title: Anti-Gal and Anti-Neu5Gc Responses in Nonimmunosuppressed Patients After Treatment With Rabbit Antithymocyte Polyclonal IgGs.
abstract: Polyclonal antihuman thymocyte rabbit IgGs (antithymocyte 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 Study of Thymoglobulin to arrest Type 1 Diabetes (START) trial of ATG therapy in new-onset type 1 diabetes.
  
  
  
  Using enzyme-linked immunosorbent assay, we analyzed serial sera from the START study to decipher the various anti-ATG specificities developed by the patients in this study: antitotal ATG, but also antigalactose-α1-3-galactose (Gal) and anti-Neu5Gc antibodies, 2 xenocarbohydrate epitopes present on rabbit IgG glycans and lacking in humans.
  
  
  
  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.
  
  
  
  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 xenoantigens may improve safety and efficacy of ATG treatment.
authors.affiliation: 1 Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM, Université de Nantes, Nantes, France. 2 Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France. 3 Société d'Accélération du Transfert de Technologies Ouest Valorisation, Rennes, France. 4 Xenothera, Nantes, France. 5 Biomarker Discovery Research, Immune Tolerance Network, Bethesda, MD, USA. 6 IECM, Immuno-endocrinology, EA4644 Oniris, University of Nantes, USC1383 INRA, Oniris, Nantes, France. 7 Clinical Trials Group, Immune Tolerance Network, San Francisco, CA. 8 Division of Pediatric Endocrinology and Diabetes, University of California San Francisco, San Francisco, CA.
authors.forename: Apolline
authors.initials: A
authors.lastname: Salama
authors.forename: Gwénaëlle
authors.initials: G
authors.lastname: Evanno
authors.forename: Noha
authors.initials: N
authors.lastname: Lim
authors.forename: Juliette
authors.initials: J
authors.lastname: Rousse
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Le Berre
authors.forename: Arnaud
authors.initials: A
authors.lastname: Nicot
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bach
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ehlers
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D016035:Pancreas Transplantation / Q000009:adverse effects*; D011817:Rabbits; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; C512542:thymoglobulin