BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia A mice develop high-titer inhibitors to recombinant human FVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-β1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.
BACKGROUND: Formation of inhibitory antibodies is a frequent and serious complication of factor (F) VIII replacement therapy for the X-linked bleeding disorder hemophilia A. Similarly, hemophilia Amice develop high-titer inhibitors to recombinant humanFVIII after a few intravenous injections. OBJECTIVE: Using the murine model, the study sought to develop a short regimen capable of inducing tolerance to FVIII. METHODS: A 1-month immunomodulatory protocol, consisting of FVIII administration combined with oral delivery of rapamycin, was developed. RESULTS: The protocol effectively prevented formation of inhibitors to FVIII upon subsequent intravenous treatment (weekly for 3.5 months). Control mice formed high-titer inhibitors and had CD4(+) T effector cell responses characterized by expression of IL-2, IL-4 and IL-6. Tolerized mice instead had a CD4(+)CD25(+)FoxP3(+) T cell response to FVIII that suppressed antibody formation upon adoptive transfer, indicating a shift from Th2 to Treg if FVIII antigen was introduced to T cells during inhibition with rapamycin. CD4(+) T cells from tolerized mice also expressed TGF-β1 and CTLA4, but not IL-10. The presence of FVIII antigen during the time of rapamycin administration was required for specific tolerance induction. CONCLUSIONS: The study shows that a prophylactic immune tolerance protocol for FVIII can be developed using rapamycin, a drug that is already widely in clinical application. Immune suppression with rapamycin was mild and highly transient, as the mice regained immune competence within a few weeks.
Authors: David T Teachey; Dana A Obzut; Kelly Axsom; John K Choi; Kelly C Goldsmith; Junior Hall; Jessica Hulitt; Catherine S Manno; John M Maris; Nicholas Rhodin; Kathleen E Sullivan; Valerie I Brown; Stephan A Grupp Journal: Blood Date: 2006-06-06 Impact factor: 22.113
Authors: Laura I Salazar-Fontana; Dharmesh D Desai; Tarik A Khan; Renuka C Pillutla; Sandra Prior; Radha Ramakrishnan; Jennifer Schneider; Alexandra Joseph Journal: AAPS J Date: 2017-01-12 Impact factor: 4.009
Authors: Moanaro Biswas; Debalina Sarkar; Sandeep R P Kumar; Sushrusha Nayak; Geoffrey L Rogers; David M Markusic; Gongxian Liao; Cox Terhorst; Roland W Herzog Journal: Blood Date: 2015-04-01 Impact factor: 22.113
Authors: Megan L Cramer; Guohong Shao; Louise R Rodino-Klapac; Louis G Chicoine; Paul T Martin Journal: Hum Gene Ther Date: 2017-03-23 Impact factor: 5.695