Methods for assaying responses to vaccines
Inventors
Sukumar, Selva • El Shikh, Mohey Eldin M. • Tew, John G. • Sanchez-Schmitz, Guzman • Drake, III, Donald • Mosquera, Luis • Li, Conan • Kachurin, Anatoly M. • Higbee, Russell • Fahlenkamp, Heather • Mishkin, Eric • Warren, William L.
Assignees
Virginia Commonwealth University • Sanofi Pasteur VaxDesign Corp
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Publication Number
US-8669105-B2
Publication Date
2014-03-11
Expiration Date
Abstract
The present invention incorporates germinal centers (GCs) into three-dimensional (3D) engineered tissue constructs (ETCs). In an embodiment, we have incorporated the GC in the design of an artificial immune system (AIS) to examine immune responses to vaccines and other compounds. Development of an in vitro GC adds functionality to an AIS, in that it enables generation of an in vitro human humoral response by human B lymphocytes that is accurate and reproducible, without using human subjects. The invention also permits evaluation of, for example, vaccines, allergens, and immunogens, and activation of human B cells specific for a given antigen, which can then be used to generate human antibodies. In an embodiment of the present invention the function of the in vitro GC is enhanced by placing FDCs and other immune cells in a 3D ETC; FDCs appear more effective over a longer time (antibody production is sustained for up to about 14 days.
Core Innovation
The invention relates to an in vitro method for assessing the potential of a subject to immunologically respond to a vaccine. A vaccine is administered to an in vitro cellular system that includes an engineered tissue construct with at least one three-dimensional artificial germinal center. The three-dimensional artificial germinal center comprises a plurality of follicular dendritic cells, a plurality of B cells, and a plurality of T cells, and the B cells and T cells are cells isolated from the same subject.
The method evaluates B cell, T cell, or both B cell and T cell responses to the vaccine. A poor B cell or T cell response, or no B cell or T cell response, identifies the subject as having a low potential of immunologically responding to the vaccine. The artificial immune system is used to generate accurate, reproducible human humoral responses without administering to subjects.
The approach emphasizes placing follicular dendritic cells in a three-dimensional engineered tissue construct to support sustained antibody production and germinal-center-like function. Immune-complex trapping and signaling through complement-related and Fc receptor pathways, including CD21 ligand and CD21/CD19/CD81 co-receptor complex and FcγRIIB, are described as enabling class switching, somatic hypermutation, affinity maturation, and memory B-cell responses.
Claims Coverage
The provided independent claim specifies a three-dimensional artificial germinal center embedded in or fixed on an engineered tissue construct and populated by subject-matched B cells and T cells, with follicular dendritic cells included, followed by evaluating B and/or T cell responses to determine low immunological responsiveness. Across the provided content, three inventive features are identified.
Subject-matched three-dimensional artificial germinal center in an engineered tissue construct
An in vitro cellular system includes an engineered tissue construct containing at least one three-dimensional artificial germinal center embedded in or fixed on the engineered tissue construct, wherein the artificial germinal center comprises a plurality of follicular dendritic cells, a plurality of B cells, and a plurality of T cells, and wherein the B cells and T cells are cells isolated from the same subject.
Vaccine administration to the engineered in vitro cellular system
A vaccine is administered to the in vitro cellular system.
Evaluation of B cell, T cell, or both responses to identify low responder subjects
B cell, T cell, or both B cell and T cell responses are evaluated to the vaccine, wherein a poor B cell or T cell response or no B cell or T cell response identifies the subject as having a low potential of immunologically responding to the vaccine.
The coverage centers on an in vitro engineered tissue construct containing a three-dimensional artificial germinal center with follicular dendritic cells and subject-matched B and T cells, and on evaluating vaccine-driven B and/or T cell responses to classify a subject as a low potential responder.
Stated Advantages
Enables accurate, reproducible human humoral responses without administering to subjects.
Poor B cell or T cell response or no B cell or T cell response identifies the subject as having low potential of immunologically responding to the vaccine.
Documented Applications
Assessing a subject's potential to immunologically respond to a vaccine using an in vitro cellular system containing an engineered tissue construct with at least one three-dimensional artificial germinal center.
Evaluating adjuvant activity of a test agent by administering the test agent with a vaccine in the same in vitro cellular system and comparing B cell and/or T cell responses to a no-test-agent control.
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