Cytokine profile associated with selective removal of natural anti-αGal antibodies in a sepsis model in Gal-KO mice

Abstract

Selective depletion of natural anti-Galα1-3Galβ1-4GlcNAc (so-called anti-αGal) antibodies is achieved in α1,3-galactosyltransferase knockout (Gal-KO) mice by administration of the soluble glycoconjugate of αGal GAS914. This molecule removed up to 90% of natural circulating anti-αGal antibodies without causing unspecific production of cytokines in wild-type (CBA) and Gal-KO mice. However, the removal of anti-αGal antibodies in Gal-KO mice with GAS914 in the context of sepsis after cecal ligation and puncture (CLP) was associated with a significant increase in the production of leptin, CXLC1, CXLC13, and TIMP-1 cytokines compared to vehicle (PBS)-treated controls. Despite the current lack of understanding of the underlying mechanism, our data suggest a putative role of natural anti-αGal antibodies in the regulation of some cytokines during sepsis.

Gut Microbiota Abrogates Anti-α-Gal IgA Response in Lungs and Protects against Experimental Aspergillus Infection in Poultry

“…Interaction between host anti-α-Gal Abs and pathogens expressing α-Gal might play a role in benefit of pathogen survival, as shown for the blood isolate #21 of Serratia marcescens , where binding of anti-α-Gal Abs to the bacterial lipopolysaccharide (LPS) blocked alternative complement pathway (ACP)-mediated lysis of the bacteria [ 50 ]. Likewise, depletion of inhibitory serum anti-α-Gal Abs by a soluble trisaccharide-polylysine conjugate (commercial name RA-01, ) protected patients from multidrug-resistant Gram-negative bacteria, including E. coli , Pseudomonas aeruginosa , and Klebsiella pneumonia expressing α-Gal [ 50 , 51 , 52 ]. In the present study, A. fumigatus was the sole Ascomycota expressing α-Gal.…”

Poly-L-Lysine-Based αGal-Glycoconjugates for Treating Anti-αGal IgE-Mediated Diseases

“…Anti-αGal antibodies inhibition with monovalent compounds has been demonstrated as inefficient due to their low affinity for single oligosaccharides ( 53 ). Previously, GAS914 has shown a maximal increase in avidity (relative to the monomer) by anti-αGal IgM and IgG antibodies ( 53 , 70 ). Nevertheless, there is no data on whether the anti-αGal IgE inhibition could be affected using multivalent αGal compounds.…”

“…However, the significant contribution of anti-αGal IgG to the total IgG2b was surprising, indicating a preferential induction of this IgG subclass. GalT-KO mice naturally produce anti-αGal antibodies ( 15 , 70 ), with IgG3 as the predominant IgG subclass (manuscript submitted to publication). In mice, the IgG3 subclass is functionally equivalent to human IgG2, which predominantly recognizes carbohydrate epitopes ( 84 , 85 ).…”