Exposure to Factor VIII Protein in the Presence of Phosphatidylserine Induces Hypo-responsiveness toward Factor VIII Challenge in Hemophilia A Mice

Gaitonde, Puneet; Ramakrishnan, Radha; Chin, Jamie; Kelleher, Raymond J.; Bankert, Richard B.; Balu‐Iyer, Sathy V.

doi:10.1074/jbc.c112.396325

Cited by 27 publications

(52 citation statements)

References 19 publications

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“…Strategies that reduce unwanted immune responses could greatly improve these issues. Recently, we have demonstrated that pre-exposure of Factor VIII (FVIII) in the presence of phosphatidylserine (PS) induces an antigen-specific, hypo-responsiveness towards a re-challenge with FVIII in a mouse model of Hemophilia A 2 . Based on these recent observations in our laboratory we concluded that PS could convert an immunogen to a tolerogen.…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease

Schneider

Balu‐Iyer

2016

Journal of Pharmaceutical Sciences

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Development of unwanted immune responses against therapeutic proteins is a major clinical complication. Recently, we have shown that exposure of Factor VIII (FVIII) in the presence of phosphatidylserine (PS) induces antigen-specific hypo-responsiveness to FVIII re-challenge, suggesting that PS is not immune suppressive, but rather immune regulatory in that PS converts an immunogen to a tolerogen. Since PS is exposed in the outer leaflet during apoptosis, we hypothesize that PS imparts tolerogenic activity to this natural process. Thus, immunization with PS containing liposomes would mimic this natural process. Here, we investigate the immune regulatory effects of PS in inducing tolerance towards recombinant human acid alpha-glucosidase (rhGAA). rhGAA was found to complex with PS liposomes through hydrophobic interactions and incubation PS-rhGAA with dendritic cells resulted in the increased secretion of TGF-β. Immunization with PS-rhGAA or OPLS-rhGAA led to a reduction in anti-rhGAA antibody response which persisted despite re-challenge with free rhGAA. Importantly, the titer levels in a majority of these animals remained unchanged after rechallenge and can be considered non-responders. These data provide evidence that PS liposomes can be utilized to induce tolerance towards therapeutic proteins, in general.

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Section: Introductionmentioning

confidence: 99%

Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease

Schneider

Balu‐Iyer

2016

Journal of Pharmaceutical Sciences

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“…PS either directly or indirectly through Tregs are capable of inhibiting memory B cell development. These properties of PS together are capable of converting an immunogen to a tolerogen 2–4 .…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have shown that pre-exposure of FVIII in the presence of PS led to hyporesponsiveness towards FVIII upon subsequent rechallenges with the free FVIII alone in a HA mouse model 2 . This effect was found to be antigen specific.…”

Section: Introductionmentioning

confidence: 97%

Effect of Biophysical Properties of Phosphatidylserine Particle on Immune Tolerance Induction Toward Factor VIII in a Hemophilia A Mouse Model

Ramakrishnan

Balu‐Iyer²

2016

Journal of Pharmaceutical Sciences

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A major complication in the replacement therapy of Factor FVIII (FVIII) for Hemophilia A (HA) is the development of unwanted immune responses. Previous studies from our lab have shown that pretreatment of FVIII in the presence of Phosphatidylserine (PS) resulted in hyporesponsiveness to subsequent administration of FVIII alone, due to the ability of PS to convert an immunogen to a tolerogen. We investigated the importance of biophysical properties of PS liposomes on its ability to convert an immunogen to a tolerogen. PS particles were prepared differing in size, protein-lipid topology, lamellarity and % association to FVIII keeping the composition of the particle same. PS particles were prepared in two different sizes with differing biophysical properties, smaller particles in the nanometer range (200 nm) and larger size particles in the micron range (2um). HA animals treated with both the nanometer and micron size PS particle showed a significant reduction in anti-FVIII antibody titers when compared to animals receiving free FVIII alone. Upon rechallenge with free FVIII animals that received FVIII along with the nanometer size particle continued to show reduced antibody responses. Animals receiving the micron size particle showed a slight increase in titers although they remained significantly lower than the free FVIII treated group. Upon culture with bone marrow dendritic cells (BMDCs), the nanometer size particle showed a reduction in CD40 expression and an increase in TGF-β cytokine production; which was not observed with the micron size particle. These results show that biophysical properties of PS play an important role in tolerance.

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“…When chemically conjugated to recombinant Factor VIII and administered to hemophilic mice, the incorporated phosphatidylserine effectively reduced DC activation, drove T cell expression of IL-10 and TGF-b, and induced FoxP3 + regulatory T cells (Tregs) [24]. By deceiving APCs into recognizing the therapeutically administered Factor VIII as a product of an apoptotic cell, Gaitonde and colleagues were able to induce tolerance to the therapeutic protein in mice and enabled follow-on treatment with wild-type Factor VIII without the generation of antiFactor VIII antibodies [25].…”

Section: Antigen Targeting To Dendritic Cellsmentioning

confidence: 96%

Engineering antigen-specific immunological tolerance

Kontos¹,

Grimm

Hubbell

2015

Current Opinion in Immunology

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Exposure to Factor VIII Protein in the Presence of Phosphatidylserine Induces Hypo-responsiveness toward Factor VIII Challenge in Hemophilia A Mice

Cited by 27 publications

References 19 publications

Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease

Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease

Effect of Biophysical Properties of Phosphatidylserine Particle on Immune Tolerance Induction Toward Factor VIII in a Hemophilia A Mouse Model

Engineering antigen-specific immunological tolerance

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