- Dr Barbara A. Wasowska, Principal Investigator
- Johns Hopkins University, Baltimore, USA
- Sialylated IgG Antibodies Inhibit Inflammation and Graft Rejection
Alloantibody-mediated organ rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has recently been recognized as a major cause of allograft loss. High level of circulating anti-HLA alloantibodies and ABO incompatibility remain the two major obstacles to optimal use of organs for successful transplantation, especially kidneys, from living donors. Almost 30% of patients are on renal transplant waiting list due to a positive cross-match.
All IgG antibodies are glycoproteins that contain a branched sugar structure attached to the aspargine 297 residue within Fc fragment of antibody (N-linked glycan). The level of sialylation/glycosylation of this glycan is crucial for the effector pro- or anti-inflammatory functions of antibody, resulting in complement activation and interaction with Fc receptors.
To date there were no studies on the effects of highly sialylated antibodies on endothelial cell protection/accommodation. This project is designed to test in vivo and in vitro models of cardiac injury the hypothesis that the sialyc acid residues-enriched populations of IgG significantly contribute to inhibition of pro-inflammatory immune responses leading to EC accommodation and graft protection.
In the Specific Aims 1 and 2 we will test separately in vitro the anti-inflammatory effects of sialyc acid residue-enriched populations of allo-monoclonal antibodies (allo-mAbs) specific for MHC class I (H-2Kk) on inhibition of complement and Fc receptor (FcR) pathways leading to EC protection/accommodation. In the Specific Aim 3, highly sialylated glycoforms of allo-mAbs will be tested in vivo in Ig knock-out mice with cardiac transplants, where both complement and FcR-dependent pathways are involved. In the Specific Aim 4 we will screen human sera from the unique group of highly sensitized and ABO incompatible patients transplanted at Johns Hopkins Comprehensive Transplant Center.
These experiments will provide the first data regarding the potential functional properties of alloantibodies and ABO isoagglutinins that may contribute to pro-and/or anti-inflammatory immune-mediated effector functions resulting in graft rejection or protection.