been shown to express hCE-1 (Su et al, 2004;Liu et al, 2006;see Supplemental Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Drug Targeting to Monocytes and Macrophages Using Esterase-Sensitive Chemical Motifs

Needham¹,

Davidson²,

Bawden³

et al. 2011

J Pharmacol Exp Ther

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“…Complementary RNA was synthesized and amplified using biotin-labeled ribonucleotides and T7 RNA polymerase (25,26). Biotin-labeled cRNA was then hybridized to human genome U133A and B GeneChips (Affymetrix), which contain Ͼ44,000 probes sets representing ϳ39,000 transcripts.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Resting Human Memory B Cells Are Intrinsically Programmed for Enhanced Survival and Responsiveness to Diverse Stimuli Compared to Naive B Cells

Good

Avery

Tangye

2009

The Journal of Immunology

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243

241

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“…cRNA was synthesized and amplified using biotinlabeled ribonucleotides and T7 RNA polymerase (26,48,49). Biotin-labeled cRNA was then hybridized to Human Genome U133 Set GeneChips (Affymetrix), and resulting data analyzed by Affymetrix Microarray Suite software.…”

Section: Gene Expression Analysismentioning

confidence: 99%

“…Biotin-labeled cRNA was then hybridized to Human Genome U133 Set GeneChips (Affymetrix), and resulting data analyzed by Affymetrix Microarray Suite software. Heat maps were generated using Spotfire DecisionSite software (49). Gene expression profiles of cell populations were performed in duplicate from different donors.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

Good

Bryant

Tangye

2006

The Journal of Immunology

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247

237

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Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.

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Immune cell transcriptome datasets reveal novel leukocyte subset–specific genes and genes associated with allergic processes

Cited by 42 publications

References 48 publications

Drug Targeting to Monocytes and Macrophages Using Esterase-Sensitive Chemical Motifs

Drug Targeting to Monocytes and Macrophages Using Esterase-Sensitive Chemical Motifs

Resting Human Memory B Cells Are Intrinsically Programmed for Enhanced Survival and Responsiveness to Diverse Stimuli Compared to Naive B Cells

Kinetics of Human B Cell Behavior and Amplification of Proliferative Responses following Stimulation with IL-21

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