Heparan Sulfate Proteoglycan Metabolism and the Fate of Grafted Tissues

Abstract

Tissue and organ transplants between genetically distinct individuals are always or nearly always rejected. The universality and speed of transplant rejection distinguishes this immune response from all others. Although this distinction is incompletely understood, some efforts to shed light on transplant rejection have revealed broader insights, including a relationship between activation of complement in grafted tissues, the metabolism of heparan sulfate proteoglycan and the nature of immune and inflammatory responses that ensue. Complement activation on cell surfaces, especially on endothelial cell surfaces, causes the shedding heparan sulfate, an acidic saccharide, from the cell surface and neighboring extracellular matrix. Solubilized in this way, heparan sulfate can activate leukocytes via toll like receptor-4, triggering inflammatory responses and activating dendritic cells, which migrate to regional lymphoid organs where they spark and to some extent govern cellular immune responses. In this way local ischemia, tissue injury and infection, exert systemic impact on immunity. Whether or in what circumstances this series of events explains the distinct characteristics of the immune response to transplants is still unclear but the events offer insight into the inception of immunity under the sub-optimal conditions accompanying infection and mechanisms by which infection and tissue injury engender systemic inflammation.

The complex functioning of the complement system in xenotransplantation

“…Ergidina, a neutralizing recombinant anti‐C5 antibody, protected rat kidneys from IRI by binding to injured endothelium . The glycocalyx has been proven to be critical for protecting endothelial cells from activation during xenotransplantion . The application of heparin onto mesenchymal stem cells, or endothelial cells, which would help to avoid or mitigate the shedding of the glycocalyx on the cell surface, may inhibit complement activation and improve graft cell viability.…”

Accommodation in ABO‐incompatible organ transplants

“…The responses of blood vessels to activation of complement (and/or interaction with activated phagocytes) characteristic of rejection reflect initial physiologic responses to foreign agents and noxious conditions. 19,80,83 At sites where an infectious agent or toxin is located, the responses wall off microorganisms or toxins, preventing systemic spread (the problem in transplantation is that the assault and the response is diffuse in the grafted organ). The processes we think reflect accommodation, then, are likewise orchestrated to reverse the physiology introduced by the initial defenses once the organism or toxin is destroyed.…”

“…The surface of endothelial cells is decorated by acidic saccharides, such as heparan sulfate, and by complement regulatory proteins that slow and potentially block activation of complement. 19 Further, nucleated cells actively dispose of the products of complement activation, profoundly modifying the kinetics F I G U R E 1 Chronology of rejection and accommodation of ABO-incompatible kidney transplants. A, Rejection of ABO-incompatible kidney transplants.…”

Danger signals in regulating the immune response to solid organ transplantation

“…Both surface-bound and soluble HS can act as DAMPs to initiate the immune response in the context of cell injury. Moreover, cell surface HS can enable the response to other DAMPs, specifically HMGB1, by facilitating the oligomerization of RAGE, an essential step in RAGE signal transduction, while soluble HS can interact with TLR4 to release proinflammatory cytokines and promote DC maturation (66)(67)(68).…”