Long-term tolerance to factor VIII is achieved by administration of interleukin-2/interleukin-2 monoclonal antibody complexes and low dosages of factor VIII

C. L. Liu, P. Ye, J. Lin, D. Djukovic, C. H. Miao

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Summary: Background: Regulatory T cells (Tregs) play a pivotal role in regulating anti-factor VIII (FVIII) immune responses. Interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb; JES6-1) can induce the selective expansion of Tregs in vivo. Methods: In the prevention experiments, we treated mice with hemophilia A with IL-2/IL-2mAb complexes (three times per week) and concurrently with FVIII protein (80 U kg-1 per week) for 4 weeks. Generation of anti-FVIII immune responses was examined afterward. Next, to induce long-term tolerance to FVIII, a series of treatment dosages and schedules for administering IL-2/IL-2mAb complexes and FVIII protein in mice with hemophilia A was evaluated. Results: Compared to control mice that were treated with only FVIII, which produced high-titer anti-FVIII antibodies, mice treated with IL-2/IL-2mAb complexes plus FVIII produced no antibodies. A marked seven-fold increase in CD4+CD25+Foxp3+Helios+ natural Tregs was maintained for 4 weeks in blood, spleen, and lymph nodes and then dropped to normal levels within the next 10 days. The suppressive functions of expanded Tregs were demonstrated with suppressive, proliferative, and cytokine assays. The administration of anti-CD25 mAb (PC-61) blocked this protective effect, confirming the involvement of Tregs in suppressing anti-FVIII immune responses. Importantly, administration of IL-2/IL-2mAb complexes (three times per week for 8 weeks) combined with contiguous weekly injections of low-dosage FVIII protein (20 U kg-1 per week for 18 weeks) not only abrogated the formation of anti-FVIII antibodies but also induced long-term tolerance to FVIII. Conclusions: Treatment with IL-2/IL-2mAb complexes is highly promising for the induction and maintenance of FVIII-specific tolerance after FVIII protein replacement therapy.

Original languageEnglish
Pages (from-to)921-931
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Volume12
Issue number6
DOIs
Publication statusPublished - 2014
Externally publishedYes

Fingerprint

Factor VIII
Interleukin-2
Monoclonal Antibodies
Interleukins
Hemophilia A
Antibodies
Proteins
Regulatory T-Lymphocytes
Appointments and Schedules
Therapeutics
Spleen

Keywords

  • Factor VIII
  • Hemophilia
  • IL-2/IL-2mAb complexes
  • Immune tolerance
  • Immunomodulation
  • Regulatory T cells

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

Long-term tolerance to factor VIII is achieved by administration of interleukin-2/interleukin-2 monoclonal antibody complexes and low dosages of factor VIII. / Liu, C. L.; Ye, P.; Lin, J.; Djukovic, D.; Miao, C. H.

In: Journal of Thrombosis and Haemostasis, Vol. 12, No. 6, 2014, p. 921-931.

Research output: Contribution to journalArticle

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abstract = "Summary: Background: Regulatory T cells (Tregs) play a pivotal role in regulating anti-factor VIII (FVIII) immune responses. Interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb; JES6-1) can induce the selective expansion of Tregs in vivo. Methods: In the prevention experiments, we treated mice with hemophilia A with IL-2/IL-2mAb complexes (three times per week) and concurrently with FVIII protein (80 U kg-1 per week) for 4 weeks. Generation of anti-FVIII immune responses was examined afterward. Next, to induce long-term tolerance to FVIII, a series of treatment dosages and schedules for administering IL-2/IL-2mAb complexes and FVIII protein in mice with hemophilia A was evaluated. Results: Compared to control mice that were treated with only FVIII, which produced high-titer anti-FVIII antibodies, mice treated with IL-2/IL-2mAb complexes plus FVIII produced no antibodies. A marked seven-fold increase in CD4+CD25+Foxp3+Helios+ natural Tregs was maintained for 4 weeks in blood, spleen, and lymph nodes and then dropped to normal levels within the next 10 days. The suppressive functions of expanded Tregs were demonstrated with suppressive, proliferative, and cytokine assays. The administration of anti-CD25 mAb (PC-61) blocked this protective effect, confirming the involvement of Tregs in suppressing anti-FVIII immune responses. Importantly, administration of IL-2/IL-2mAb complexes (three times per week for 8 weeks) combined with contiguous weekly injections of low-dosage FVIII protein (20 U kg-1 per week for 18 weeks) not only abrogated the formation of anti-FVIII antibodies but also induced long-term tolerance to FVIII. Conclusions: Treatment with IL-2/IL-2mAb complexes is highly promising for the induction and maintenance of FVIII-specific tolerance after FVIII protein replacement therapy.",
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T1 - Long-term tolerance to factor VIII is achieved by administration of interleukin-2/interleukin-2 monoclonal antibody complexes and low dosages of factor VIII

AU - Liu, C. L.

AU - Ye, P.

AU - Lin, J.

AU - Djukovic, D.

AU - Miao, C. H.

PY - 2014

Y1 - 2014

N2 - Summary: Background: Regulatory T cells (Tregs) play a pivotal role in regulating anti-factor VIII (FVIII) immune responses. Interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb; JES6-1) can induce the selective expansion of Tregs in vivo. Methods: In the prevention experiments, we treated mice with hemophilia A with IL-2/IL-2mAb complexes (three times per week) and concurrently with FVIII protein (80 U kg-1 per week) for 4 weeks. Generation of anti-FVIII immune responses was examined afterward. Next, to induce long-term tolerance to FVIII, a series of treatment dosages and schedules for administering IL-2/IL-2mAb complexes and FVIII protein in mice with hemophilia A was evaluated. Results: Compared to control mice that were treated with only FVIII, which produced high-titer anti-FVIII antibodies, mice treated with IL-2/IL-2mAb complexes plus FVIII produced no antibodies. A marked seven-fold increase in CD4+CD25+Foxp3+Helios+ natural Tregs was maintained for 4 weeks in blood, spleen, and lymph nodes and then dropped to normal levels within the next 10 days. The suppressive functions of expanded Tregs were demonstrated with suppressive, proliferative, and cytokine assays. The administration of anti-CD25 mAb (PC-61) blocked this protective effect, confirming the involvement of Tregs in suppressing anti-FVIII immune responses. Importantly, administration of IL-2/IL-2mAb complexes (three times per week for 8 weeks) combined with contiguous weekly injections of low-dosage FVIII protein (20 U kg-1 per week for 18 weeks) not only abrogated the formation of anti-FVIII antibodies but also induced long-term tolerance to FVIII. Conclusions: Treatment with IL-2/IL-2mAb complexes is highly promising for the induction and maintenance of FVIII-specific tolerance after FVIII protein replacement therapy.

AB - Summary: Background: Regulatory T cells (Tregs) play a pivotal role in regulating anti-factor VIII (FVIII) immune responses. Interleukin (IL)-2 mixed with a particular IL-2 monoclonal antibody (mAb; JES6-1) can induce the selective expansion of Tregs in vivo. Methods: In the prevention experiments, we treated mice with hemophilia A with IL-2/IL-2mAb complexes (three times per week) and concurrently with FVIII protein (80 U kg-1 per week) for 4 weeks. Generation of anti-FVIII immune responses was examined afterward. Next, to induce long-term tolerance to FVIII, a series of treatment dosages and schedules for administering IL-2/IL-2mAb complexes and FVIII protein in mice with hemophilia A was evaluated. Results: Compared to control mice that were treated with only FVIII, which produced high-titer anti-FVIII antibodies, mice treated with IL-2/IL-2mAb complexes plus FVIII produced no antibodies. A marked seven-fold increase in CD4+CD25+Foxp3+Helios+ natural Tregs was maintained for 4 weeks in blood, spleen, and lymph nodes and then dropped to normal levels within the next 10 days. The suppressive functions of expanded Tregs were demonstrated with suppressive, proliferative, and cytokine assays. The administration of anti-CD25 mAb (PC-61) blocked this protective effect, confirming the involvement of Tregs in suppressing anti-FVIII immune responses. Importantly, administration of IL-2/IL-2mAb complexes (three times per week for 8 weeks) combined with contiguous weekly injections of low-dosage FVIII protein (20 U kg-1 per week for 18 weeks) not only abrogated the formation of anti-FVIII antibodies but also induced long-term tolerance to FVIII. Conclusions: Treatment with IL-2/IL-2mAb complexes is highly promising for the induction and maintenance of FVIII-specific tolerance after FVIII protein replacement therapy.

KW - Factor VIII

KW - Hemophilia

KW - IL-2/IL-2mAb complexes

KW - Immune tolerance

KW - Immunomodulation

KW - Regulatory T cells

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