Phosphatidylserine-Based Nanoparticles For Tolerance Induction Towards Therapeutic Proteins

Phosphatidylserine (PS) is the most abundant negatively charged phospholipid in the cell membrane. Despite comprising 12% of total phospholipid and being restricted primarily in the inner leaflet of the membrane bilayer, the consequences of PS externalization to the outer leaflet is biologically significant, especially in hemostasis and apoptosis. The exposure of PS on the surface of apoptotic cells functions as an “eat me” signal that initiates macrophage recognition, uptake, and removal of the apoptotic debris. The apoptotic process is an immunologically silent event, as these apoptotic cells are cleared without activation of the immune system. There is considerable literature evidence that support the fact that PS is a critical mediator in apoptosis, facilitating the efficient removal of cell debris in order to maintain tolerance to self-proteins by immunosuppressive mechanisms and tissue homeostasis. The key function of PS exposure in apoptosis could be exploited for therapeutic implications, such as mitigation of immunogenicity towards therapeutic proteins. The focus of our laboratory is the development of tolerogenic liposomal formulations to reduce immunogenicity and induce immunological hypo-responsiveness towards therapeutic proteins. Factor VIII (FVIII) served as the model protein, as the dysfunction or deficiency of FVIII manifests in Hemophilia A (HA). Despite enzyme replacement therapy as the first line of therapy, about 30% of severe HA patients develop neutralizing (NAbs) or inhibitory titers, severely complicating efficacy of therapy. As a result, any approach designed to reduce immunogenicity and induce tolerance would address an unmet clinical need. Previous studies have shown that subcutaneous pre-treatment of FVIII in the presence of PS liposomes induced hypo-responsiveness after subsequent rechallenge to free FVIII in HA mice. The PS-mediated mechanism involves induction of tolerogenic dendritic cells, secretion of regulatory cytokine TGF-β, generation of regulatory T cells, inhibition of memory B cell development, and reduction of antibody production, resulting in the property of PS to convert an immunogen to a tolerogen. The overall goal of this dissertation is to extend the application of our PS tolerance strategy into multiple sclerosis, a model disease for autoimmunity, as well as to develop and optimize this strategy to enhance the tolerogenic effects of PS tolerance induction.

Grantor dc:publisher

State University of New York at Buffalo

Year dc:date.issued

2018

Author dc:creator

• Glassman, Fiona

Contributors dc:contributor

• Balu-Iyer, Sathy
• Pharmaceutical Sciences

• pharmaceutical sciences

Statement dc:rights

• Users of works found in University at Buffalo Institutional Repository (UBIR) are responsible for identifying and contacting the copyright owner for permission to reuse. University at Buffalo Libraries do not manage rights for copyright-protected works and cannot assist with permissions.
• Copyright retained by author.

Language dc:language

eng

Handle dc:identifier

http://hdl.handle.net/10477/77945

OAI record oai:identifier

https://ubir.buffalo.edu/oai/request?verb=GetRecord&metadataPrefix=qdc&identifier=oai%3Aubir.buffalo.edu%3A10477%2F77945