Review Article | Published:

Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases

Nature Reviews Drug Discovery volume 16, pages 5370 (2017) | Download Citation


Granulocyte–macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF; also known as CSF1), granulocyte colony-stimulating factor (G-CSF) and interleukin-3 (IL-3) can each play a part in the host response to injury and infection, and there is burgeoning interest in targeting these CSFs in inflammatory and autoimmune disorders, as well as in cancer. For success in clinical medicine, therapeutic targeting will need to be delineated from current strategies. The individual CSFs have unique biological roles, suggesting that they could be used to target specific conditions. This Review compares the CSFs, with a focus on how they could be targeted, discusses the relevant clinical trial data and summarizes the potential clinical applications of targeting each CSF. Importantly, we discuss the novelty of CSF biology and attempt to clarify some of the surrounding misconceptions and issues that can affect therapeutic decisions.

Key points

  • Colony-stimulating factors (CSFs) are pleiotropic, but each has its own unique biological role.

  • All CSFs control myeloid cell numbers, but each has a level of specificity in regard to its target cells and effects.

  • Preclinical and/or clinical data suggest that targeting granulocyte–macrophage CSF (GM-CSF), CSF1, granulocyte CSF (G-CSF) or IL-3 could be useful in the treatment of numerous autoimmune and/or inflammatory pathologies, including rheumatoid arthritis and multiple sclerosis. Further investigation of the potential of targeting CSFs in other pathologies is warranted.

  • CSF targeting, as well as associated patient stratification, should be based on the specific CSF biology.

  • There is not necessarily an inverse relationship between the effects of CSF blockade and administration of the protein itself on a particular pathology.

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The authors thank N. Wilson, A. Lopez and F. Dodeller for fruitful discussion and R. Sallay for typing the Review. J.A.H. and A.D.C. were supported in part from grants (1032147, 1085240 and 1080560) and J.A.H. by a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia.

Author information


  1. University of Melbourne, Department of Medicine at The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia

    • John A. Hamilton
    •  & Andrew D. Cook
  2. GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, UK.

    • Paul P. Tak


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Competing interests

The employer of J.A.H. and A.D.C., the University of Melbourne, has licensed technologies in this area to MorphoSys AG. P.P.T. is an employee and shareholder of GlaxoSmithKline (GSK); GSK is evaluating the efficacy and safety of GSK3196165, an investigational anti-GM-CSF antibody, in patients with rheumatoid arthritis and inflammatory hand osteoarthritis.

Corresponding author

Correspondence to John A. Hamilton.



The production of blood cells and platelets, which usually occurs in the bone marrow.

Plasmacytoid dendritic cells

(pDCs). A subset of DCs that specializes in the production of type I interferons. These cells promote antiviral immune responses and are implicated in the pathogenesis of autoimmune diseases that are characterized by a type I interferon gene expression signature.

Invariant natural killer T cells

(Also known as type I natural killer T cells). This well-characterized subset of CD1d-dependent cells expresses an invariant T cell receptor α-chain. These cells recognize lipid antigens presented by CD1d and respond rapidly to danger signals and pro-inflammatory cytokines. Once activated, they engage in multiple effector functions.

Dendritic cell

(DC). An antigen-presenting cell that processes antigen material and presents it on its cell surface to T cells as its main function within the immune system. DCs act as messengers between the innate and the adaptive immune systems.

CD103+ dendritic cells

(CD103+ DCs). A subset of the mouse DC population that is distinguished from other DCs by αE integrin expression. They can be found in many, if not all, lymphoid and non-lymphoid organs.

Myasthenia gravis

A rare, chronic autoimmune disease marked by muscle weakness due to a defect in the action of acetylcholine at neuromuscular junctions.

Experimental autoimmune encephalomyelitis

(EAE). An inflammatory, demyelinating disease of the central nervous system that is the most commonly used model for multiple sclerosis. It is also the prototype for T cell-mediated autoimmune diseases.

T helper cells

(TH cells). A type of T cell that has an important role in the immune system. They help other immune cells by releasing T cell cytokines, thereby helping to regulate immune responses. They are essential for B cell antibody class switching, the activation and growth of cytotoxic T cells and maximizing the bactericidal activity of phagocytes, such as macrophages.

FOXP3+ regulatory T cells

The transcription factor forkhead box P3 (FOXP3) serves as a lineage-specific factor of regulatory T cells, which play a central part in the negative regulation of the immune response to numerous antigens.

CD11c+MHCII+ macrophages

A population of macrophages that is usually present at sites of tissue inflammation. These cells are often called monocyte-derived dendritic cells.

Macrophage polarization

Macrophages respond to diverse microenvironmental signals that trigger different responses, thus resulting in differential polarization patterns into a spectrum of phenotypes from M1 to M2. They are classically activated towards the M1 phenotype by microbial products or interferon-γ and can thereby eradicate invading organisms and promote type I immune responses. Alternative activation by stimulation with interleukin-4 (IL-4), IL-13 or IL-10 drives macrophages towards the M2 phenotype, which is characterized by hyporesponsiveness to pro-inflammatory stimuli and involvement in processes such as debris scavenging, angiogenesis, tissue remodelling, wound healing and the promotion of type II immunity.

Pulmonary alveolar proteinosis

(PAP). A rare lung disease in which an abnormal accumulation of pulmonary surfactant occurs, thereby interfering with gas exchange.

Mononuclear phagocyte system

(MPS). Part of the immune system that consists of the phagocytic cells located in reticular connective tissue. It comprises monocytes, macrophages and dendritic cells and was formerly termed the reticuloendothelial system.

LY6C blood monocytes

A subset of mouse blood monocytes that is generally believed to be the most mature subset and contributes to the immune system through its scavenging and patrolling functions. The analogous population in humans is CD16+ monocytes.

CD16+ monocytes

The most mature subset of human blood monocytes. This population is analogous to LY6C monocytes in mice.

Csf1op/Csf1op mice

These mice have an inactive colony-stimulating factor 1 (Csf1) gene, which results in a developmental defect in several macrophage lineage populations, including osteoclasts. They have an osteopetrotic (op) phenotype.

3xTg-AD mice

Triple-transgenic mice, harbouring presenilin 1 (PSEN1; also known as PS1), amyloid-β precursor protein (APP) and microtubule-associated protein tau (MAPT) transgenes. They progressively develop amyloid-β deposition and neurofibrillary tangles as in Alzheimer disease.


The presence of abnormally few neutrophils in the blood, which leads to an increased susceptibility to infection.


An increased sensitivity to pain.

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