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Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers
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Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 10740

Special Issue Editor

Dr. Mihai Oltean

E-Mail Website
Guest Editor
1. Department of Surgery at Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, 413 90 Göteborg, Sweden
2. The Transplant Institute, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden
Interests: transplantation; transplant immunology; organ transplantation; liver transplantation; kidney transplantation; intestinal transplantation; biomarkers; rejection monitoring; acute allograft injury

Special Issue Information

Dear Colleagues, 

The progress achieved concerning organ transplantation has been the result of a mix of serendipity and sustained basic and translational research. Acute rejection is the most important complication following organ transplantation, significantly impacting both short and long-term outcomes. In spite of modern immunosuppressive drugs and strategies, its frequency still reaches up to 30–50% depending on the organ type. Whereas calcineurin inhibitors have dramatically impacted the entire transplantation field by effectively curbing the development of T-cell-mediated rejection, their limits and long-term side effects have resulted in the search for new immunobiological paradigms, including the use of biologics (monoclonal antibodies and costimulatory blockade) or immunomodulatory cells. In addition, taking advantage of the progress in diagnosing well-defined biological alterations through novel circulating biomarkers and “liquid biopsies” may reveal less invasive sampling alternatives than graft biopsies, and move organ transplantation from a biopsy-intensive field to a more “molecular” landscape.

This Special Issue aims to gather recent experimental and clinical advancements in understanding the immunobiology of allograft rejection, whether it pertains to the mechanisms of cellular or humoral rejection, biomarkers of rejection or molecular events occurring during the course of acute rejection. Original research articles and review articles within the described research field are welcome.

Dr. Mihai Oltean
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cellular rejection
  • humoral rejection
  • signaling pathways
  • biomarkers
  • cell-free DNA
  • transcriptomics
  • transplantation
  • organ transplantation

Published Papers (6 papers)

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Editorial

Jump to: Research, Review

4 pages, 188 KiB  
Editorial
Transplant Immunobiology: Many Answers Raising Even More Questions
by Mihai Oltean
Int. J. Mol. Sci. 2023, 24(16), 12674; https://doi.org/10.3390/ijms241612674 - 11 Aug 2023
Viewed by 673
Abstract
Immunologic complications following organ, cell, or tissue transplantation still raise significant challenges related to their diagnosis and treatment [...] Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)

Research

Jump to: Editorial, Review

15 pages, 1521 KiB  
Article
Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease
by Gaurav Tripathi, Rutvij A. Khanolkar, Rehan M. Faridi, Amit Kalra, Poonam Dharmani-Khan, Meer-Taher Shabani-Rad, Noureddine Berka, Andrew Daly, Jan Storek and Faisal M. Khan
Int. J. Mol. Sci. 2022, 23(24), 15888; https://doi.org/10.3390/ijms232415888 - 14 Dec 2022
Cited by 4 | Viewed by 1595
Abstract
The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching [...] Read more.
The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching in 315 myeloablative, 10/10 HLA-matched donor–recipient pairs. Recipients of a graft carrying the -1082GG IL10 gene promoter region variant had a three-fold lower incidence of grade II–IV acute GVHD compared to IL10-1082AA graft recipients (SHR = 0.25, p = 0.005). This was most evident in matched unrelated donor (MUD) transplants, where the greatest alloreactivity is expected. IL10-1082GG transplants did not experience an increased incidence of relapse, and, consequently, overall survival was two-fold higher in IL10-1082GG MUD transplants (HR = 0.17, p = 0.023). Longitudinal post-transplant measurements demonstrated that -1082GG is a high-IL10-producing and -expressing genotype with attenuated CD8+ T-cell reconstitution. High post-transplant donor chimerism in T- and myeloid-cells (>95%) confirmed a predominant donor, rather than recipient, genotype effect on immune function and aGVHD. To date, this is the first study to report corroborating genome-to-cellular evidence for a non-HLA donor immunogenetic variant that appears to be protective against GVHD. The incorporation of IL10 variants in donor selection criteria and clinical-management decisions has the potential to improve patient outcomes. Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)
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10 pages, 3695 KiB  
Article
Innate Immune Response Analysis in Meniscus Xenotransplantation Using Normal and Triple Knockout Jeju Native Pigs
by Seungwon Yoon, Yunhui Min, Chungyu Park, Dahye Kim, Yunji Heo, Mangeun Kim, Eugene Son, Mrinmoy Ghosh, Young-Ok Son and Chang-Gi Hur
Int. J. Mol. Sci. 2022, 23(18), 10416; https://doi.org/10.3390/ijms231810416 - 8 Sep 2022
Cited by 3 | Viewed by 1881
Abstract
Although allogenic meniscus grafting can be immunologically safe, it causes immune rejection due to an imbalanced tissue supply between donor and recipient. Pigs are anatomically and physiologically similar to adult humans and are, therefore, considered to be advantageous xenotransplantation models. However, immune rejection [...] Read more.
Although allogenic meniscus grafting can be immunologically safe, it causes immune rejection due to an imbalanced tissue supply between donor and recipient. Pigs are anatomically and physiologically similar to adult humans and are, therefore, considered to be advantageous xenotransplantation models. However, immune rejection caused by genetic difference damages the donor tissue and can sometimes cause sudden death. Immune rejection is caused by genes; porcine GGTA1, CMAH, and B4GLANT2 are the most common. In this study, we evaluated immune cells infiltrating the pig meniscus transplanted subcutaneously into BALB/c mice bred for three weeks. We compared the biocompatibility of normal Jeju native black pig (JNP) meniscus with that of triple knockout (TKO) JNP meniscus (α-gal epitope, N-glycolylneuraminic acid (Neu5Gc), and Sd (a) epitope knockout using CRISPR-Cas 9). Mast cells, eosinophils, neutrophils, and macrophages were found to have infiltrated the transplant boundary in the sham (without transplantation), normal (normal JNP), and test (TKO JNP) samples after immunohistochemical analysis. When compared to normal and sham groups, TKO was lower. Cytokine levels did not differ significantly between normal and test groups. Because chronic rejection can occur after meniscus transplantation associated with immune cell infiltration, we propose studies with multiple genetic editing to prevent immune rejection. Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)
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17 pages, 3562 KiB  
Article
Activation of Humoral Immunity during the Pathogenesis of Experimental Chronic Lung Allograft Dysfunction
by Martin Reichert, Srebrena Atanasova, Kathrin Petri, Marian Kampschulte, Baktybek Kojonazarov, Gabriele Fuchs-Moll, Gabriele A. Krombach, Winfried Padberg and Veronika Grau
Int. J. Mol. Sci. 2022, 23(15), 8111; https://doi.org/10.3390/ijms23158111 - 23 Jul 2022
Cited by 1 | Viewed by 1467
Abstract
Alloreactive and autoreactive antibodies have been associated with the development of chronic lung allograft dysfunction (CLAD), but their pathogenic role is disputed. Orthotopic left lung transplantation was performed in the Fischer-344 to Lewis rat strain combination followed by the application of ciclosporine for [...] Read more.
Alloreactive and autoreactive antibodies have been associated with the development of chronic lung allograft dysfunction (CLAD), but their pathogenic role is disputed. Orthotopic left lung transplantation was performed in the Fischer-344 to Lewis rat strain combination followed by the application of ciclosporine for 10 days. Four weeks after transplantation, lipopolysaccharide (LPS) was instilled into the trachea. Lungs were harvested before (postoperative day 28) and after LPS application (postoperative days 29, 33, 40, and 90) for histopathological, immunohistochemical, and Western blot analyses. Recipient serum was collected to investigate circulating antibodies. Lung allografts were more strongly infiltrated by B cells and deposits of immunoglobulin G and M were more prominent in allografts compared to right native lungs or isografts and increased in response to LPS instillation. LPS induced the secretion of autoreactive antibodies into the circulation of allograft and isograft recipients, while alloreactive antibodies were only rarely detected. Infiltration of B cells and accumulation of immunoglobulin, which is observed in allografts treated with LPS but not isografts or native lungs, might contribute to the pathogenesis of experimental CLAD. However, the LPS-induced appearance of circulating autoreactive antibodies does not seem to be related to CLAD, because it is observed in both, isograft and allograft recipients. Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)
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18 pages, 1799 KiB  
Article
Combined Analysis of HLA Class II Eplet Mismatch and Tacrolimus Levels for the Prediction of De Novo Donor Specific Antibody Development in Kidney Transplant Recipients
by Hyeyoung Lee, Ji Won Min, Hyunhye Kang, Hanbi Lee, Sang Hun Eum, Yohan Park, Chul Woo Yang, Byung Ha Chung and Eun-Jee Oh
Int. J. Mol. Sci. 2022, 23(13), 7357; https://doi.org/10.3390/ijms23137357 - 1 Jul 2022
Cited by 4 | Viewed by 2143
Abstract
We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total [...] Read more.
We investigated whether HLA class II eplet mismatch was related to dnDSA development and analyzed its combined impact with tacrolimus levels for kidney transplantation outcomes. A total of 347 kidney transplants were included. HLA Matchmaker was used for the single molecular eplet, total eplet, antibody (Ab)-verified eplet mismatch analyses, and Ab-verified single molecular analysis to identify HLA-DR/DQ molecular thresholds for the risk of dnDSA development. A time-weighted tacrolimus trough level (TAC-C0) of 5 ng/mL and a TAC-C0 time-weighted coefficient variability (TWCV) of 20% were applied to find the combined effects on dnDSA development. A high level of mismatch for single molecular eplet (DQ ≥ 10), total eplet (DQ ≥ 12), Ab-verified eplet (DQ ≥ 4), and Ab-verified single molecular eplet (DQ ≥ 4) significantly correlated with HLA class II dnDSA development. Class II dnDSA developed mostly in patients with low TAC-C0 and high eplet mismatch. In the multivariable analyses, low TAC-C0 and high eplet mismatch showed the highest hazard ratio for the development of dnDSA. No significant combined effect was observed in dnDSA development according to TWCV. In conclusion, the determination of HLA class II eplet mismatch may improve the risk stratification for dnDSA development, especially in conjunction with tacrolimus trough levels. Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)
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Review

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17 pages, 1123 KiB  
Review
Intestinal Transplant Immunology and Intestinal Graft Rejection: From Basic Mechanisms to Potential Biomarkers
by Martin Rumbo and Mihai Oltean
Int. J. Mol. Sci. 2023, 24(5), 4541; https://doi.org/10.3390/ijms24054541 - 25 Feb 2023
Cited by 9 | Viewed by 2209
Abstract
Intestinal transplantation (ITx) remains a lifesaving option for patients suffering from irreversible intestinal failure and complications from total parenteral nutrition. Since its inception, it became obvious that intestinal grafts are highly immunogenic, due to their high lymphoid load, the abundance in epithelial cells [...] Read more.
Intestinal transplantation (ITx) remains a lifesaving option for patients suffering from irreversible intestinal failure and complications from total parenteral nutrition. Since its inception, it became obvious that intestinal grafts are highly immunogenic, due to their high lymphoid load, the abundance in epithelial cells and constant exposure to external antigens and microbiota. This combination of factors and several redundant effector pathways makes ITx immunobiology unique. To this complex immunologic situation, which leads to the highest rate of rejection among solid organs (>40%), there is added the lack of reliable non-invasive biomarkers, which would allow for frequent, convenient and reliable rejection surveillance. Numerous assays, of which several were previously used in inflammatory bowel disease, have been tested after ITx, but none have shown sufficient sensibility and/or specificity to be used alone for diagnosing acute rejection. Herein, we review and integrate the mechanistic aspects of graft rejection with the current knowledge of ITx immunobiology and summarize the quest for a noninvasive biomarker of rejection. Full article
(This article belongs to the Special Issue Allograft Rejection: Emerging Molecular Mechanisms and Biomarkers)
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