scholarly journals M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanwen Zhang ◽  
Zhuonan Li ◽  
Wei Li
Keyword(s):  
Allograft Rejection ◽  
Chronic Rejection ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Innate Immune ◽  
Sterile Inflammation ◽  
Solid Organ ◽  
M2 Macrophages ◽  
Innovative Strategies ◽  
Chronic Allograft Rejection

Allograft functional failure due to acute or chronic rejection has long been a major concern in the area of solid organ transplantation for decades. As critical component of innate immune system, the macrophages are unlikely to be exclusive for driving acute or chronic sterile inflammation against allografts. Traditionally, macrophages are classified into two types, M1 and M2 like macrophages, based on their functions. M1 macrophages are involved in acute rejection for triggering sterile inflammation thus lead to tissue damage and poor allograft survival, while M2 macrophages represent contradictory features, playing pivotal roles in both anti-inflammation and development of graft fibrosis and resulting in chronic rejection. Macrophages also contribute to allograft vasculopathy, but the phenotypes remain to be identified. Moreover, increasing evidences are challenging traditional identification and classification of macrophage in various diseases. Better understanding the role of macrophage in chronic rejection is fundamental to developing innovative strategies for preventing late graft loss. In this review, we will update the recent progress in our understanding of diversity of macrophage-dominated innate immune response, and reveal the roles of M2 macrophages in chronic allograft rejection as well.

Role of Endothelial Cells in Allograft Rejection

1997 ◽  
Vol 2 (2) ◽  
pp. 105-114 ◽  
Author(s):  
Marlene L Rose
Keyword(s):  
Endothelial Cells ◽  
Mhc Class Ii ◽  
Allograft Rejection ◽  
Chronic Rejection ◽  
Solid Organ Transplantation ◽  
Hla Antigens ◽  
Constitutive Expression ◽  
Class Ii ◽  
Solid Organ ◽  
Antigen Presenting

The immunological properties of endothelial cells suggest they perform a pivotal role in acute and chronic rejection following solid organ transplantation. Their constitutive expression of MHC class II molecules (which initiate allograft rejection by activating CD4 T cells) and accessory molecules allows them to present foreign antigen by both the direct and indirect route to the recipient's immune system. The costimulatory molecules used by endothelial cells appear to differ from those used by traditional antigen-presenting cells such as B cells and dendritic cells. Release of non-HLA antigens from damaged endothelial cells results in a chronic antibody response — possibly contributing to graft vasculopathy and chronic rejection. Further understanding of the factors that regulate MHC class II and accessory molecule expression on endothelial cells could lead to novel strategies of therapeutic intervention.

HLA-B7 β-pleated sheet-derived synthetic peptides are immunodominant T-cell epitopes regulating alloresponses

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3286-3292 ◽  
Author(s):  
Anja Freese ◽  
Nicholas Zavazava
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Rejection ◽  
Graft Loss ◽  
Peptide Binding ◽  
Solid Organ Transplantation ◽  
Target Cells ◽  
Solid Organ ◽  
T Cell Epitopes ◽  
Pleated Sheet

Abstract Chronic rejection of transplanted allografts is the major cause of graft loss after clinical solid organ transplantation. Recent data link the indirect presentation of allopeptides to chronic graft loss; thus, identification of immunodominant epitopes on major histocompatibility complex (MHC) antigens could significantly contribute to establishing novel ways for monitoring and managing chronic rejection. Here, we show that synthetic allo-MHC–derived peptides covering the polymorphic region 56 to120 of HLA-B7 modulate alloresponses. In particular, the 2 β-pleated sheet-derived peptides covering residues 91 to 105 and 96 to 120, respectively, but not sequences from the α1 helix, were presented by autologous peripheral blood lymphocytes to induce T-cell proliferation. In addition, the 2 β-pleated sheet-derived peptides and the α1-derived peptide residues 60 to 75 abrogated lysis of HLA-B7 target cells by anti–HLA-B7 cytotoxic T lymphocytes (CTLs). Although most residues between 91 and 120 are normally not directly accessible to T cells, our results indicate that peptides derived from the lower surface of the peptide-binding groove of HLA-B7 are immunodominant in HLA-B7 alloresponses. To characterize the binding and stability of allopeptides to T cells, the 62-70 peptide—derived from the 60-75 allopeptide that blocked cytotoxicity of anti–HLA-B7 CTL—was synthesized and coupled with fluorescein isothiocyanate. The peptide specifically labeled anti-B7 CTL, but not anti–HLA-A2 CTL as measured by flow cytometry. Peptide binding to CTL was specific at 4°C and remained stable for 12 hours, whereas it remained stable for less than 2 hours at 37°C. These studies allow the identification of HLA-B7 T-cell epitopes and reveal for the first time a novel, previously unrecognized application of synthetic HLA-derived allopeptides to visualize alloreactive T cells.

scholarly journals Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy

2021 ◽  
Vol 14 (6) ◽  
pp. 1718-1724
Author(s):  
Yalda Dehghan ◽  
Gabriel T. Schnickel ◽  
Mojgan Hosseini ◽  
Adam M. Burgoyne ◽  
Veeral H. Ajmera ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Allograft Rejection ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Hepatic Necrosis ◽  
Solid Organ ◽  
Extreme Caution ◽  
Rejection Rates

AbstractImmune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.

Clinical epigenetics and acute/chronic rejection in solid organ transplantation: An update

2021 ◽  
pp. 100609
Author(s):  
Maria Vasco ◽  
Giuditta Benincasa ◽  
Carmela Fiorito ◽  
Mario Faenza ◽  
Paride De Rosa ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Chronic Rejection ◽  
Solid Organ Transplantation ◽  
Solid Organ

scholarly journals Advanced Genomics-Based Approaches for Defining Allograft Rejection With Single Cell Resolution

2021 ◽  
Vol 12 ◽  
Author(s):  
Tiffany Shi ◽  
Krishna Roskin ◽  
Brian M. Baker ◽  
E. Steve Woodle ◽  
David Hildeman
Keyword(s):  
Single Cell ◽  
Allograft Rejection ◽  
Immune Cell ◽  
Transplant Rejection ◽  
Solid Organ Transplantation ◽  
Genomic Analysis ◽  
Solid Organ ◽  
Single Cell Level ◽  
Cell Level ◽  
Network Analyses

Solid organ transplant recipients require long-term immunosuppression for prevention of rejection. Calcineurin inhibitor (CNI)-based immunosuppressive regimens have remained the primary means for immunosuppression for four decades now, yet little is known about their effects on graft resident and infiltrating immune cell populations. Similarly, the understanding of rejection biology under specific types of immunosuppression remains to be defined. Furthermore, development of innovative, rationally designed targeted therapeutics for mitigating or preventing rejection requires a fundamental understanding of the immunobiology that underlies the rejection process. The established use of microarray technologies in transplantation has provided great insight into gene transcripts associated with allograft rejection but does not characterize rejection on a single cell level. Therefore, the development of novel genomics tools, such as single cell sequencing techniques, combined with powerful bioinformatics approaches, has enabled characterization of immune processes at the single cell level. This can provide profound insights into the rejection process, including identification of resident and infiltrating cell transcriptomes, cell-cell interactions, and T cell receptor α/β repertoires. In this review, we discuss genomic analysis techniques, including microarray, bulk RNAseq (bulkSeq), single-cell RNAseq (scRNAseq), and spatial transcriptomic (ST) techniques, including considerations of their benefits and limitations. Further, other techniques, such as chromatin analysis via assay for transposase-accessible chromatin sequencing (ATACseq), bioinformatic regulatory network analyses, and protein-based approaches are also examined. Application of these tools will play a crucial role in redefining transplant rejection with single cell resolution and likely aid in the development of future immunomodulatory therapies in solid organ transplantation.

STING and transplantation: can targeting this pathway improve outcomes?

Blood ◽  
2021 ◽  
Vol 137 (14) ◽  
pp. 1871-1878
Author(s):  
Cameron S. Bader ◽  
Lei Jin ◽  
Robert B. Levy
Keyword(s):  
Solid Organ Transplantation ◽  
Cell Types ◽  
Malignant Cell ◽  
Innate Immune ◽  
Host Cells ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Unique Role ◽  
Graft Versus Host ◽  
Autologous Hsct

Abstract Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review, we discuss STING in allo-HSCT and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.

scholarly journals Chronic Rejection and Extrahepatic Biliary Tract Obstruction 8 Years After Orthotopic Liver Transplantation Using the Gallbladder-Conduit Technique

HPB Surgery ◽  
1991 ◽  
Vol 5 (1) ◽  
pp. 17-22 ◽  
Author(s):  
J. Lerut ◽  
A. Zimmermann ◽  
Ph. Gertsch ◽  
R. Preisig ◽  
L. H. Blumgart
Keyword(s):  
Liver Transplantation ◽  
Orthotopic Liver Transplantation ◽  
Biliary Tract ◽  
Significant Role ◽  
Allograft Rejection ◽  
Chronic Rejection ◽  
Biliary Obstruction ◽  
Chronic Allograft Rejection ◽  
Extrahepatic Biliary Obstruction

A case of delayed biliary obstruction and cholangitis, occurring in the setting of chronic allograft rejection, 8 years after liver transplantation using the gallbladder-conduit, is presented. Extrahepatic biliary obstruction may be seen in the late follow-up of liver grafting and rejection phenomena may play a significant role in the development of such obstruction.

scholarly journals Epitope-Level Matching—A Review of the Novel Concept of Eplets in Transplant Histocompatibility

2021 ◽  
Vol 2 (3) ◽  
pp. 336-347
Author(s):  
André Renaldo ◽  
Adriel Roa-Bautista ◽  
Elena González-López ◽  
Marcos López-Hoyos ◽  
David San Segundo
Keyword(s):  
De Novo ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Human Leukocyte ◽  
Future Research ◽  
Solid Organ ◽  
Leukocyte Antigen ◽  
Definition Of ◽  
Novel Concept ◽  
Hla Compatibility

The development of de novo donor-specific antibodies is related to the poor matching of the human leukocyte antigen (HLA) between donor and recipient, which leads to dismal clinical outcomes and graft loss. However, new approaches that stratify the risks of long-term graft failure in solid organ transplantation have emerged, changing the paradigm of HLA compatibility. In addition, advances in software development have given rise to a new structurally based algorithm known as HLA Matchmaker, which determines compatibility at the epitope rather than the antigen level. Although this technique still has limitations, plenty of research maintains that this assessment represents a more complete and detailed definition of HLA compatibility. This review summarizes recent aspects of eplet mismatches, highlighting the most recent advances and future research directions.

Anti-CD20 Monoclonal Antibody (rituximab) for Refractory PTLD after Pediatric Solid Organ Transplantation: Multicenter Experience from a Registry and from a Prospective Clinical Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 746-746 ◽  
Author(s):  
Steven Webber ◽  
William Harmon ◽  
Albert Faro ◽  
Michael Green ◽  
Minnie Sarwal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
B Cell ◽  
Organ Transplantation ◽  
Graft Loss ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Refractory Disease ◽  
First Line

Abstract Background: Anti B cell antibodies have been proposed as a treatment for post-transplant lymphoproliferative disorders (PTLD). Experience in children is limited. Methods and Results: We report experience (n=40) with use of the chimeric mouse/human antiCD20 monoclonal antibody (rituximab) in pediatric PTLD patients with refractory disease (no response to reduced immunosuppression, progressive or relapsed disease, or concomitant allograft rejection). Initial experience was through a voluntary registry (n=26), and most recent experience is from an onging prospective, non-randomized clinical trial (n=14). Use of chemotherapy or other experimental therapies were an exclusion criteria for both studies. All PTLD were of B cell origin and expressed CD20 and all but 2 (both in registry cohort) were EBV positive. The first cohort (registry) comprised 26 solid organ recipients from 12 centers (heart 11, kidney 6, lung 4, other 5) with mean age of 12.5 years, 29 months (range 2–132) from transplant. Histology revealed these lesions: polymorphic 17, monomorphic 7 (including 1 Burkitts-like), Hodgkins-like 1, unspecified 1. 21/26 received 375mg/m2 x 4 doses. There were no SAE’s. 18 pts (69%) showed CR, and 4 (16%) showed PR. The 4 non-responders comprised the 2 EBV negative cases, the Burkitts-like disease and the earliest onset case (fulminant disease at 2 months post-transplant). At latest follow-up (mean 41 months), 73% survive with one graft loss (kidney). In the prospective clinical trial, 14 patients (to date) with refractory disease were enrolled. The protocol comprises 4 doses of 375mg/m2 (weeks 1–4) with no further treatment for patients with CR or for those with no response. Patients with PR receive 4 further doses (weeks 5–8). The 14 patients were from 5 centers (lung 5, kidney 5, heart 4) with mean age of 6.5 years, 41 months (range 4–120) from transplant. Histology revealed the following: polymorphic 10, monomorphic 3, Hodgkin-like 1. There were no SAE’s. Two are still recieving therapy. Of the other 12, 9 (75%) acheived CR and 10 pts (83%) are alive with one graft loss (kidney) at mean follow-up of 1.5 years. The two deaths were due to fungal pneumonia and complications of elective surgery in a patient in CR (both lung recipients). Conclusions: These results suggest that rituximab may have an important role to play in management of refractory PTLD in solid organ recipients (CR rate approx. 70–75% with low incidence of graft loss). This group of patients traditionally has high mortality and has been treated with chemotherapy. Rituximab should be considered as first line treatment for refractory polymorphic PTLD in children after solid organ transplantation. Role in monomorphic disease requires further investigation. Use of rituximab as first line therapy is under investigation.

scholarly journals A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy

2008 ◽  
Vol 205 (13) ◽  
pp. 3133-3144 ◽  
Author(s):  
Xueli Yuan ◽  
Jesus Paez-Cortez ◽  
Isabela Schmitt-Knosalla ◽  
Francesca D'Addio ◽  
Bechara Mfarrej ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Allograft Rejection ◽  
Th17 Cells ◽  
Vascular Inflammation ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Proinflammatory Response ◽  
Ifn Γ ◽  
Intractable Problem

T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in the development of allograft rejection in an established MHC class II–mismatched (bm12 into B6) model of chronic allograft vasculopathy (CAV). Intriguingly, and in contrast to IFN-γ−/− mice that are protected from CAV, T-bet−/− recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17–producing CD4 T cells. Concurrently, T-bet−/− mice exhibit a T helper type 1 (Th1)–deficient environment characterized by profound IFN-γ deficiency, a Th2 switch characterized by increased production of interleukin (IL) 4, IL-5, IL-10, and IL-13 cytokines, as well as increased production of the proinflammatory cytokines IL-6, IL-12p40, and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection and vasculopathy in T-bet−/− mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet−/− mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first study establishing that in the absence of Th1-mediated alloimmune responses, CD4 Th17 cells mediate an aggressive proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for the development of novel therapies to target this intractable problem in clinical solid organ transplantation.

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