Immune status of patients with haemophilia A before exposure to factor <scp>VIII</scp>: first results from the <scp>HEMFIL</scp> study

Jardim, Letícia Lemos; Chaves, Daniel Gonçalves; Silveira-Cassette, Amanda C. O.; Silva, Ana Cristina Simões e; Santana, Marcio P; Cerqueira, M.; Prezotti, Alessandra Nunes Loureiro; Lorenzato, Cláudia Santos; Franco, Vivian Karla Brognoli; Bom, Johanna G. van der; Rezende, Suely Meireles

doi:10.1111/bjh.14799

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…In addition to characterizing the ADAs themselves, immunoprofiling of patient plasma samples has demonstrated differences in circulating cytokines and in types of microparticles between naïve HA subjects, age-matched healthy controls [138] and HA subjects with and without a neutralizing ADA response [139,140,141,142,143]. However, none of these differences has yet been incorporated into general clinical practice or shown to be predictive, as the studies have been primarily cross-sectional.…”

Section: Prediction Of Immunogenicity and Patient Outcomesmentioning

confidence: 99%

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

Pratt

2018

Antibodies

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Abstract:The development of anti-drug antibodies (ADAs) following administration of biotherapeutics to patients is a vexing problem that is attracting increasing attention from pharmaceutical and biotechnology companies. This serious clinical problem is also spawning creative research into novel approaches to predict, avoid, and in some cases even reverse such deleterious immune responses. CD4 + T cells are essential players in the development of most ADAs, while memory B-cell and long-lived plasma cells amplify and maintain these responses. This review summarizes methods to predict and experimentally identify T-cell and B-cell epitopes in therapeutic proteins, with a particular focus on blood coagulation factor VIII (FVIII), whose immunogenicity is clinically significant and is the subject of intensive current research. Methods to phenotype ADA responses in humans are described, including T-cell stimulation assays, and both established and novel approaches to determine the titers, epitopes and isotypes of the ADAs themselves. Although rational protein engineering can reduce the immunogenicity of many biotherapeutics, complementary, novel approaches to induce specific tolerance, especially during initial exposures, are expected to play significant roles in future efforts to reduce or reverse these unwanted immune responses.

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Section: Prediction Of Immunogenicity and Patient Outcomesmentioning

confidence: 99%

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

Pratt

2018

Antibodies

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“…Vesicles shed by cell lines of non-small-cell lung carcinoma, pancreatic adenocarcinoma, and colorectal adenocarcinoma stimulated chemotaxis of granulocytes, lymphocytes, and monocytes in vitro [36]. While in the plasma of hemophilia A patients, higher levels of MVs derived from endothelial cells, neutrophils, T lymphocytes, erythrocytes, and platelets were observed after exposure to exogenous FVIII, with distinct immunological profiles [37]. Human eosinophils could secrete cytokines, chemokines and cationic proteins, trafficking, and releasing them for roles in inflammation and other immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…In the cohort of previously untreated hemophilia A patients, immunological profiles were distinct, higher levels of IL8, IL6, IL4, IL10, IL2, IL17A, and lower levels of CXCL10 and CCL2 were observed compared with non-haemophiliac cohorts. Also, higher levels of MVs derived from endothelial cells, neutrophils, T lymphocytes, erythrocytes, and platelets were observed [37]. Few leukemia-associated antigens (LAA) are characterized for acute myeloid leukemia (AML), apoptotic tumor cells constitute an attractive LAA source for personalized DC-based vaccines.…”

Section: Introductionmentioning

confidence: 99%

Microvesicles and chemokines in tumor microenvironment: mediators of intercellular communications in tumor progression

et al. 2019

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Increasing evidence indicates that the ability of cancer cells to convey biological information to recipient cells within the tumor microenvironment (TME) is crucial for tumor progression. Microvesicles (MVs) are heterogenous vesicles formed by budding of the cellular membrane, which are secreted in larger amounts by cancer cells than normal cells. Recently, several reports have also disclosed that MVs function as important mediators of intercellular communication between cancerous and stromal cells within the TME, orchestrating complex pathophysiological processes. Chemokines are a family of small inflammatory cytokines that are able to induce chemotaxis in responsive cells. MVs which selective incorporate chemokines as their molecular cargos may play important regulatory roles in oncogenic processes including tumor proliferation, apoptosis, angiogenesis, metastasis, chemoresistance and immunomodulation, et al. Therefore, it is important to explore the association of MVs and chemokines in TME, identify the potential prognostic marker of tumor, and develop more effective treatment strategies. Here we review the relevant literature regarding the role of MVs and chemokines in TME.

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“…All of these prenatal events, combined with each individual's genetics, likely leads to different immune profiles of infants with haemophilia before their first exposure. There is evidence that immune profiles of haemophilia infants may be distinct before the first FVIII exposure . Common childhood immune events may or may not influence inhibitor development …”

Section: Resultsmentioning

confidence: 99%

The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

Johnsen

Brown

2019

Haemophilia

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Introduction Patients with haemophilia can develop inhibitors to exogenous coagulation factors. Some patients are tolerant to factor, while those who develop inhibitors do so early in life. Genetics and environmental factors are known to contribute to inhibitor risk. However, it is not yet possible to predict inhibitor formation or treatment responsiveness in individuals. We hypothesize that factors in the antenatal/neonatal period inform inhibitor risk development. Aim To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand haemophilia inhibitors. Methods A working group was formed for the NHLBI State of the Science Workshop: Factor VIII Inhibitors: Generating a National Blueprint for Future Research to solicit input from the US haemophilia community and international collaborators to consider design of pregnancy/birth longitudinal cohorts that leverage ‐omics, existing phenotypic data, and in silico modelling to study inhibitors. Results An antenatal/neonatal longitudinal cohort should begin with enrolment of pregnant genetic carriers of haemophilia and span the at‐risk period for inhibitor development in the child. Data and samples from the mother, placenta, neonate and young child can be obtained that are amenable to existing assays, genomics and other ‐omics studies. Data can inform in silico prediction and mathematical models. Conclusion A longitudinal study beginning before birth offers the unique opportunity to study factors that influence inhibitor development prior to exposure. Advances in ‐omics and computational biology can study complex phenotypes in this rare disease. This study could be accomplished through interdisciplinary efforts and patient community engagement.

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Immune status of patients with haemophilia A before exposure to factor VIII: first results from the HEMFIL study

Cited by 16 publications

References 30 publications

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

Anti-Drug Antibodies: Emerging Approaches to Predict, Reduce or Reverse Biotherapeutic Immunogenicity

Microvesicles and chemokines in tumor microenvironment: mediators of intercellular communications in tumor progression

The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity: NHLBI State of the Science (SOS) Workshop on factor VIII inhibitors

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