Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model

Joseph, Alexandra; Munroe, Kenneth J.; Housman, Max; Garman, Richard D.; Richards, Susan

doi:10.1111/j.1365-2249.2008.03602.x

Cited by 83 publications

(75 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Strategies to induce tolerance include conjugating antigen to splenocytes [8], immature dendritic cells (DC) [9,10], or synthetic microparticles [11,12], oral tolerance [13], gene therapy [14] or co-treatment with immunosuppressive drugs, such as methotrexate [15]. Recently, it has been reported that systemic co-administration of rapamycin, a immunosuppressant drug commonly used to prevent transplant rejection, prevented immune response and induced tolerance to FIX and FVIII in mouse models of hemophilia A and B, respectively [29,30].…”

Section: Introductionmentioning

confidence: 99%

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Zhang

Rossi

Yoon

et al. 2016

Cellular Immunology

View full text Add to dashboard Cite

a b s t r a c tThe immune response of hemophilia A patients to administered FVIII is a major complication that obviates this very therapy. We have recently described the use of synthetic, biodegradable nanoparticles carrying rapamycin and FVIII peptide antigens, to induce antigen-specific tolerance. Herein we test the tolerogenicity of nanoparticles that contains full length FVIII protein in hemophilia A mice, focusing on anti-FVIII humoral immune response. As expected, recipients of tolerogenic nanoparticles remained unresponsive to FVIII despite multiple challenges for up to 6 months. Furthermore, therapeutic treatments in FVIII-immunized mice with pre-existing anti-FVIII antibodies resulted in diminished antibody titers, albeit efficacy required longer therapy with the tolerogenic nanoparticles. Interestingly, durable FVIII-specific tolerance was also achieved in animals co-administered with FVIII admixed with nanoparticles encapsulating rapamycin alone. These results suggest that nanoparticles carrying rapamycin and FVIII can be employed to induce specific tolerance to prevent and even reverse inhibitor formation.Published by Elsevier Inc.

show abstract

Section: Introductionmentioning

confidence: 99%

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Zhang

Rossi

Yoon

et al. 2016

Cellular Immunology

View full text Add to dashboard Cite

show abstract

“…Diphenhydramine (15 mg/kg) was intraperitoneally injected 10-15 min prior to each enzyme administration to prevent anaphylactic reactions [23].…”

Section: Treatment Of Young Adult Gaa-ko Mice With Fabgaamentioning

confidence: 99%

Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease

Sun

Armstrong

et al. 2017

J Mol Med

View full text Add to dashboard Cite

Pompe disease is characterized by accumulation of both lysosomal and cytoplasmic glycogen primarily in skeletal and cardiac muscles. Mannose-6-phosphate receptor-mediated enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) targets the enzyme to lysosomes and thus is unable to digest cytoplasmic glycogen. Studies have shown that anti-DNA antibody 3E10 penetrates living cells and delivers Bcargo^proteins to the cytosol or nucleus via equilibrative nucleoside transporter ENT2. We speculate that 3E10-mediated ERT with GAA will target both lysosomal and cytoplasmic glycogen in Pompe disease. A fusion protein (FabGAA) containing a humanized Fab fragment derived from the murine 3E10 antibody and the 110 kDa human GAA precursor was constructed and produced in CHO cells. Immunostaining with an anti-Fab antibody revealed that the Fab signals did not co-localize with the lysosomal marker LAMP2 in cultured L6 myoblasts or Pompe patient fibroblasts after incubation with FabGAA. Western blot with an anti-GAA antibody showed presence of the 150 kDa full-length FabGAA in the cell lysates, in addition to the 95-and 76 kDa processed forms of GAA that were also seen in the rhGAA-treated cells. Blocking of mannose-6-phosphate receptor with mannose-6-phosphate markedly reduced the 95-and the 76 kDa forms but not the 150 kDa form.

show abstract

“…The mechanism by which methotrexate exerts these effects is presumed to be through killing proliferating cells by inhibiting dihydrofolate reductase and inducing immunosuppression (9,10). Our laboratory has also demonstrated that methotrexate can significantly reduce inflammatory responses against protein therapeutics (11,12). In particular, we have shown that methotrexate significantly decreases the development of antidrug Abs, however, not through immunosuppression but rather through the induction of immune tolerance because only a few short courses of methotrexate can significantly reduce Abs that develop in mice against the enzyme replacement therapies, Fabrazyme and Myozyme, for extended periods of time (11,12).…”

mentioning

confidence: 92%

“…For these studies, methotrexate was tested as an immune tolerance inducing agent to mATG and was administered in a similar regimen to that used to tolerize Myozyme and Fabrazyme (11,12). Administration of 5 mg/kg methotrexate within 15 min of as well as 24 and 48 h following the initial three mATG treatments, significantly reduced anti-drug Ab titers by 69% through 6 mo of monthly mATG administration (Fig.…”

Section: Serum Alloantibody Levelsmentioning

confidence: 99%

“…Our laboratory has also demonstrated that methotrexate can significantly reduce inflammatory responses against protein therapeutics (11,12). In particular, we have shown that methotrexate significantly decreases the development of antidrug Abs, however, not through immunosuppression but rather through the induction of immune tolerance because only a few short courses of methotrexate can significantly reduce Abs that develop in mice against the enzyme replacement therapies, Fabrazyme and Myozyme, for extended periods of time (11,12). We have also shown that in the context of Fabrazyme, methotrexateinduced control of anti-drug Abs is Ag specific (12).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

Joseph¹,

Neff²,

Richard³

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Rabbit anti-thymocyte globulin (Thymoglobulin) effectively treats transplant rejection but induces anti-rabbit Ab responses, which limits routine readministration. Aiming to tolerize anti-rabbit responses, we coadministered a brief methotrexate regimen with a murine version of Thymoglobulin (mATG) for effects on anti-mATG Abs and cardiac allotransplantation in mice. Although both single and three courses of methotrexate could significantly inhibit anti-drug Ab titers to repeated mATG treatment, surprisingly, the single course given at the first mATG administration was most effective (>99% reduction). The transient methotrexate treatment also significantly improved pharmacokinetics and pharmacodynamics of repeated mATG administration. In the cardiac allograft model, the combination of transient mATG and methotrexate given only at the time of transplant dramatically improved allograft survival (>100 d) over either agent alone (<30 d). Anti-drug Ab titers were reduced and mATG exposure was increased which resulted in prolonged rather than enhanced mATG-mediated effects when combined with methotrexate. Moreover, methotrexate administration significantly reduced alloantibodies, suggesting that methotrexate not only decreases anti-drug Ab responses but also reduces Ab responses to multiple tissue-derived alloantigens simultaneously. These data suggest that mATG and methotrexate together can provide long-term allograft survival potentially through the induction of immune tolerance.

show abstract

Immune tolerance induction to enzyme-replacement therapy by co-administration of short-term, low-dose methotrexate in a murine Pompe disease model

Cited by 83 publications

References 38 publications

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation

Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease

Transient Low-Dose Methotrexate Induces Tolerance to Murine Anti-Thymocyte Globulin and Together They Promote Long-Term Allograft Survival

Contact Info

Product

Resources

About