Transplant Immunology in Liver Transplant, Rejection, and Tolerance

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article by Yokoyama and collaborators is well written and argued and could be advisable for publication with minor corrections.

1. In the abstract there is a "trans-plantion", you must correct it.

2. There are misuses of abbreviations in the writing of the article. These are explained and named the first time and from that moment on the abbreviation is used, e.g. APC, LSEC, HSC, MHC, ACR, TCR, DC, DSA, Tregs, KC or HDCs.

3. There is some space before parentheses that is missing and also that is left over after period and followed in various parts of the manuscript. Review.

4. Finally, there is an article on the role of antibodies in liver transplantation that explains the possible multiple causes of why antibodies do not affect rejection in this type of transplant that you have not mentioned. I recommend it be cited and discussed briefly. This article is:

 

Humoral Response in Liver Allograft Transplantation: A Review of the Role of Anti-Human Leukocyte Antigen (HLA) Antibodies. Curr Protein Pept Sci. 2016;17(8):776-784. doi: 10.2174/1389203717666160226145101

Comments on the Quality of English Language

The authors must review abbreviations 

Author Response

Prof. Dr. Giuliano Ramadori

Guest Editor

Livers

 

Thank you for reviewing and editing our paper Manuscript ID livers-3015854 entitled "Transplant Immunology in Liver Transplant, Rejection, and Tolerance." .

I appreciated the editor’s and reviewers’ educational suggestions.

Copyediting reviewers’ comments and our comments are listed as follows. The revisions are underlined and highlighted. Please see them below.

 

Reviewer: 1

Comments to the Author

The article by Yokoyama and collaborators is well written and argued and could be advisable for publication with minor corrections.

 

1. In the abstract there is a "trans-plantion", you must correct it.

 

→ Corrected.

 

2. There are misuses of abbreviations in the writing of the article. These are explained and named the first time and from that moment on the abbreviation is used, e.g. APC, LSEC, HSC, MHC, ACR, TCR, DC, DSA, Tregs, KC, or HDCs.

 

→ To ensure no confusion or misuse, we spelled out each abbreviation when using it in a new section of the paper, or when the word is mentioned on a new page without immediate within-sentence context.

 

3. There is some space before parentheses that is missing and also that is left over after period and followed in various parts of the manuscript. Review.

 

→ Reviewed and corrected.

 

4. Finally, there is an article on the role of antibodies in liver transplantation that explains the possible multiple causes of why antibodies do not affect rejection in this type of transplant that you have not mentioned. I recommend it be cited and discussed briefly.

 

→ After reading and discussion, we have briefly summarized the majority of these causes and cited the article you suggested (16). See exact changes highlighted.

 

Acute AMR, previously referred to as humoral rejection, is rare for a number of possible causes, occurring in fewer than 1% of liver transplant recipients. Among these factors are the liver’s dual blood supply causing a low sinusoidal flow state, lower expression of Human Leukocyte Antigen (HLA) class II antigens, and particular cell populations. These cells maintain a self-regulating network of epigenetic, microenvironmental, and surface states including negative immune regulators [16,17,18]. The presence of ABO incompatibility or a positive cross-match does not necessarily rule out liver transplantation, as the liver can effectively eliminate donor-specific antibodies (DSAs).

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The authors attempt to review what is currently understood about both diagnosing as well as what underpins the various types of immunologic mediated rejection that can occur in liver transplant recipients, along with the implications, followed by covering what is known about the immunology behind achieving tolerance.

The limited coverage of some of the important facets of these subtopics means that sweeping statements are made at times in the manuscript when in fact there are a number of other considerations that need to be expanded upon. These include-

1) the limitations of using the Banff schema in practice, particularly when it comes to diagnosing either acute or chronic antibody mediated rejection (which can be subclinical at times). This adds to the known complexities of both making a diagnosis in a timely manner along with what is then the best way of managing the patients according to which type of rejection is occurring

2) Of note, there are different types of DSA's that can be involved with acute rejection-ie against HLA class 1 or class 2 or instead non HLA. Plus, there is now some consensus on what is the minimum MFI which triggers concern that some form of rejection may be an issue. This all needs to be expanded on

3) For the section on Tolerance, no mention is made of the data from clinical studies (albeit in limited numbers of patients) of either successful immunosuppression withdrawal or where patients have been discovered to have some degree of chimerism. This is partly what drives the ongoing research effort-ie the knowledge that partial/full tolerance is possible in a small subgroup of patients. Plus, additional attention to this whole section needs to be made so that the reader can readily detect what of all of the various results that are being discussed have resulted from in vitro laboratory studies, versus from animal models, versus from clinical studies on humans. It is apparent that a lot of the discussion in this section revolves around the findings obtained from rodent models (which is potentially a significant limitation in the absence of more data from humans). Hence the limitations of the current research need to be acknowledged along with where the future directions might lie.

 

Author Response

Dear Reviewer,

Thank you for reviewing our paper Manuscript ID livers-3015854 entitled "Transplant Immunology in Liver Transplant, Rejection, and Tolerance" .

I appreciated the editor’s and reviewers’ educational suggestions.

Copyediting reviewers’ comments and our comments are listed as follows. Please see them below.

 

Reviewer: 2

Comments to the Author

The authors attempt to review what is currently understood about both diagnosing as well as what underpins the various types of immunologic mediated rejection that can occur in liver transplant recipients, along with the implications, followed by covering what is known about the immunology behind achieving tolerance.

The limited coverage of some of the important facets of these subtopics means that sweeping statements are made at times in the manuscript when in fact there are a number of other considerations that need to be expanded upon. These include-

(1) the limitations of using the Banff schema in practice, particularly when it comes to diagnosing either acute or chronic antibody mediated rejection (which can be subclinical at times). This adds to the known complexities of both making a diagnosis in a timely manner along with what is then the best way of managing the patients according to which type of rejection is occurring

(Response)
Thank you very much for pointing this out, we mentioned diagnostic criteria for AMR that was made in Banff Working Group in 2016 and its complexity and difficulties of management. We have attached changes as below.
“The diagnostic criteria for AMR were published in a report by the Banff Working Group in 2016. The definition of acute AMR includes the following four criteria: 1) Histopatho-logical pattern of injury consistent with acute AMR; 2) Positive serum DSA; 3) Diffuse mi-crovascular C4d deposition; 4) Reasonable exclusion of other insults that might cause a similar pattern of injury. However, there are cases where not all these criteria are present, especially when TCMR is also present. In suspected cases of AMR, not all four criteria may be met, making the diagnosis challenging. These criteria should aim to link allograft dysfunction with corresponding histological findings and be refined to address the fre-quency and severity of rejection injuries, as well as their response to therapy. Acute AMR presenting with severe allograft injury is usually refractory to potent steroid therapy and difficult to manage.”

(2) Of note, there are different types of DSA's that can be involved with acute rejection-ie against HLA class 1 or class 2 or instead non HLA. Plus, there is now some consensus on what is the minimum MFI which triggers concern that some form of rejection may be an issue. This all needs to be expanded on

(Response)
Thank you very much for pointing this out, we mentioned types of antibodies and indicator of MFI. We have attached changes as below.
“Acute AMR presenting with severe allograft injury is usually refractory to potent steroid therapy and difficult to manage. Analysis of DSA, whether HLA class I or class II, is also an important step in making a diagnosis. While there is no clear-cut consensus on the mean fluorescence intensity (MFI) threshold for clinical transplantation, an MFI of >3,000–5,000 might be an indicator.”

(3) For the section on Tolerance, no mention is made of the data from clinical studies (albeit in limited numbers of patients) of either successful immunosuppression withdrawal or where patients have been discovered to have some degree of chimerism. This is partly what drives the ongoing research effort-ie the knowledge that partial/full tolerance is possible in a small subgroup of patients. Plus, additional attention to this whole section needs to be made so that the reader can readily detect what of all of the various results that are being discussed have resulted from in vitro laboratory studies, versus from animal models, versus from clinical studies on humans. It is apparent that a lot of the discussion in this section revolves around the findings obtained from rodent models (which is potentially a significant limitation in the absence of more data from humans). Hence the limitations of the current research need to be acknowledged along with where the future directions might lie.

(Response)
Thank you very much for pointing this out, we changed the tolerance section so that readers understand what is being discussed whether the data arose from in vitro or in vivo experiments, and we added minimizing or withdrawing immunosuppression trial and its result. Sentences that have changed are highlighted. 

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

This was a narrative review on immunological complications after liver transplantation. The paper is well written and the references are updated.

I think that the Authors should add a Figure describing pathophysiological basis of one of the discussed topics (tolerance or rejection).

Moreover, I suggest to briefly explain what molecules are currently used in clinical practice for prophylaxis against rejection.

Comments on the Quality of English Language

There are only few typos.

Author Response

Dear Reviewer,

Thank you for reviewing and editing our paper Manuscript ID livers-3015854 entitled "Transplant Immunology in Liver Transplant, Rejection, and Tolerance" .
I appreciated the editor’s and reviewers’ educational suggestions.
Copyediting reviewers’ comments and our comments are listed as follows. Please see them below.

This was a narrative review on immunological complications after liver transplantation. The paper is well written and the references are updated.

I think that the Authors should add a Figure describing pathophysiological basis of one of the discussed topics (tolerance or rejection).

(Response)
Thank you very much for your suggestion. We have included figures that explain the pathophysiological basis of rejection. Please see the attached file.


Moreover, I suggest to briefly explain what molecules are currently used in clinical practice for prophylaxis against rejection.

(Response)
Thank you very much for your suggestion. We have mentioned CTLA4Ig and explained its clinical trials. We have attached changes as below.

“CTLA4Ig (belatacept) was approved by the Food and Drug Administration in 2011 for use in renal transplantation patients. There was a clinical trial investigating belatacept for liver transplantation, but it was terminated due to graft dysfunction and acute rejection occur-ring around 10 weeks post-transplant [65]. Additionally, a phase II trial in adult liver transplant patients revealed that belatacept treatment led to a higher incidence of acute rejection and graft loss”

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors appear to have revised the manuscript in light of the reviewers concerns/comments

Mention is made in the manuscript of three Figures, however none of them have been included in -v2.

This needs to be rectified, that is the version of the manuscript with the Figures in it needs to be uploaded for peer review (should the authors wish for these Figures to form part of the manuscript).

 

Author Response

Dear Reviewer,

Thank you for reviewing our paper Manuscript ID livers-3015854 entitled "Transplant Immunology in Liver Transplant, Rejection, and Tolerance" .
I appreciated the editor’s and reviewers’ educational suggestions.
Copyediting reviewers’ comments and our comments are listed as follows. Please see them below.

Reviewer: 2
Comments to the Author
The authors attempt to review what is currently understood about both diagnosing as well as what underpins the various types of immunologic mediated rejection that can occur in liver transplant recipients, along with the implications, followed by covering what is known about the immunology behind achieving tolerance.
The limited coverage of some of the important facets of these subtopics means that sweeping statements are made at times in the manuscript when in fact there are a number of other considerations that need to be expanded upon. These include-

1)    the limitations of using the Banff schema in practice, particularly when it comes to diagnosing either acute or chronic antibody mediated rejection (which can be subclinical at times). This adds to the known complexities of both making a diagnosis in a timely manner along with what is then the best way of managing the patients according to which type of rejection is occurring

(Response)
Thank you very much for pointing this out, we mentioned diagnostic criteria for AMR that was made in Banff Working Group in 2016 and its complexity and difficulties of management. We have attached changes as below.
“In 2016, Banff Working Group announced four diagnostic criteria for AMR. These in-cluded histopathologic disruption consistent with acute AMR, positive serum DSA, dispersed C4d deposits in microvasculature, and exclusion of other pathologies with a similar presenta-tion. However, some cases do not include all four criteria, especially when co-present with TCMR, making identification difficult. Thus, the criteria should be developed to link allo-graft dysfunction with histological findings, in order to correlate with both the frequency and severity of rejection injuries, in addition to predicting therapeutic efficacy.”

2)    Of note, there are different types of DSA's that can be involved with acute rejection-ie against HLA class 1 or class 2 or instead non HLA. Plus, there is now some consensus on what is the minimum MFI which triggers concern that some form of rejection may be an issue. This all needs to be expanded on

(Response)
Thank you very much for pointing this out, we mentioned types of antibodies and indicator of MFI. We have attached changes as below.
“determination of HLA class I and II molecules through DSA analysis is another important step in making a diagnosis. Most of the time, the focus is on anti-HLA, but DSAs can target class I or II HLA or non-HLA antigens, such as the angiotensin II type-1 receptor. While no official criteria on the mean fluorescence intensity (MFI) during re-jection, some consensus shows an MFI of >3,000–5,000 to be predictive”

3)     For the section on Tolerance, no mention is made of the data from clinical studies (albeit in limited numbers of patients) of either successful immunosuppression withdrawal or where patients have been discovered to have some degree of chimerism. This is partly what drives the ongoing research effort-ie the knowledge that partial/full tolerance is possible in a small subgroup of patients. Plus, additional attention to this whole section needs to be made so that the reader can readily detect what of all of the various results that are being discussed have resulted from in vitro laboratory studies, versus from animal models, versus from clinical studies on humans. It is apparent that a lot of the discussion in this section revolves around the findings obtained from rodent models (which is potentially a significant limitation in the absence of more data from humans). Hence the limitations of the current research need to be acknowledged along with where the future directions might lie.

(Response)
Thank you very much for pointing this out, we changed the tolerance section so that readers understand what is being discussed whether the data arose from in vitro or in vivo experiments, and we added minimizing or withdrawing immunosuppression trial and its result. Sentences that have changed are highlighted. 

Author Response File: Author Response.docx