PONE-D-19-21251

Autoantibody Production Significantly Decreased with APRIL/BLyS Blockade in Murine Chronic Rejection Kidney Transplant Model

PLOS ONE

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Please address our reviewers comments.

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Additional Editor Comments:

Decreased production of autoantibodies is an expected result of the therapy with APRIL/BLyS blockade. This study does help to direct efforts toward answering the question on whether therapy for AMR would have a direct effect on cellular mediated rejection in kidney transplantation. I agree with the authors that perhaps if follow up time was increased, it would be possible to see a difference in the treated versus untreated group. Study was well conducted.

Please address the comments of our reviewers.

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #3: Yes

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Reviewer #1: Relevant manuscript, well written and provided testing the use of APRIL/BLyS blockade as a potential therapeutic target to prevent allograft rejection in an in vivo mouse model of kidney transplant, comparing pathological findings with clinical measures.

Comments

1. Line 316: "Seventy-five percent (n=3) in the untretaed group had no proteinuria compared to 33.33% (n=1) in the treated group". Please change 33.33% to 25%, if in deed your total N=4.

2. Figure 1, panel C. Arrow is supposed to indicated negative staining, but the arrow is actually pointing to a green area of less intensity when compared to panel B. This could be still interpreted as a positive staining, although difference in intensity is noticeable. Is this auto-fluorescence?

Reviewer #2: This study done by Dr. N. M. Bath et al is a well done study. They have described outcomes of blockade of April/BlyS in a murine cAMR kidney transplant model, showing decrease in autoantibody production and altered splenic germinal center however it also shows there were no differences in kidney transplant pathology. The results from this study suggest that APRIL/BLyS blockade may have a role in decreasing antibody formation in long-term in kidney transplantation. Over all the methods applied are satisfactory and the figures represent mentioned results. Also this study enhances our knowledge about chronic anti body medicated rejection animal model in kidney transplant.

Reviewer #3: Overall, I found the manuscript interesting as the management of chronic antibody mediated rejection of the transplanted kidney remains a major challenge for practicing nephrologists and has a significant impact on the allograft longevity. The problem is a relevant one and newer/better therapies are much needed.

One of my concerns is about the novel chronic kidney rejection model used. The previously described vasculopathic changes from the heart transplant literature could not be reproduced in any of the transplant kidney biopsies. Along the same lines, no other histological changes consistent with chronic AMR or chronic active AMR were seen in the sensitized animals irrespective of the treatment arm.

The experiments were well described and consistent with previous publications by your group. The small sample size and short follow-up time added to the concerns about the model actually representing the disease certainly limit the conclusions.

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Reviewer #1: No

Reviewer #2: Yes: Aditya Singh Pawar

Reviewer #3: No

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Autoantibody Production Significantly Decreased with APRIL/BLyS Blockade in Murine Chronic Rejection Kidney Transplant Model

PONE-D-19-21251R1

Dear Dr. Redfield III,

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With kind regards,

Maria Lourdes Gonzalez Suarez, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for addressing reviewers comments. Manuscript is improved and ready for acceptance.

Reviewers' comments: