http://cybernephrology.ualberta.ca/Banff/2015/Publications/banff09.pdf

Banff '09 meeting report: Antibody mediated graft deterioration and implementation of Banff working groups

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2011.03836.x

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-6143.2009.02819.x

Effect of antibodies on endothelium.

Bacterial contamination and emerging infections combined with increased international travel pose a great risk to the safety of the blood supply. Tests to detect the presence of infection in a donor have a 'window period' during which infections cannot be detected but the donor may be infectious. Agents and their transmission routes need to be recognized before specific tests can be developed. Pathogen reduction of blood components represents a means to address these concerns and is a proactive approach for the prevention of transfusion-transmitted diseases. The expectation of a pathogen reduction system is that it achieves high enough levels of pathogen reduction to reduce or prevent the likelihood of disease transmission while preserving adequate cell and protein quality. In addition the system needs to be non-toxic, non-mutagenic and should be simple to use. The Mirasol® Pathogen Reduction Technology (PRT) System for Platelets and Plasma uses riboflavin (vitamin B2) plus UV light to induce damage in nucleic acid-containing agents. The system has been shown to be effective against clinically relevant pathogens and inactivates leukocytes without significantly compromising the efficacy of the product or resulting in product loss. Riboflavin is a naturally occurring vitamin with a well-known and well-characterized safety profile. The same methodology is currently under development for the treatment of whole blood, making pathogen reduction of all blood products using one system achievable. This review gives an overview of the Mirasol PRT System, summarizing the mechanism of action, toxicology profile, pathogen reduction performance and clinical efficacy of the process.

/pdf/pathogen-reduction-technology-treatment-of-platelets-plasma-1zh7rcm71p.pdf

Pathogen Reduction Technology Treatment of Platelets, Plasma and Whole Blood Using Riboflavin and UV Light.

https://www.kidney-international.org/article/S0085-2538(15)55377-5/pdf

Pros and cons for C4d as a biomarker

Background Antibody-mediated rejection is characterized by macrophage margination against vascular endothelium. The potential interactions triggered by antibodies between endothelial cells (EC) and macrophages have not been examined thoroughly in transplants. We used in vivo and in vitro models of antibody-mediated rejection. Methods Passive transfer of monoclonal alloantibodies (Allo-mAbs) to donor major histocompatibility complex-class I antigens was used to restore acute rejection of B10.A (H-2a) hearts to C57BL/6 (H-2b) immunoglobulin knockout (IgKO) recipients. Intragraft cytokine mRNA expression was measured by real-time polymerase chain reaction. In vitro, mouse EC were cultured in the presence of Allo-mAbs to donor major histocompatibility complex class I antigens and mononuclear cells. Levels of cytokines in culture supernatants were determined in enzyme-linked immunosorbent assay. Results Expression of MCP-1, IL-6 and IL-1alpha mRNA was higher in rejecting transplants from recipients treated with Allo-mAbs compared to non-rejecting transplants. EC sensitized with Allo-mAbs produced high levels of MCP-1 and KC. The addition of macrophages to sensitized EC stimulated high levels of IL-6 in addition to MCP-1, KC, Rantes, and TIMP-1. The levels of MCP-1 and IL-6 were significantly lower in co-cultures of EC sensitized with IgG1 Allo-mAbs in the presence of mononuclear cells from Fcgamma-Receptor III KO (FcgammaRIII-KO) graft recipients compared to co-cultures with wild-type cells. The levels of both cytokines were also lower in co-cultures of EC stimulated with F(ab')2 fragments of antibody. Conclusions Our findings indicate that IgG1 Allo-mAbs to major histocompatibility complex class I antigens can augment graft injury by stimulating EC to produce MCP-1 and by activating mononuclear cells through their Fc receptors.

The involvement of FcR mechanisms in antibody-mediated rejection.

Background. Functional leukocytes in blood transfusions can cause alloimmunization. Previous studies have shown that exposure of platelet concentrates to riboflavin and light (Mirasol PRT treatment) causes irreparable modification of nucleic acids. This treatment does not interfere with platelet function but does inhibit a wide range of immunological functions of leukocytes present in platelet concentrates. The current study evaluated the ability of Mirasol treatment to prevent alloimmunization by platelet transfusions in rats. Methods. Lewis rats received eight transfusions of untreated or Mirasol-treated platelets containing leukocytes from DA rats. Animals were subsequently challenged with a heart transplant under cyclosporine treatment. Results. Mirasol treatment caused apoptosis of the leukocytes as measured by annexin V and CD45 staining. Complement split products were deposited on the apoptotic bodies in the platelet pack. The primary and secondary immunoglobulin (Ig) M and IgG responses in rats that received Mirasol-treated platelets were almost completely abolished compared to animals that received untreated platelets. Untreated platelet transfusions elicited strong IgG responses that were associated with rapid rejection of subsequent heart transplants. Rejected hearts contained macrophage infiltrates and C4d deposits. In contrast, no grafts were rejected by recipients transfused with Mirasol-treated platelets. Macrophage infiltrates and C4d deposits were decreased in these grafts. Recipients that were presensitized to untreated platelets were capable of producing a memory response to Mirasol-treated platelets that caused accelerated rejection of subsequent transplants. Conclusions. Transfusions of platelets that were treated with riboflavin and ultraviolet light prevented presensitization to transplants. However, Mirasol-treated platelets were immunogenic in presensitized recipients.

Melek M. Erdinc

Papers

The involvement of FcR mechanisms in antibody-mediated rejection.

Treatment with riboflavin and ultraviolet light prevents alloimmunization to platelet transfusions and cardiac transplants.