Relative roles of hCD46 and hCD55 in the regulation of hyperacute rejection

Verbakel, Caroline; Bonthuis, Fred; Eerhart, S.E.; Dixhoorn, M. van; Grosveld, Frank; Marquet, R. L.; IJzermans, Jan N.M.

doi:10.1016/s0041-1345(00)01030-7

Cited by 3 publications

(2 citation statements)

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“…Large recombinant molecules are expensive to produce, and TP10 never came to routine clinical use. Other regulators like CD55, CD46, and CD59 have also been made recombinantly as possible drugs and tested experimentally (Verbakel et al, 2000).…”

Section: Monoclonal Antibodies and Their Derivativesmentioning

confidence: 99%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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The complement system was discovered at the end of the 19th century as a heat-labile plasma component that “complemented” the antibodies in killing microbes, hence the name “complement.” Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. Significance Statement The complement system is the host’s defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host’s enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

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Section: Monoclonal Antibodies and Their Derivativesmentioning

confidence: 99%

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

2021

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“…The Langendorff perfusion system has been employed by us to evaluate the relative importance of human CRPs on the performance of mouse hearts perfused with human serum. In this ex vivo model of xenotransplantation, we showed that over‐expression of human MCP (hCD46) or human DAF (hCD55), but not hCD59, protected hearts against hyperacute rejection [10–13].…”

Section: Introductionmentioning

confidence: 99%

Contrast in the efficacy of hDAF mouse hearts between ex vivo perfusion and transplantation into primates

Verbakel

Bruin

Bonthuis

et al. 2001

Xenotransplantation

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In recent experiments, in which we compared hDAF transgenic rat hearts perfused with 15% human serum in the Langendorff device and hDAF rat hearts transplanted into cynomolgus monkeys, we demonstrated that in the ex vivo heart perfusion model both homozygous and heterozygous hDAF hearts survived longer as nontransgenic controls. Surprisingly, we found that only homozygous hDAF hearts were protected against hyperacute rejection in vivo. The first aim of this study was to determine whether perfusion of mouse hearts with higher human serum concentrations or human blood might explain some of the differences found in survival time of the recently performed experiments with rat heart xenografts. Secondly, we investigated whether the observed differences in survival times of rat xenografts between in vivo and ex vivo transplantation would also hold for mouse hearts transgenic for hDAF. An ex vivo model was used to perfuse hDAF mouse hearts and controls with human serum or blood, and hDAF transgenic hearts and controls were transplanted into cynomolgus monkeys. hDAF transgenic mouse hearts survived significantly longer than their controls when perfused with 15% human serum, but no difference was found when 30% human serum was used, or when these hearts were transplanted into cynomolgus monkeys. However, in both the in vivo and ex vivo models the amount of PMNs adhering to the vascular endothelium was significantly lower in hDAF transgenes as compared with their controls. In conclusion, in the ex vivo situation, the efficacy of hDAF transgenesis in preventing HAR is limited by serum complement concentration.

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The regulation of the complement system: insights from genetically-engineered mice

Turnberg

2003

Molecular Immunology

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Relative roles of hCD46 and hCD55 in the regulation of hyperacute rejection

Cited by 3 publications

References 3 publications

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics

Contrast in the efficacy of hDAF mouse hearts between ex vivo perfusion and transplantation into primates

The regulation of the complement system: insights from genetically-engineered mice

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