Mast Cells as a Target—A Comprehensive Review of Recent Therapeutic Approaches

Round 1

Reviewer 1 Report

The review by Baran et al. is an interesting overview of recent therapeutic approaches involved in mast cell activities. The authors describe potential therapies targeting mast cells in different context such as mast cell degranulation, anaphylaxis, and tumors. I have some specific comments that I would like to see addressed.

 

Major comments:

1.             Readers of this review article would be highly benefited if authors could include tables summarising the:

1. Inhibitor of mast cell degranulation

2. Mast cell therapeutic target in allergic inflammation

And 3.Mast cell targeted strategies in cancer therapy

Table columns could include - a) name of the drug, b) origin or family of the drug molecule, c) Target, d) Results, d) Disease, animal or cell model, c) references

 

2.             Line 34-35: “MCs are derived from multipotential stem cells in the bone marrow”. They are several publication demonstrating the dual developmental origin of tissue specific Mast Cells namely yolk sac and bone marrow. Please could you add those findings in the text.

3.             Figure 1A. Please add C3aR in the GPCRs group. Complement component C3a activates human mast cells via its cell surface G protein coupled receptor (GPCR) C3aR.

4.             Line 82: “Mast cell degranulation can be monitored via various assays”. In many studies, Mast cell degranulation is assessed by flow cytometry. Please include this technic in addition to ELISA or colorimetric assays. Same comments for the line 481.

5.             Line 259: “Mast cells are the first cells that are responding to IgE-mediated anaphylaxis”. Basophils are also on the effector cell to respond to IgE. Please rephrase.

6.             Line 395-396: “growing number of clinical studies have associated high TAMC numbers with tumor progression and worse prognosis in patients”. Mast cell play a role in melanoma as well, recent studies showed that human melanoma-associated Mast cells characterized by an upregulation of the complement component 3 correlates With Poor Prognosis. Please add this findings to your text.

7.             Line 490: Here, the authors should discuss the results observed using the compounds, many of the studies were done in RBL cells, mouse models. What is relevant for humans, please comment.

 

Minor points:

Figure 2B: The antihistamines is difficult to read because of the blue background: Please change the color.

Line 181: “IFN gamma and TNF “. Please specify which TNF.

Line 260: “orplants” please check spelling

Line 342:  “[58, s. 2].” Please check the reference s.2.

Author Response

Reviewer no 1:

We thank the Reviewer for taking the time to review our manuscript. We believe that the Reviewer’s valuable input has made our manuscript better and it will help us communicate with the potential readers more clearly. We have addressed Reviewer’s comments in the following point-by-point answers. In the revised manuscript, we have marked the texts in red where changes were made based on the Reviewers’ suggestions.

Major comments:

1. Readers of this review article would be highly benefited if authors could include tables summarising the:
2. Inhibitor of mast cell degranulation
3. Mast cell therapeutic target in allergic inflammation

And 3. Mast cell targeted strategies in cancer therapy

Table columns could include - a) name of the drug, b) origin or family of the drug molecule, c) Target, d) Results, d) Disease, animal or cell model, c) references

Thank you for this suggestion, the tables have been prepared as the Reviewer recommended.

• Table 1. Compounds and drugs inhibiting mast cell degranulation.
• Table 2. Drugs for anaphylactic shock treatment.
• Table 3. Mast cell targeted strategies in cancer therapy.

In each table, the following topics were raised: Name of the drug; Origin or family of the drug molecule; Target, Disease, animal or cell model; References.

 

These tables summarize the described examples of drug/compound application from each subsection and the main result, in each example, was the inhibition of mast cell degranulation. As the treatment results (for example, decreased production of a particular mediator) are in detail described in these sections, we have excluded the ‘Results column’ from the table as it would be a repetition of the same text and the tables would be less readable due to the available space in columns.

Despite this minor change to the Reviewer's proposal, we hope that the prepared tables fulfill their task and well summarize the presented examples.

 

2. Line 34-35: “MCs are derived from multipotential stem cells in the bone marrow”. They are several publication demonstrating the dual developmental origin of tissue specific Mast Cells namely yolk sac and bone marrow. Please could you add those findings in the text.

Thank you for pointing this out. This information was added to the article with a proper citation (Gentek et al. 2018, Immunity 48, 1160–1171).

 

3. Figure 1A. Please add C3aR in the GPCRs group. Complement component C3a activates human mast cells via its cell surface G protein coupled receptor (GPCR) C3aR.

Thank you for this suggestion. Figure 1A was corrected according to the Reviewer's recommendation (C3aR was added to the GPCRs group).

 

4. Line 82: “Mast cell degranulation can be monitored via various assays”. In many studies, Mast cell degranulation is assessed by flow cytometry. Please include this technic in addition to ELISA or colorimetric assays. Same comments for the line 481.

We thank the Reviewer for drawing our attention to this important method. The relevant fragment was added to the article.

“Mast cell degranulation can be monitored via various assays, including ELISA tests, flow cytometry, or colorimetric assays. (…) With flow cytometry, three approaches to detect mast cell degranulation predominate: detecting the appearance or up-regulation of surface biomarkers (e.g. CD63 and CD107a), measuring changes in the mediator content (like histamine, chemokine (C-C motif) ligand 4 (CCL4) and chemokine (C-X-C motif) ligand 8 (CXCL8)), and staining of intracellular calcium ions. To enable the detection of degranulating cells in this method, fluorescently labeled antibodies or other labeled compounds with fluorochromes must be applied (Elst et al. 2021). (…) The main difference between these methods is associated with the number of received information about the degranulating cells. The flow cytometry can show individual cells undergoing degranulation, whereas ELISA tests, as well as the colorimetric assays focus on the average cells.”

 

5. Line 259: “Mast cells are the first cells that are responding to IgE-mediated anaphylaxis”. Basophils are also on the effector cell to respond to IgE. Please rephrase.

This part of the text was rephrased according to the Reviewer’s suggestion.

“Mast cells together with basophils are the first cells that are responding to IgE-mediated anaphylaxis.”

 

6. Line 395-396: “growing number of clinical studies have associated high TAMC numbers with tumor progression and worse prognosis in patients”. Mast cell play a role in melanoma as well, recent studies showed that human melanoma-associated Mast cells characterized by an upregulation of the complement component 3 correlates With Poor Prognosis. Please add this findings to your text.

The findings were added to the manuscript according to the Reviewer’s recommendation.

“Furthermore, recent studies showed that human melanoma-associated Mast Cells characterized by an upregulation of the complement component C 3 correlates with poor prognosis [https://doi.org/10.3389/fimmu.2022.861545]”

 

7. Line 490: Here, the authors should discuss the results observed using the compounds, many of the studies were done in RBL cells, mouse models. What is relevant for humans, please comment.

We thank the Reviewer for this suggestion. The relevant fragment was added to the article.

“Several types of models can be applied for the investigation of mast cell degranulation. The in vitro studies include primary human and animal mast cells from the skin, the bone marrow-derived mast cells (BMMCs) or the peripheral blood mononuclear cells (PBMCs), as well as human and animal commercial cell lines (Baran et al. 2022, Journal of Current Science and Technology, 12, 3, 592-604). During the in vivo studies, the most popular organisms are mice, rats, and pigs. However, as several studies presented results on different models may significantly differ. The same compound/drug may inhibit mast cell degranulation in one model but not in another model (Piasek and Sobiepanek et al. 2023, in book CANNABIS, CANNABINOIDS AND ENDOCANNABINOIDS, Academic Press). Thus, it is important to check the influence of potential drugs on various models.”

 

 

Minor points:

Figure 2B: The antihistamines is difficult to read because of the blue background: Please change the color.

Line 181: “IFN gamma and TNF “. Please specify which TNF.

Line 260: “orplants” please check spelling

Line 342:  “[58, s. 2].” Please check the reference s.2.

All minor suggestions and corrections were introduced in the revised manuscript.

 

 

 

We thank the Reviewer for taking the time to review our manuscript. All mistakes were changed in the revised manuscript.

 

Reviewer 2 Report

This proposed review focuses on the possible therapies connected to overactivity and pathological states of mast cells and current drugs presenting activity towards them. Thus, the review is structured around 6 topics: 1) Introduction about mast cells; 2) Mast cells’ receptors and mediators including Figure 1 that shows didactically several types of receptors and coreceptors on mast cell surface; 3) Mast cells degranulation and its inhibitors with the Figure 2 that illustrates this aspect in a good way to understand; 4) Mast cells as a therapeutic target in allergic inflammation with the Figure 3 about mast cells’ pathways targeted in anaphylaxis therapy; 5) Mast Cell-Targeted Strategies in Cancer Therapy; 6) Conclusions – consistent with the arguments presented. Overall, this manuscript is well written, the sections follow clearly and easy to read and includes a pertinent bibliography (106 references).

 

Minor points:

 

-          Page 10, line 393: check spelling errors on sentence “…with o poor clinical prognosis…”.

 

-          Page 11, line 421: check spelling errors on sentence “…dramatically changed the outlook of these diseases. was the first cancer…”.

 

-          Page 12, line 468: Change item 5 for 6 (Conclusions)

Author Response

Reviewer no 2

• Page 10, line 393: check spelling errors on sentence “…with o poor clinical prognosis…”.
• Page 11, line 421: check spelling errors on sentence “…dramatically changed the outlook of these diseases. was the first cancer…”.
• Page 12, line 468: Change item 5 for 6 (Conclusions).

 

We thank the Reviewer for taking the time to review our manuscript. All mistakes were changed in the revised manuscript.

Round 2

Reviewer 1 Report

The authors have satisfactorily addressed all my concerns.