Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10162252 | Journal of Pharmaceutical Sciences | 2014 | 7 Pages |
Abstract
The clinical use of therapeutic proteins can be complicated by the development of antiâproduct antibodies. We have previously observed that Oâphosphoâlâserine (OPLS) reduced antibody response to FVIII in HemophiliaâA (HA) mice. However, the mechanism underlying this observation is not clear. We hypothesize that OPLS reduces immunogenicity by inducing tolerogenic properties in dendritic cells (DCs). We tested this hypothesis using in vivo, in vitro, and ex vivo methods. Naive HA mice that were preâexposed to FVIII in the presence of OPLS showed substantially lower antibody response following rechallenge with OPLS free FVIII as compared with dexamethasoneâpretreated mice. Exposure of OPLS to boneâmarrowâderived dendritic cells (BMDCs) in culturing conditions resulted in an increase in the regulatory cytokine TGFâβ and a decrease in proinflammatory cytokines TNFâα and IL12p70. This was accompanied by a significant reduction in upregulation of costimulatory marker CD40, as measured by flow cytometry. Furthermore, ex vivo matured BMDCs in the presence of FVIII and OPLS failed to elicit a robust immune response in HA mice compared with FVIIIâtreated BMDCs. Our data suggest that OPLS modulates the immune response by altering the function and maturation of DCs, resulting in the induction of tolerogenic properties. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3457-3463, 2014
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Authors
Anas M. Fathallah, Radha Ramakrishnan, Sathy V. BaluâIyer,