INSERM UMR 1064 Center of Research in Transplantation and Immunology
ITUN Institut Transplantation Urologie Néphrologie
Increased late graft loss in kidney recipients with serum sickness disease following anti-thymocyte globulin induction: relation with an anti-Neu5Gc response
Apolline Salama1,2, Grégoire Couvrat-Desvergnes1, Ludmilla Le Berre1, Gwénaëlle Evanno1,3, Ondrej Viklicky4, Petra Hruba4, Pavel Vesely5, Pierrick Guerif1, Thomas Dejoie6, Arnaud B Nicot1, Jean-Marie Bach7, Sophie Brouard1, Stéphanie Castagnet8, Magali Giral1, Jean Harb1, Yohann Foucher1,9, Marine Lorent1,9, Jean-Paul Soulillou1.
1Institut de Transplantation-Urologie-Néphrologie ITUN, INSERM UMR 1064, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France; 2Société d'Accélération du Transfert de Technologies Ouest Valorisation, Rennes, France; 3Xenothera, Nantes, France; 4Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 5Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic; 6Biochemistry laboratory, Centre Hospitalier Universitaire CHU de Nantes, Nantes, France; 7Immuno-endocrinology Unit IECM, EA4644 University/ONIRIS USC1383 INRA, ONIRIS, Nantes, France; 8Etablissement Français du sang Pays de la Loire, Laboratoire HLA, Nantes, France; 9EA 4275 SPHERE, bioStatistics, Pharmacoepidemiology and Human sciEnces REsearch, Nantes, France
Rabbit IgGs against human T cells, such as anti-thymocyte globulins (ATG), are widely used as an induction treatment in kidney allograft recipients. However, these animal-derived polyclonal IgGs can induce immune-complex diseases in human recipients, including serum sickness (SSD). Notably, rabbit and human IgGs differ in the expression of the glycolyl form of neuraminic acid Neu5Gc, and humans exhibit preexisting and produce elicited anti-Neu5Gc antibodies. The aim of this study was first to evaluate a possible link between SSD following ATG induction treatment and long term graft outcome, and second to assess anti-Neu5Gc antibodies in grafted patients exhibiting a SSD.
To assess the role of SSD on long-term allograft outcome, a cohort of 889 first kidney graft recipients with ATG induction, grafted between 1985 and 1998 (n=86 with overt SSD (SSD+) and n=803 without SSD (SSD-)), was extracted from the DIVAT database. From this large cohort, we show that SSD is associated with the risk of graft failure (death-censored, HR=1.72, p=0.022).
The immunization status against xeno-antigens was then specifically analyzed in a subgroup of this population. Levels of total anti-ATG and anti-Neu5Gc IgGs, as well as antibodies against galactose-α(1,3)-galactose (α1-3 Gal) were analyzed in a case-control subgroup constituted of 13 SSD+ patients, paired with 13 SSD- control patients matched for 5 variables (recipient age ±10 years, transplantation year ±2 years, PRA class I positivity, PRA class II positivity and number of HLA mismatches (³4/<4)). All patients displayed preexisting antibodies. No significant differences were found in preexisting antibodies of any type, and baseline levels did not differ from levels found in a cohort of 70 healthy individuals matched for gender and age. SSD+ patients exhibited elevated titers of anti-ATG (p=0.001) and anti-Neu5Gc (p=0.054) between pre-graft and late post-graft samples (>4 years post-graft). Importantly, anti-ATG and anti-Neu5Gc IgGs were increased in late post-graft sera of SSD+ patients when compared to SSD- patients (p=0.043 and p=0.007 respectively). Anti-Gal antibody levels were not informative, as no difference was observed at any time point. Finally, pilot data suggest that late graft failure is associated with high anti-Neu5Gc IgG levels in late post-graft samples, independently of the SSD status (p=0.004).
In conclusion, our data indicate that ATG-induced SSD is an independent risk factor of graft failure, and suggest that anti-Neu5Gc antibodies could have a role in allograft outcome following SSD.
Société d’Accélération du Transfert de Technologies Ouest Valorisation. European FP7 ‘Translink’ research program (n°603049). French National Agency of Research (ANR-11-JSV1-0008-01). Labex Transplantex.
15:30 - 16:30
|Non-Gal Antibodies||Increased late graft loss in kidney recipients with serum sickness disease following anti-thymocyte globulin induction: relation with an anti-Neu5Gc response||Room 109|
15:30 - 17:00
|Genetic Engineering; Methodology||Immune phenotype and IgG characteristics of Neu5Gc and alpha-1-3-Gal double knock-out pigs||Room 109|