Highlights
- •The lymphoid organ developing high-titer anti-FVIII antibodies remains unclear.
- •We analyzed the contribution of spleen when inhibitor production is increased.
- •Splenic FVIII-PCs produce approximately 80% of anti-FVIII antibodies.
- •The spleen is a critical to initiate and enhance high-titer inhibitor production.
Abstract
Background
Hemophilia A (HA) is a hereditary bleeding disorder caused by defects in endogenous
factor (F)VIII. Approximately 30 % of patients with severe HA treated with FVIII develop
neutralizing antibodies (inhibitors) against FVIII, which render the therapy ineffective.
The managements of HA patients with high-titter inhibitors are especially challenging.
Therefore, it is important to understand the mechanism(s) of high-titer inhibitor
development and dynamics of FVIII-specific plasma cells (FVIII-PCs).
Aims
To identify the dynamics of FVIII-PCs and the lymphoid organs in which FVIII-PCs are
localized during high-titer inhibitor formation.
Methods and results
When FVIII-KO mice were intravenously injected with recombinant (r)FVIII in combination
with lipopolysaccharide (LPS), a marked enhancement of anti-FVIII antibody induction
was observed with increasing FVIII-PCs, especially in the spleen. When splenectomized
or congenitally asplenic FVIII-KO mice were treated with LPS + rFVIII, the serum inhibitor
levels decreased by approximately 80 %. Furthermore, when splenocytes or bone marrow
(BM) cells from inhibitor+ FVIII-KO mice treated with LPS + rFVIII were grafted into immune-deficient mice,
anti-FVIII IgG was detected only in the serum of splenocyte-administered mice and
FVIII-PCs were detected in the spleen but not in the BM. In addition, when splenocytes
from inhibitor+ FVIII-KO mice were grafted into splenectomized immuno-deficient mice, inhibitor levels
were significantly reduced in the serum.
Conclusion
The spleen is the major site responsible for the expansion and retention of FVIII-PCs
in the presence of high-titer inhibitors.
Keywords
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Article info
Publication history
Published online: March 16, 2023
Accepted:
March 13,
2023
Received in revised form:
January 22,
2023
Received:
October 25,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Ltd. All rights reserved.
