Dynamical properties of feedback signalling in B lymphopoiesis: A mathematical modelling approach

Chulián, Salvador; Martínez-Rubio, Álvaro; Marciniak–Czochra, Anna; Stiehl, Thomas; Goñi, Cristina Blázquez; Gutiérrez, Josefina; Ramírez, Manuel; Robleda, Ana Castillo; Pérez-Garcı́a, Vı́ctor M.; Rosa, María

doi:10.1016/j.jtbi.2021.110685

Cited by 5 publications

(10 citation statements)

References 63 publications

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“…Alternatively, these proportions can be found in ref. [40]. The total B-cell population in these conditions would be around 3 × 10 10 cells.…”

Section: Parameter Estimationmentioning

confidence: 96%

“…This paper looks at two main biological processes within each B-cell compartment: proliferation ρ i and maturation γ j . In previous works, we followed the hypothesis that the regulation of cell production occurs through a negative feedback signal affecting proliferation s B (t), where k represents the intensity of the signal [40]. This compartmentalized structure with proliferation, maturation, and regulatory feedback has already been used in mathematical models of B-cell hematopoiesis [41].…”

Section: Memory Car-t Cellsmentioning

confidence: 99%

“…We studied proliferation and differentiation parameters in a previous work [40], where the evolution of the three CD19 + cellular compartments (B 1 , B 2 , and B 3 ) was compared to clinical and literature data to obtain characteristic parameter values. We followed the reasoning in that work to provide values for the Pro-B compartment and for the leukemic cell population.…”

Section: Parameter Estimationmentioning

confidence: 99%

“…In the latter, B cells were mainly composed of the CD19 − Pro-B cell compartment, and the remaining compartments were ordered according to their maturation stage. In normal conditions, the Pre-BII compartment is the most abundant, followed by the immature compartment [38,40]. Reports of successful CAR T therapy in B-cell malignancies indicate BCA in peripheral blood as a marker of therapy response [14][15][16].…”

Section: Effector and Memory Car T-cells Are Able To Control The Diseasementioning

confidence: 99%

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A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

Martínez-Rubio

Chulián

Goñi

et al. 2021

IJMS

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Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients’ experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

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“…Alternatively, these proportions can be found in ref. [40]. The total B-cell population in these conditions would be around 3 × 10 10 cells.…”

Section: Parameter Estimationmentioning

confidence: 96%

Section: Memory Car-t Cellsmentioning

confidence: 99%

Section: Parameter Estimationmentioning

confidence: 99%

Section: Effector and Memory Car T-cells Are Able To Control The Diseasementioning

confidence: 99%

See 2 more Smart Citations

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

Martínez-Rubio

Chulián

Goñi

et al. 2021

IJMS

Self Cite

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“…Other differentiated cells are also produced during hematopoiesis, as for example platelets, erythrocytes, or lymphocytes. Some mathematical models have focused on describing the production of a given mature cell type (megakaryopoiesis [4], erythropoiesis [11], lymphopoiesis [9]) when others have modeled multiple cell lineages [10,34]. In our case, the hematopoietic dynamics is described by the following system of (linear) ordinary differential equations (ODEs):…”

Section: Base Modelmentioning

confidence: 99%

Mathematical modelling, selection and hierarchical inference to determine the minimal dose in IFN$α$ therapy against Myeloproliferative Neoplasms

Hermange¹,

Vainchenker²,

Plo³

et al. 2021

Preprint

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Myeloproliferative Neoplasms (MPN) are blood cancers that appear after acquiring a driver mutation in a hematopoietic stem cell. These hematological malignancies result in the overproduction of mature blood cells and, if not treated, induce a risk of cardiovascular events and thrombosis. Pegylated IFNα is commonly used to treat MPN, but no clear guidelines exist concerning the dose prescribed to patients. We applied a model selection procedure and ran a hierarchical Bayesian inference method to decipher how dose variations impact the response to the therapy. We inferred that IFNα acts on mutated stem cells by inducing their differentiation into progenitor cells, the higher the dose, the higher the effect. We found that when a sufficient (patient-dependent) dose is reached, the treatment can induce a long-term remission. We determined this minimal dose for individuals in a cohort of patients and estimated the most suitable starting dose to give to a new patient to increase the chances of being cured.

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Multiplicity of Time Scales in Blood Cell Formation and Leukemia

Stiehl

2023

Mathematics Online First Collections

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Dynamical properties of feedback signalling in B lymphopoiesis: A mathematical modelling approach

Cited by 5 publications

References 63 publications

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

Mathematical modelling, selection and hierarchical inference to determine the minimal dose in IFN$α$ therapy against Myeloproliferative Neoplasms

Multiplicity of Time Scales in Blood Cell Formation and Leukemia

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