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: 30 Oct 2019  
 
Reviewer: Saurabh Mehandru  
 
Reviewer's report:  
In the submitted manuscript, Allner and colleagues report on identification of novel biomarkers 
in response to Vedolizumab (VDZ). To this effect, they conduct retrospective analyses  on a 
small cohort of 23 subjects with IBD (21 with UC and 2 with CD). The authors employ an in -
vitro assay, previously reported by the same group, that utilizes MAdCAM coated capillaries 
perfused with CD4+ T cells with time -lapse visualization of MAdCAM -adherent CD4+ T cells 
using confocal microscopy. Adherence of CD4+ T cells is then compared to clinical response 
following VDZ using clinical Mayo indices (for UC) and Harvey Bradshaw Index (for CD).  
The authors determine that higher frequency of MAdCAM -adherent CD4+ T cells is associated 
with clinical response to VDZ. Additionally, the authors also determine that effective inhibition 
of CD4 -MAdCAM binding also associated with better clinical response. The authors also 
quantify a4b1 integrin on circulating CD4+ T cells ex -vivo and report that non -responders to 
VDZ have a higher frequency of a4b1hi cells compared to VDZ responders. Finally, in this small 
cohort, the authors determine AUC for MAdCAM -adherent cells as a novel biomarker for 
determining VDZ -respo nse. 
 
The paper is written clearly. The premise of the study is strong - there is an unmet need for 
developing novel biomarkers to VDZ. The data provided in this manuscript should spur further 
investigation in this area and help move the field forward.  
 
In the same vein, one has to acknowledge that there are multiple short comings in this paper 
well. These include:  
1. Small cohort size  
2. Retrospective clinical analyses, failure to include rectal bleeding score (which is a good 
surrogate for disease activity  in UC)  
3. Lack of understanding regarding the range of the assay - i.e. what is the reproducibility, 
false negatives and false positives of the assay?  
4. While novel, the practical applicability of this assay in broad clinical settings is 
questionable  
5. Minor grammatical errors which will editing  
 
Overall, the rationale of the paper is well justified and it would appear that the assay could 
generate useful clinical/research -related data. However, due to the small cohort size, the data has 
to be received w ith caution. Finally, the practical generalizability of the adhesion assay is 
somewhat questionable  
 
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
No 
 
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.  
 
Not relevant to this manuscript  
 
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: 30 Oct 2019  
 
Reviewer: Saurabh Mehandru  
 
Reviewer's report:  
In the submitted manuscript, Allner and colleagues report on identification of novel biomarkers 
in response to Vedolizumab (VDZ). To this effect, they conduct retrospective analyses  on a 
small cohort of 23 subjects with IBD (21 with UC and 2 with CD). The authors employ an in -
vitro assay, previously reported by the same group, that utilizes MAdCAM coated capillaries 
perfused with CD4+ T cells with time -lapse visualization of MAdCAM -adherent CD4+ T cells 
using confocal microscopy. Adherence of CD4+ T cells is then compared to clinical response 
following VDZ using clinical Mayo indices (for UC) and Harvey Bradshaw Index (for CD).  
The authors determine that higher frequency of MAdCAM -adherent CD4+ T cells is associated 
with clinical response to VDZ. Additionally, the authors also determine that effective inhibition 
of CD4 -MAdCAM binding also associated with better clinical response. The authors also 
quantify a4b1 integrin on circulating CD4+ T cells ex -vivo and report that non -responders to 
VDZ have a higher frequency of a4b1hi cells compared to VDZ responders. Finally, in this small 
cohort, the authors determine AUC for MAdCAM -adherent cells as a novel biomarker for 
determining VDZ -respo nse. 
 
The paper is written clearly. The premise of the study is strong - there is an unmet need for 
developing novel biomarkers to VDZ. The data provided in this manuscript should spur further 
investigation in this area and help move the field forward.  
 
In the same vein, one has to acknowledge that there are multiple short comings in this paper 
well. These include:  
1. Small cohort size  
2. Retrospective clinical analyses, failure to include rectal bleeding score (which is a good 
surrogate for disease activity  in UC)  
3. Lack of understanding regarding the range of the assay - i.e. what is the reproducibility, 
false negatives and false positives of the assay?  
4. While novel, the practical applicability of this assay in broad clinical settings is 
questionable  
5. Minor grammatical errors which will editing  
 
Overall, the rationale of the paper is well justified and it would appear that the assay could 
generate useful clinical/research -related data. However, due to the small cohort size, the data has 
to be received w ith caution. Finally, the practical generalizability of the adhesion assay is 
somewhat questionable  
 
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
No 
 
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.  
 
Not relevant to this manuscript  
 
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: 30 Oct 2019  
 
Reviewer: Saurabh Mehandru  
 
Reviewer's report:  
In the submitted manuscript, Allner and colleagues report on identification of novel biomarkers 
in response to Vedolizumab (VDZ). To this effect, they conduct retrospective analyses  on a 
small cohort of 23 subjects with IBD (21 with UC and 2 with CD). The authors employ an in -
vitro assay, previously reported by the same group, that utilizes MAdCAM coated capillaries 
perfused with CD4+ T cells with time -lapse visualization of MAdCAM -adherent CD4+ T cells 
using confocal microscopy. Adherence of CD4+ T cells is then compared to clinical response 
following VDZ using clinical Mayo indices (for UC) and Harvey Bradshaw Index (for CD).  
The authors determine that higher frequency of MAdCAM -adherent CD4+ T cells is associated 
with clinical response to VDZ. Additionally, the authors also determine that effective inhibition 
of CD4 -MAdCAM binding also associated with better clinical response. The authors also 
quantify a4b1 integrin on circulating CD4+ T cells ex -vivo and report that non -responders to 
VDZ have a higher frequency of a4b1hi cells compared to VDZ responders. Finally, in this small 
cohort, the authors determine AUC for MAdCAM -adherent cells as a novel biomarker for 
determining VDZ -respo nse. 
 
The paper is written clearly. The premise of the study is strong - there is an unmet need for 
developing novel biomarkers to VDZ. The data provided in this manuscript should spur further 
investigation in this area and help move the field forward.  
 
In the same vein, one has to acknowledge that there are multiple short comings in this paper 
well. These include:  
1. Small cohort size  
2. Retrospective clinical analyses, failure to include rectal bleeding score (which is a good 
surrogate for disease activity  in UC)  
3. Lack of understanding regarding the range of the assay - i.e. what is the reproducibility, 
false negatives and false positives of the assay?  
4. While novel, the practical applicability of this assay in broad clinical settings is 
questionable  
5. Minor grammatical errors which will editing  
 
Overall, the rationale of the paper is well justified and it would appear that the assay could 
generate useful clinical/research -related data. However, due to the small cohort size, the data has 
to be received w ith caution. Finally, the practical generalizability of the adhesion assay is 
somewhat questionable  
 
 
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.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in yo ur comments to the authors.  
 
No 
 
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.  
 
Not relevant to this manuscript  
 
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