A transgenic mouse model for studying the clearance of blood-borne pathogens via human complement receptor 1 (CR1)

Abstract

SummaryComplement receptor 1 (CR1) on the surface of human erythrocytes facilitates intravascular clearance of complement-opsonized pathogens. The need for complement activation can be circumvented by directly coupling the organism to CR1 using a bispecific monoclonal antibody heteropolymer (HP). Lack of a functional homologue to CR1 on mouse erythrocytes has made it difficult to study HP-dependent clearance of pathogens in small animals. We have developed a transgenic mouse that expresses human CR1 on erythrocytes. CR1 antigen is of appropriate size and in a clustered distribution as confirmed by immunoblotting and fluorescence microscopy, respectively. HP that immobilized bacteriophage F F F F X174 prototype pathogen to erythrocyte CR1 of the transgenic mice increased the rate of clearance of the virus compared with HP that bound bacteriophage, but not CR1. This transgenic mouse model will allow evaluation of different HPs for their in vivo efficacy and potential as human therapeutics.

Abnormal Immune Complex Processing and Spontaneous Glomerulonephritis in Complement Factor H-Deficient Mice with Human Complement Receptor 1 on Erythrocytes

“…2A, apoferritin-immunized CR1 hu Tg but not CFH 2/2 mice had platelet-associated IgG, which is consistent with the importance of platelet-associated CFH to bind ICs. Interestingly, CR1 hu Tg/CFH 2/2 mice immunized with apoferritin had some platelet-associated IgG, perhaps owing to platelet-associated CR1 hu (25). Only CR1 hu Tg mice immunized with apoferritin had Eassociated IgG, with slightly less present in CR1 hu Tg/CFH 2/2 mice relative to CR1 hu Tg mice with intact CFH, possibly reflecting the acquired hypocomplementemia in the former, which could reduce IC binding to CR1.…”

“…To examine a system potentially more relevant to humans, in which E CR1 is responsible for IC processing, we used transgenic mice expressing human CR1 under a GATA1 promoter that drives expression in erythroid cells (CR1 hu Tg) (25). We generated CR1 hu Tg/ CFH 2/2 mice to simulate and study IC processing by E-CR1.…”

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood

“…In vivo models that have been used before are transgenic mice that express CAR or CR1 or immunodeficient NOD-SCID mice injected with human erythrocytes. [31][32][33] In these models, the circulation time increased and hepatocytic infection decreased because of erythrocyte binding and are in that way more similar to the human situation. Although these models provide a step forward, the transgenic mice have either CAR or CR1 but not both receptors.…”

The erythrocyte viral trap: Transgenic expression of viral receptor on erythrocytes attenuates coxsackievirus B infection

“…Deliberate construction of these reagents should avoid clearance by the immune system and permit the receptor to persist on the erythrocyte surface for the normal life of the cell. We have successfully used heteropolymers composed of two antibodies to clear phage from the bloodstream (43) and expect that receptor-antibody heteropolymer also will be effective.…”