Reviewer ’s report  
 
Title: Baseline levels of dynamic CD4+ T cell adhesion to M AdCAM -1 correlate with clinical 
response to vedolizumab treatment in ulcerative colitis: a cohort study  
 
Version: 1 Date: 17 Nov 2019  
 
Reviewer: Michel Maillard  
 
Reviewer's report:  
In this manuscript, Allner C et al provide some e vidence on predictive factors of response to 
vedolizumab(VDZ) therapy. In an effort to identify novel biomarkers of response, they 
characterize adhesion dynamic profiles of CD4+ cells isolated from IBD patients prior to and 
after VDZ -therapy. They show tha t adhesion is higher in responder than non -responders and that 
VDZ exposure leads to a significant reduction in T cell adherence in responders. They finally 
show that α4β1 expression is also higher in responders to VDZ. Using those markers, they are 
able t o efficiently predict response with reasonable specificity and positive predictive value.  
 
This is an interesting study performed in a well —established and renowned center. It is correctly 
conducted and reported. I believe that it is worth considering for publication, provided they can 
address some of the below -listed concerns:  
 
1. The main parameter analyzed is T cell adhesion to a MadCam -coated matrix. As integrin -
ligand binding is supposedly stable, it is unclear how adhesion might increase in responders . 
Could this be related to an increased α4β7 cell surface expression? Or an increase in downstream 
signaling pathways? It would be interesting to have FACS analyses of α4β7 expression looking 
at % cell expression but also mean fluorescence intensity in the  various groups.  
2. In the same idea, T -cell exposure to VDZ was shown to efficiently reduce T -cell 
adhesion. It is however unclear whether this is related to an increase in % surface a4b7 blockade 
or to some other off -target effects. FACS analyses of α4β 7 surface binding site occupancy could 
be interesting to better describe the mechanisms leading to reduced T -cell adhesion upon VDZ 
exposure.  
3. The authors show data on CD4+ cells, but are the data similar with other α4β7+ cell 
types? How do α4β7 - cells b ehave? Is there a clear difference with the positive subset? It needs 
to be reported as a negative control.  
 
4. As there only are two CD patients, I wonder whether it really is necessary to show the 
complete set of patients and then only the UC patients. Th e key message is the same and 
showing both analyses adds redundancy in the paper. I would try to include more CD patients 
and publish this maybe later on separately. Indeed, CD patients might actually behave differently 
but this is not addressable with 2 p atients.  
5. The α4β1 data comes a bit "out of nowhere" as an additional data put together. It would 
be interesting to try to merge the two datasets and provide some triple stainings with α4, β7 and 
β1. It would address whether α4β7 low cells are indeed α4β1 high.  
 
Minor points  
1. Figure resolution is too low. It might be related to uploading problems.  
2. Figure legends could be improved and mention the number of experiments done, the 
number of subjects and the statistics used.  
3. Figure 4. I don't see the schematic depiction of vedolizumab treatment but only FACS 
profiles and graphs.  
4. Table 1: Smoking status should be reported as well as past surgery and prior biological 
therapies. Where they exposed to anti -TNFs before VDZ?  
5. Table 2 is redundant with the text. E ither you leave the table and don't mention all 
numbers in the text or vice versa.  
6. I believe the manuscript needs some proof -reading for English mistakes/typos  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your c omments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in y our comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publi cation of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named repo rt 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understan d that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Baseline levels of dynamic CD4+ T cell adhesion to M AdCAM -1 correlate with clinical 
response to vedolizumab treatment in ulcerative colitis: a cohort study  
 
Version: 1 Date: 17 Nov 2019  
 
Reviewer: Michel Maillard  
 
Reviewer's report:  
In this manuscript, Allner C et al provide some e vidence on predictive factors of response to 
vedolizumab(VDZ) therapy. In an effort to identify novel biomarkers of response, they 
characterize adhesion dynamic profiles of CD4+ cells isolated from IBD patients prior to and 
after VDZ -therapy. They show tha t adhesion is higher in responder than non -responders and that 
VDZ exposure leads to a significant reduction in T cell adherence in responders. They finally 
show that α4β1 expression is also higher in responders to VDZ. Using those markers, they are 
able t o efficiently predict response with reasonable specificity and positive predictive value.  
 
This is an interesting study performed in a well —established and renowned center. It is correctly 
conducted and reported. I believe that it is worth considering for publication, provided they can 
address some of the below -listed concerns:  
 
1. The main parameter analyzed is T cell adhesion to a MadCam -coated matrix. As integrin -
ligand binding is supposedly stable, it is unclear how adhesion might increase in responders . 
Could this be related to an increased α4β7 cell surface expression? Or an increase in downstream 
signaling pathways? It would be interesting to have FACS analyses of α4β7 expression looking 
at % cell expression but also mean fluorescence intensity in the  various groups.  
2. In the same idea, T -cell exposure to VDZ was shown to efficiently reduce T -cell 
adhesion. It is however unclear whether this is related to an increase in % surface a4b7 blockade 
or to some other off -target effects. FACS analyses of α4β 7 surface binding site occupancy could 
be interesting to better describe the mechanisms leading to reduced T -cell adhesion upon VDZ 
exposure.  
3. The authors show data on CD4+ cells, but are the data similar with other α4β7+ cell 
types? How do α4β7 - cells b ehave? Is there a clear difference with the positive subset? It needs 
to be reported as a negative control.  
 
4. As there only are two CD patients, I wonder whether it really is necessary to show the 
complete set of patients and then only the UC patients. Th e key message is the same and 
showing both analyses adds redundancy in the paper. I would try to include more CD patients 
and publish this maybe later on separately. Indeed, CD patients might actually behave differently 
but this is not addressable with 2 p atients.  
5. The α4β1 data comes a bit "out of nowhere" as an additional data put together. It would 
be interesting to try to merge the two datasets and provide some triple stainings with α4, β7 and 
β1. It would address whether α4β7 low cells are indeed α4β1 high.  
 
Minor points  
1. Figure resolution is too low. It might be related to uploading problems.  
2. Figure legends could be improved and mention the number of experiments done, the 
number of subjects and the statistics used.  
3. Figure 4. I don't see the schematic depiction of vedolizumab treatment but only FACS 
profiles and graphs.  
4. Table 1: Smoking status should be reported as well as past surgery and prior biological 
therapies. Where they exposed to anti -TNFs before VDZ?  
5. Table 2 is redundant with the text. E ither you leave the table and don't mention all 
numbers in the text or vice versa.  
6. I believe the manuscript needs some proof -reading for English mistakes/typos  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your c omments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in y our comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publi cation of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named repo rt 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understan d that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Baseline levels of dynamic CD4+ T cell adhesion to M AdCAM -1 correlate with clinical 
response to vedolizumab treatment in ulcerative colitis: a cohort study  
 
Version: 1 Date: 17 Nov 2019  
 
Reviewer: Michel Maillard  
 
Reviewer's report:  
In this manuscript, Allner C et al provide some e vidence on predictive factors of response to 
vedolizumab(VDZ) therapy. In an effort to identify novel biomarkers of response, they 
characterize adhesion dynamic profiles of CD4+ cells isolated from IBD patients prior to and 
after VDZ -therapy. They show tha t adhesion is higher in responder than non -responders and that 
VDZ exposure leads to a significant reduction in T cell adherence in responders. They finally 
show that α4β1 expression is also higher in responders to VDZ. Using those markers, they are 
able t o efficiently predict response with reasonable specificity and positive predictive value.  
 
This is an interesting study performed in a well —established and renowned center. It is correctly 
conducted and reported. I believe that it is worth considering for publication, provided they can 
address some of the below -listed concerns:  
 
1. The main parameter analyzed is T cell adhesion to a MadCam -coated matrix. As integrin -
ligand binding is supposedly stable, it is unclear how adhesion might increase in responders . 
Could this be related to an increased α4β7 cell surface expression? Or an increase in downstream 
signaling pathways? It would be interesting to have FACS analyses of α4β7 expression looking 
at % cell expression but also mean fluorescence intensity in the  various groups.  
2. In the same idea, T -cell exposure to VDZ was shown to efficiently reduce T -cell 
adhesion. It is however unclear whether this is related to an increase in % surface a4b7 blockade 
or to some other off -target effects. FACS analyses of α4β 7 surface binding site occupancy could 
be interesting to better describe the mechanisms leading to reduced T -cell adhesion upon VDZ 
exposure.  
3. The authors show data on CD4+ cells, but are the data similar with other α4β7+ cell 
types? How do α4β7 - cells b ehave? Is there a clear difference with the positive subset? It needs 
to be reported as a negative control.  
 
4. As there only are two CD patients, I wonder whether it really is necessary to show the 
complete set of patients and then only the UC patients. Th e key message is the same and 
showing both analyses adds redundancy in the paper. I would try to include more CD patients 
and publish this maybe later on separately. Indeed, CD patients might actually behave differently 
but this is not addressable with 2 p atients.  
5. The α4β1 data comes a bit "out of nowhere" as an additional data put together. It would 
be interesting to try to merge the two datasets and provide some triple stainings with α4, β7 and 
β1. It would address whether α4β7 low cells are indeed α4β1 high.  
 
Minor points  
1. Figure resolution is too low. It might be related to uploading problems.  
2. Figure legends could be improved and mention the number of experiments done, the 
number of subjects and the statistics used.  
3. Figure 4. I don't see the schematic depiction of vedolizumab treatment but only FACS 
profiles and graphs.  
4. Table 1: Smoking status should be reported as well as past surgery and prior biological 
therapies. Where they exposed to anti -TNFs before VDZ?  
5. Table 2 is redundant with the text. E ither you leave the table and don't mention all 
numbers in the text or vice versa.  
6. I believe the manuscript needs some proof -reading for English mistakes/typos  
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your c omments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in y our comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publi cation of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you curr ently applying for any patents  relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any  other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named repo rt 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understan d that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant