3 results
Search Results
2. A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia.
- Author
-
Martínez-Rubio, Álvaro, Chulián, Salvador, Blázquez Goñi, Cristina, Ramírez Orellana, Manuel, Pérez Martínez, Antonio, Navarro-Zapata, Alfonso, Ferreras, Cristina, Pérez-García, Victor M., and Rosa, María
- Subjects
- *
BONE marrow , *LYMPHOBLASTIC leukemia , *ACUTE leukemia , *AUTOMOBILES , *BONE marrow cells , *T cells , *B cells - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Immunological tolerance then and now: was the Medawar school right?
- Author
-
Nossal, G. J. V.
- Subjects
- *
IMMUNOLOGICAL tolerance , *IMMUNOLOGY , *T cells , *IMMUNE response , *B cells , *IMMUNOGLOBULINS , *BONE marrow , *ANTIGENS , *GENETIC mutation - Abstract
As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]
- Published
- 1989
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.