Strategies to target long-lived plasma cells for treating hemophilia A inhibitors

Liu, Chao Lien; Lyle, Meghan J.; Shin, Simon; Miao, Carol H.

doi:10.1016/j.cellimm.2016.01.005

Cited by 17 publications

(15 citation statements)

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“…Sle1Yaa murine lupus model, which improved nephritis and reduced anti‐chromatin autoantibody production . In a murine model of factor VIII hemophilia, CXCR4 blockade with AMD3100 in combination with granulocyte‐CSF (G‐CSF) resulted in the depletion of long‐lived memory plasma cells, including such secreting alloantibodies against factor VIII .…”

Section: Discussionmentioning

confidence: 90%

CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

et al. 2018

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Antibody-secreting cells (ASCs), including short-lived plasmablasts and long-lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C-X-C motif chemokine-12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C-X-C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1 mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti-OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long-term (five-month) CXCR4 blockade with AMD3100 after effective short-term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4-CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.

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Section: Discussionmentioning

confidence: 90%

CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

et al. 2018

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“…Our recommendation of starting ITI immediately is in contrast to past practice, where most clinicians would wait until the inhibitor titre had dropped to a value of <10 BU . This trend of starting ITI as soon as possible after inhibitor development has been driven in part by a desire to avoid bleeds in patients with high pre‐ITI titres and in the hope of suppressing the maturation of the anti‐FVIII immune response with the production of long‐lived plasma cells …”

Section: Part A: Fit Group Appraisal Of Current Itimentioning

confidence: 88%

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Carção

Escuriola‐Ettingshausen²,

Santagostino³

et al. 2019

Haemophilia

138

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IntroductionAs a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed.AimThe Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors.Discussion and ConclusionsDespite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further.

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“…A small CXCR4 antagonist, AMD3100, is currently used in combination with G-CSF (Granulocyte Colony-Stimulating Factor) as stem-cell mobilizing agent to treat non-Hodgkin’s lymphoma and multiple myeloma [ 35 ]. AMD3100 in combination with G-CSF, anti-CD20 and IL2/anti-IL2 mAb (monoclonal Antibody) complexes has been tested as a treatment to induce tolerance in a mouse model of hemophilia A with ADAs against Factor VIII, and it achieved a successful stable reduction of long-lived ADA-producing plasma cells and of ADA titers [ 41 ]. Thus, CXCL12 could be an interesting drug target for the treatment and prevention of ADAs.…”

Section: Discussionmentioning

confidence: 99%

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

Hässler¹,

Bachelet²,

Duhazé³

et al. 2020

PLoS Med

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Background Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. Methods and findings The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn’s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253–0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437–0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616–4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319–3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923–5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139–6.764], p < 1 × 10 −5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum w...

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Strategies to target long-lived plasma cells for treating hemophilia A inhibitors

Cited by 17 publications

References 50 publications

CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

CXCR4–CXCL12 interaction is important for plasma cell homing and survival in NZB/W mice

The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

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