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Role of IgM/IgG Donor-Specific HLA Antibodies (DSAs) in Humoral Immune Reactions against Transplanted Grafts

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A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Immunological Responses and Immune Defense Mechanisms".

Deadline for manuscript submissions: closed (10 September 2021) | Viewed by 13311

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Special Issue Editors

Dr. Yoshiko Matsuda

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Guest Editor

Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Interests: transplant immunology; kidney transplantation; liver transplantation; humoral immune monitoring; IgM donor-specific anti-HLA antibodies; antibody-mediated allograft rejection; mammalian target of rapamycin inhibitor

Dr. Takeshi Watanabe

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Guest Editor

Lab. Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8397, Japan
Interests: B cell activation and antibody diversity; T cell activation; Cancer Immunotherapy; Construction of human lymphoid organoids

Dr. Takahisa Hiramitsu

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Guest Editor

Department of Transplant Surgery, Japanese Red Cross Aichi Medical Center, Nagoya Daini Hospital, Nagoya, Aichi 4668650, Japan
Interests: nephrology; kidney transplantation; urology; transplant surgery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Currently, organ transplants are performed throughout the world. The success of this versatile life-saving procedure largely rests on the development of effective immunosuppressive therapies that prevent rejection of transplanted organ tissue.

Most of the established immunosuppressive therapies have targeted the regulation and suppression of allo-reactive T cells. On the other hand, the management for the antibody-mediated allograft rejection still remains challenging.

For example, administration of monoclonal anti-CD20 antibody targeting CD20 antigen positive B cells does not yet have a significant impact on the elimination of plasma cells in bone marrow that generate the anti-allograft antibodies. Thus, development of the efficient strategies to prevent or regulate the antibody-mediated allograft rejection is an urgent issue for achievement of the preferable organ transplantation. Likewise, desensitization therapy has been often associated with severe side effects including virus infections such as cytomegalovirus, BK virus, and Epstein-Barr virus, among others.

Viral infections may trigger immune as well as inflammatory responses that lead to graft failure or rejection.

Besides above yet outstanding obstacles, in order to improve the prognosis of the patients who receive the organ transplants, we also need to develop novel immune monitoring methods that can identify antibody-mediated allograft rejection at the earliest possible stage, ideally which is expected to respond to the treatment with minimally-invasive immunosuppressive drugs．

Although the detection of serum IgG donor-specific anti-HLA antibodies (DSAs) by Luminex assay is the conventional diagnostic method used for assessing antibody-mediated allograft rejection, we believe that evaluation of anti-HLA IgG together with anti-HLA IgM will improve diagnostic capabilities and generate positive outcomes for the patients who receive whole organ transplants. Likewise, regarding the prevention of side effects induced by desensitization therapies, it will be important to learn more about mammalian target of rapamycin (mTOR) inhibitors, which may be involved in not only the regulation of allo-rective responses, but also the prevention of viral infection.

In this Special Issue, we welcome authors to submit Original Research Articles and Review Articles focusing on, but not limited to, the following subtopics:

Clinical and basic findings that focus on the use of both IgM and IgG antibodies to monitor the humoral immune response to donor-antigens.
Exploration of various means for effective immunosuppression that will at the same time prevents virus infection without promoting antibody-mediated allograft rejection development.
Examination of the most appropriate and effective administration procedures of mTOR inhibitors in order to protect the transplanted tissues from immunological attack and simultaneously to prevent virus infection.

Dr. Yoshiko Matsuda
Dr. Takeshi Watanabe
Dr. Takahisa Hiramitsu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Antibody-mediated allograft rejection
IgM antibodies
Humoral immune monitoring
Cytomegalovirus
BK virus
Epstein-Barr virus
Mammalian target of rapamycin inhibitors

Published Papers (4 papers)

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Research

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13 pages, 978 KiB

Open AccessArticle

Neutrophil-to-Lymphocyte Ratio Predicts Mortality in Adult Renal Transplant Recipients with Severe Community-Acquired Pneumonia

by Yue Qiu, Ying Su, Guo-Wei Tu, Min-Jie Ju, Hong-Yu He, Zhun-Yong Gu, Cheng Yang and Zhe Luo

Pathogens 2020, 9(11), 913; https://doi.org/10.3390/pathogens9110913 - 4 Nov 2020

Cited by 10 | Viewed by 2186

Abstract

Mortality of renal transplant recipients with severe community-acquired pneumonia (CAP) remains high, despite advances in critical care management. There is still a lack of biomarkers for predicting prognosis of these patients. The present study aimed to investigate the association between neutrophil-to-lymphocyte ratio (NLR) and mortality in renal transplant recipients with severe CAP. A total of 111 renal transplant recipients with severe CAP admitted to the intensive care unit (ICU) were screened for eligibility between 1 January 2009 and 30 November 2018. Patient characteristics and laboratory test results at ICU admission were retrospectively collected. There were 18 non-survivors (22.2%) among 81 patients with severe CAP who were finally included. Non-survivors had a higher NLR level than survivors (26.8 vs. 12.3, p < 0.001). NLR had the greatest power to predict mortality as suggested by area under the curve (0.88 ± 0.04; p < 0.0001) compared to platelet-to-lymphocyte ratio (0.75 ± 0.06; p < 0.01), pneumonia severity index (0.65 ± 0.08; p = 0.05), CURB-65 (0.65 ± 0.08; p = 0.05), and neutrophil count (0.68 ± 0.07; p < 0.01). Multivariate logistic regression models revealed that NLR was associated with hospital and ICU mortality in renal transplant recipients with severe CAP. NLR levels were independently associated with mortality and may be a useful biomarker for predicting poor outcome in renal transplant recipients with severe CAP. Full article

(This article belongs to the Special Issue Role of IgM/IgG Donor-Specific HLA Antibodies (DSAs) in Humoral Immune Reactions against Transplanted Grafts)

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11 pages, 3035 KiB

Open AccessArticle

Impact of Immunoglobulin M-Type Donor-Specific Human Leukocyte Antigen–Antibody Levels in Supernatants from Cultured Peripheral Blood Mononuclear Cells as Predictors of Antibody-Mediated Rejection

by Ryoichi Imamura, Yoshiko Matsuda, Koichi Tsutahara, Norio Nonomura and Shiro Takahara

Pathogens 2020, 9(9), 733; https://doi.org/10.3390/pathogens9090733 - 5 Sep 2020

Cited by 4 | Viewed by 2417

Abstract

Background: Antibody-mediated rejection (AMR) is a crucial barrier in the long-term prognosis of transplant recipients. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from kidney allograft recipients (N = 41) and cultured in vitro for 1 week. Furthermore, the supernatants of the cultured PBMCs were analyzed by Luminex single-antigen beads. Results: Analyses using Luminex single-antigen beads revealed the presence of immunoglobulin (Ig) G donor-specific anti-HLA antibodies (DSAs) was detected in the supernatants of cultured PBMCs collected more frequently than IgM in de novo DSA-sensitized patients with AMR, and IgM were detectable in patients with stable graft function mainly and several IgM DSAs were detectable in the supernatants of the cultured PBMCs before detecting the IgG levels in sera. We also found that the DSA-specific IgM-secreting memory B cells (mBCs) were more sensitive to the chronic use of immunosuppressive agents than to the IgG-secreting mBCs. Conclusions: In the transplant recipients, the assessment of supernatants of cultured PBMCs provide more details of immune reactions than the commonly used method that directly measures IgG DSA levels in patient sera and some IgM DSA detection may be a better predictor of IgG DSAs production, which may cause AMR and enable early intervention, in initial stages of AMR development. Full article

(This article belongs to the Special Issue Role of IgM/IgG Donor-Specific HLA Antibodies (DSAs) in Humoral Immune Reactions against Transplanted Grafts)

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Review

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14 pages, 304 KiB

Open AccessReview

BK Virus-Associated Nephropathy after Renal Transplantation

by Yasuhito Funahashi

Pathogens 2021, 10(2), 150; https://doi.org/10.3390/pathogens10020150 - 2 Feb 2021

Cited by 15 | Viewed by 3559

Abstract

Recent advances in immunosuppressive therapy have reduced the incidence of acute rejection and improved renal transplantation outcomes. Meanwhile, nephropathy caused by BK virus has become an important cause of acute or chronic graft dysfunction. The usual progression of infection begins with BK viruria and progresses to BK viremia, leading to BK virus associated nephropathy. To detect early signs of BK virus proliferation before the development of nephropathy, several screening tests are used including urinary cytology and urinary and plasma PCR. A definitive diagnosis of BK virus associated nephropathy can be achieved only histologically, typically by detecting tubulointerstitial inflammation associated with basophilic intranuclear inclusions in tubular and/or Bowman’s epithelial cells, in addition to immunostaining with anti-Simian virus 40 large T-antigen. Several pathological classifications have been proposed to categorize the severity of the disease to allow treatment strategies to be determined and treatment success to be predicted. Since no specific drugs that directly suppress the proliferation of BKV are available, the main therapeutic approach is the reduction of immunosuppressive drugs. The diagnosis of subsequent acute rejection, the definition of remission, the protocol of resuming immunosuppression, and long-term follow-up remain controversial. Full article

(This article belongs to the Special Issue Role of IgM/IgG Donor-Specific HLA Antibodies (DSAs) in Humoral Immune Reactions against Transplanted Grafts)

21 pages, 2315 KiB

Open AccessReview

Characteristics of Immunoglobulin M Type Antibodies of Different Origins from the Immunologic and Clinical Viewpoints and Their Application in Controlling Antibody-Mediated Allograft Rejection

by Yoshiko Matsuda, Takahisa Hiramitsu, Xiao-kang Li and Takeshi Watanabe

Pathogens 2021, 10(1), 4; https://doi.org/10.3390/pathogens10010004 - 23 Dec 2020

Cited by 5 | Viewed by 4109

Abstract

Antibody-mediated allograft rejection (AMR) hinders patient prognosis after organ transplantation. Current studies concerning AMR have mainly focused on the diagnostic value of immunoglobulin G (IgG)-type donor-specific antihuman leukocyte antigen antibodies (DSAs), primarily because of their antigen specificity, whereas the clinical significance of immunoglobulin M (IgM)-type DSAs has not been thoroughly investigated in the context of organ transplantation because of their nonspecificity against antigens. Although consensus regarding the clinical significance and role of IgM antibodies is not clear, as discussed in this review, recent findings strongly suggest that they also have a huge potential in novel diagnostic as well as therapeutic application for the prevention of AMR. Most serum IgM antibodies are known to comprise natural antibodies with low affinity toward antigens, and this is derived from B-1 cells (innate B cells). However, some of the serum IgM-type antibodies reportedly also produced by B-2 cells (conventional B cells). The latter are known to have a high affinity for donor-specific antigens. In this review, we initially discuss how IgM-type antibodies of different origins participate in the pathology of various diseases, directly or through cell surface receptors, complement activation, or cytokine production. Then, we discuss the clinical applicability of B-1 and B-2 cell-derived IgM-type antibodies for controlling AMR with reference to the involvement of IgM antibodies in various pathological conditions. Full article

(This article belongs to the Special Issue Role of IgM/IgG Donor-Specific HLA Antibodies (DSAs) in Humoral Immune Reactions against Transplanted Grafts)

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