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 language | English |
|---|---|
| Pages (from-to) | 921-931 |
| Number of pages | 11 |
| Journal | Journal of Thrombosis and Haemostasis |
| Volume | 12 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2014 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=84902077525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84902077525&partnerID=8YFLogxK
U2 - 10.1111/jth.12576
DO - 10.1111/jth.12576
M3 - Article
C2 - 24684505
AN - SCOPUS:84902077525
VL - 12
SP - 921
EP - 931
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 6
ER -