Anti-Gal and anti-Neu5Gc responses in nonimmunosuppressed patients following treatment with rabbit anti-thymocyte polyclonal IgGs.

Background: Polyclonal anti-human thymocyte rabbit IgGs (anti-thymocyte globulin, ATG) are popular immunosuppressive drugs used to prevent or treat organ or bone-marrow allograft rejection, graft versus host disease, and autoimmune diseases. However, animal-derived glycoproteins are also strongly immunogenic and rabbit ATG induces serum sickness disease in almost all patients without additional immunosuppressive drugs, as seen in the START trial of ATG therapy in new-onset type 1 diabetes. Methods: Using ELISA, we analyzed serial sera from the START study to decipher the various anti-ATG specificities developed by the patients in this study: anti-total ATG, but also anti-galactose-[alpha]1-3-galactose (Gal) and anti-Neu5Gc antibodies, 2 xeno-carbohydrate epitopes present on rabbit IgG glycans and lacking in humans. Results: We show that diabetic patients have substantial levels of preexisting antibodies of the 3 specificities, before infusion, but of similar levels as healthy individuals. ATG treatment resulted in highly significant increases of both IgM (for anti-ATG and anti-Neu5Gc) and IgG (for anti-ATG, -Gal, and -Neu5Gc), peaking at 1 month and still detectable 1 year postinfusion. Conclusions: Treatment with rabbit polyclonal IgGs in the absence of additional immunosuppression results in a vigorous response against Gal and Neu5Gc epitopes, contributing to an inflammatory environment that may compromise the efficacy of ATG therapy. The results also suggest using IgGs lacking these major xeno-antigens may improve safety and efficacy of ATG treatment. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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