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Anti‐Gal activity In diabetic patients transplanted with fetal porcine Islet cell clusters
Author(s) -
Gaiili Uri,
Tibeil Annika,
Samuelsson Bo,
Rydberg Lennart,
Groth Carl Gustav
Publication year - 1995
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/j.1399-3089.1995.tb00092.x
Subject(s) - epitope , xenotransplantation , antibody , titer , antigen , immune system , transplantation , hemagglutination , microbiology and biotechnology , biology , isoantibodies , antibody titer , immunology , chemistry , medicine
The natural anti‐Gal antibody seems to create a major obstacle for discordant xenotransplantation in humans. It is produced in large amounts in humans (20–100 μg/ml serum), and interacts specifically with the carbohydrate structure Galα1–3Galβ1–4GlcNAc‐R (termed, the a‐galactosyl epitope). The a‐galactosyl epitope is produced in large amounts on porcine cells, as on cells of other nonprimate mammals (1×10 6 to 35×10 6 epitopes per cell). The interaction of anti‐Gal with α‐galactosyl epitopes on the xenograft was found to mediate the immune destruction of discordant xenografts. In view of the intensive production of anti‐Gal under physiologic conditions, it was of interest to determine whether the immune system in humans reacts against α‐galactosyl epitopes on xenografts by increasing the activity (i.e., titer and affinity) of this antibody. For this purpose, anti‐Gal titer and affinity were studied in sera of diabetic patients transplanted with fetal porcine islet cell clusters (ICC) by Groth and colleagues (Lancet 1994:344:1402). Titers of anti‐Gal were determined by a hemagglutination assay with rabbit red blood cells and by ELISA with mouse laminin as a solid‐phase antigen. Affinity of the antibody was estimated by equilibrium dialysis with the radiolabeled free haptenic form of the a‐galactosyl epitope, i.e. [ 3 H]Galα1–3Galβ1–4GlcNAc. All assays revealed a marked increase in anti‐Gal activity within 5–8 weeks posttransplantation. The increase in anti‐Gal titers ranged between eight‐and sixty‐four fold. A similar increase was observed in the affinity of anti‐Gal, as assayed in equilibrium dialysis. Immunoglobulin concentration did not increase posttransplantation, suggesting that the observed increase in anti‐Gal activity is the result of a specific immune response against α‐galactosyl epitopes on the xenograft. The elevation in anti‐Gal activity was observed in all three immunoglobulin classes and the highest activity was found within the IgG class. Furthermore, analysis of antibodies against porcine endothelial cells in ELISA has indicated that most of the increased activity against these cells in the serum of the transplanted patients, may be attributed to the elevation in activity of anti‐Gal. These findings raise the possibility that anti‐Gal, which is highly active in patients with xenotransplants, may contribute to chronic rejection of the xenograft by binding effectively to α‐galactosyl epitopes on the xenograft cells and inducing inflammatory reactions against the graft.