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Carbohydrate antigen microarray analysis of serum IgG and IgM antibodies before and after adult porcine islet xenotransplantation in cynomolgus macaques - PubMed

  • ️Fri Jan 01 2021

Carbohydrate antigen microarray analysis of serum IgG and IgM antibodies before and after adult porcine islet xenotransplantation in cynomolgus macaques

Yoshihide Nanno et al. PLoS One. 2021.

Abstract

Understanding the anti-carbohydrate antibody response toward epitopes expressed on porcine cells, tissues, and organs is critical to advancing xenotransplantation toward clinical application. In this study, we determined IgM and IgG antibody specificities and relative concentrations in five cynomolgus monkeys at baseline and at intervals following intraportal xenotransplantation of adult porcine islets. This study utilized a carbohydrate antigen microarray that comprised more than 400 glycoconjugates, including historically reported α-Gal and non-α-Gal carbohydrate antigens with various modifications. The elicited anti-carbohydrate antibody responses were predominantly IgM compared to IgG in 4 out of 5 monkeys. Patterns of elicited antibody responses greater than 1.5 difference (log2 base units; 2.8-fold on a linear scale) from pre-serum to post-serum sampling specific for carbohydrate antigens were heterogeneous and recipient-specific. Increases in the elicited antibody response to α-Gal, Sda, GM2 antigens, or Lexis X antigen were found in individual monkeys. The novel carbohydrate structures Galβ1-4GlcNAcβ1-3Galβ1 and N-linked glycans with Manα1-6(GlcNAcβ1-2Manα1-3)Manβ1-4GlcNAcβ structure were common targets of elicited IgM antibodies. These results provide important insights into the carbohydrate epitopes that elicit antibodies following pig-to-monkey islet xenotransplantation and reveal possible targets for gene editing.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: BJH has an equity interest in and serves as an executive officer of Diabetes-Free, Inc, an organization that may commercially benefit from the results of this research. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies, and does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. The distribution (log-transformed base 2) of 50 highest serum IgM (A) and IgG (B) elicited antibody signals in five monkeys.

The number after the abbreviation indicates the average number of carbohydrates per molecule of albumin. The circle represents the median of the five monkeys, and the bars represent the standard deviation for the group.

Fig 2
Fig 2. Comparison of antibody signals in each monkey.

Signals for each carbohydrate in posttransplant serum were plotted against pretransplant naïve serum. Signals are on the log 2 scale. The plots in a blue triangle represent carbohydrate antigens that are increased in the posttransplant serum. The plots in a red triangle represent carbohydrate antigens that are significantly increased (the changes of normalized signal intensity ≥1.5) in the posttransplant serum. The blood type of a monkey is noted in brackets.

Fig 3
Fig 3. The list of carbohydrates that were significantly elicited in the posttransplant sera (the changes of normalized signal intensity ≥1.5; naïve sera, gray; posttransplant sera, black).

(A) IgM repertoire. (B) IgG repertoire. The number after the abbreviation indicates the average number of carbohydrates per molecule of albumin. The blood type of a monkey is noted in brackets.

Fig 4
Fig 4. The list of antibody signals against historically reported α-Gal and non-α-Gal carbohydrate antigens in IgM and IgG repertoires.

The α-Gal antigens include carbohydrate structures with Galα1-3Gal epitope. The non-α-Gal antigens include carbohydrate structures with Sda and Neu5Gc epitopes. The number after the abbreviation indicates the average number of carbohydrates per molecule of albumin. An antibody signal that is significantly increased (the changes of normalized signal intensity ≥1.5) in the posttransplant serum is marked with an asterisk.

Fig 5
Fig 5. Carbohydrate antigens elicited in common among sensitized monkey sera.

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