In medicine, physicians adopt different therapeutic strategies for different types of disorders. For some diseases, the goal is simply to provide symptomatic relief until the body has had enough time to heal (such as in the case of the common cold). In other diseases, the goal is to eliminate the agents that cause pathology (such as with the use of antibiotics in bacterial infections).
Systemic mastocytosis is a rare and potentially life-threatening disease in which mast cells are activated to an excessive degree. In light of this, Valent and colleagues proposed in the Journal of Allergy and Clinical Immunology a novel strategy to combat this disease: eradicating mast cells altogether.
“Especially in patients with both [mast cell activation syndrome] and systemic mastocytosis, where the numbers of [mast cells] are excessively elevated, a reduction in or eradication of [mast cells] could be a highly effective therapeutic maneuver,” they wrote.
Let’s explore the merits of this strategy.
The Many Roles of Mast Cells
Mast cells are most associated with inflammation, and mouse model studies have revealed they are activated in a number of inflammatory responses. In the Annual Review of Immunology, Galli and colleagues labeled mast cells as “ancient components of inflammation.”
We have known for several decades that mast cells also play a particularly important role in allergies. For example, they are implicated in allergic rhinitis, urticaria, bronchial asthma, and atopic dermatitis.
In addition, medical researchers have discovered mast cells may also play a role in tumor initiation and growth. Mast cells have also been discovered to be activated in some cases by bacterial and viral proteins.
Hence, “the spectrum of diseases in which mast cells and their mediators have been implicated has extended to include bacterial, fungal, viral, and helminth infections; several diseases of the cardiovascular and gastrointestinal systems; and the joints,” Varricchi and Marone wrote in the International Journal of Molecular Sciences.
Read more about systemic mastocytosis etiology
Scientists have observed that mast cells change in numbers and distribution during a number of immune responses. They are known to have a key role in host defense by inducing resistance to certain venoms, and they are important in suppressing severe immune responses.
This, we know that mast cells participate in both disease prevention and disease activation. Varricchi and Marone wrote, “We would like to speculate that such different, sometimes opposite effects of mast cells are made possible by the plurality of mast cell subpopulations.” There remains a great deal we do not understand about mast cells.
Mast Cell Eradication
Let’s return to the proposal by Valent et al to eradicate mast cells to treat mast cell activation disorders. If we accept the hypothesis that this strategy works, what therapeutic tools do we have to accomplish this end?
Scientists have known that the tyrosine kinase receptor KIT and the KIT ligand have an important part in the growth and maturation of tissue mast cells. Mast cells can survive for a relatively long amount of time (months or years) in local tissue microenvironments. A number of cytokines are also known to promote mast cell maturation.
The good news is that we already have KIT-blocking therapies, such as imatinib. All KIT-blocking drugs suppress KIT-dependent mast cell activation and mediator secretion.
So would a KIT-targeting drug be efficacious in eradicating mast cells? The answer is we still do not know for sure. Valent and colleagues wrote, “To date, little is known about the ability of KIT-targeting drugs to reduce or even eradicate normal [mast cells] and their progenitors in patients.”
Read more about systemic mastocytosis treatment
However, studies have indicated that mast cells can be completely eradicated by a KIT inhibitor (such as imatinib) when administered for at least 24 months. We still do not know why it takes so long, but scientists have discovered that a 12-month administration of a KIT inhibitor merely reduces the number of mast cells.
An Untested Therapeutic Approach
It must also be noted that this novel proposal for tackling mast cell activation disorders is largely untested.
Studies investigating the use of KIT inhibitors in asthma patients found certain clinical benefits associated with these medications, such as the reduced need for oral corticosteroid therapy. “To date however, long-term results are lacking,” Valent and colleagues wrote.
This means a few important questions remain unanswered. Are KIT inhibitors safe in the long term? Are allergic disorders and systemic mastocytosis strictly dependent on mast cells? Given the important immune functions of mast cells, is their long-term elimination counterproductive?
More research needs to be conducted in order for physicians to have the confidence to pursue the strategy of mast cell eradication for the purpose of treating mast cell activation disorders.
“After 140 years from their discovery, mast cells remain fascinating but still elusive cells of the immune system, Varricchi and Marone wrote. “The characterization of subpopulations of mast cells . . . will be of paramount importance to modulate the injury- or repair-inducing abilities of these immune cells.”
Varricchi G, Marone G. Mast cells: fascinating but still elusive after 140 years from their discovery. Int J Mol Sci. 2020;21(2):464. doi:10.3390/ijms21020464
Galli SJ, Gaudenzio N, Tsai M. Mast cells in inflammation and disease: recent progress and ongoing concerns. Annu Rev Immunol. 2020;38:49-77. doi:10.1146/annurev-immunol-071719-094903
Valent P, Akin C, Hartmann K, et al. Drug-induced mast cell eradication: a novel approach to treat mast cell activation disorders? J Allergy Clin Immunol. 2022;S0091-6749(22)00451-1. doi:10.1016/j.jaci.2022.04.003