Strategies to Target Long-lived Plasma Cells for Treating Hemophilia A Inhibitors

Overview

Journal Cell Immunol

Publisher Elsevier

Specialties Allergy & Immunology
Cell Biology

Date 2016 Feb 16

PMID 26877251

Citations 11

Authors

Chao Lien Liu

Meghan J Lyle

Simon C Shin

Carol H Miao

Affiliations

Soon will be listed here.

Abstract

Long-lived plasma cells (LLPCs) can persistently produce anti-factor VIII (FVIII) antibodies which disrupt therapeutic effect of FVIII in hemophilia A patients with inhibitors. The migration of plasma cells to BM where they become LLPCs is largely controlled by an interaction between the chemokine ligand CXCL12 and its receptor CXCR4. AMD3100 combined with G-CSF inhibit their interactions, thus facilitating the mobilization of CD34(+) cells and blocking the homing of LLPCs. These reagents were combined with anti-CD20 to reduce B-cells and the specific IL-2/IL-2mAb (JES6-1) complexes to induce Treg expansion for targeting anti-FVIII immune responses. Groups of mice primed with FVIII plasmid and protein respectively were treated with the combined regimen for six weeks, and a significant reduction of anti-FVIII inhibitor titers was observed, associated with the dramatic decrease of circulating and bone marrow CXCR4(+) plasma cells. The combination regimens are highly promising in modulating pre-existing anti-FVIII antibodies in FVIII primed subjects.

Citing Articles

Abnormal frequency of the memory B cell subsets and plasmablasts in patients with congenital severe hemophilia A: correlation with "Inhibitor" formation.

Zekavat O, Movahednezhad Y, Shahsavani A, Haghpanah S, Shokrgozar N, Golmoghaddam H Blood Res. 2024; 59(1):16.

PMID: 38625415 PMC: 11021380. DOI: 10.1007/s44313-024-00017-7.

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications.

Luo L, Zheng Q, Chen Z, Huang M, Fu L, Hu J Front Immunol. 2022; 13:1019275.

PMID: 36569839 PMC: 9774473. DOI: 10.3389/fimmu.2022.1019275.

Low-dose immune tolerance induction in children with severe hemophilia A with high-titer inhibitors: Type of factor 8 mutation and outcomes.

Sun J, Li Z, Li G, Huang K, Ai D, Liu G Res Pract Thromb Haemost. 2022; 6(7):e12824.

PMID: 36313984 PMC: 9606347. DOI: 10.1002/rth2.12824.

B Cell Immunity in Lung Transplant Rejection - Effector Mechanisms and Therapeutic Implications.

Ohm B, Jungraithmayr W Front Immunol. 2022; 13:845867.

PMID: 35320934 PMC: 8934882. DOI: 10.3389/fimmu.2022.845867.

B cell-activating factor modulates the factor VIII immune response in hemophilia A.

Doshi B, Rana J, Castaman G, Shaheen M, Kaczmarek R, Butterfield J J Clin Invest. 2021; 131(8).

PMID: 33651716 PMC: 8262462. DOI: 10.1172/JCI142906.

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