464165 Engineering Immune Development By Recapitulating Tissue Microenvironments
Bone marrow transplantation, also known as hematopoietic stem cell transplantation (HSCT), is a process in which healthy blood stem cells within the bone marrow of a donor are extracted and transferred into a recipient. The process is typically performed in patients with advanced blood-based diseases such as leukemia and multiple myeloma. Prior to a HSCT, the patient undergoes radiation and cytotoxic chemotherapy regimen to eradicate as much of the disease as possible. However, the process severely impairs the immune system as a side effect. The profound long-term post-transplant immunodeficiency often results in severe complications in patients such as infections, the development of graft-versus-host disease (GVHD) and the relapse of the underlying disease. Thus, while effective, HSCT continues to be a risky procedure. One way to alleviate the risk is to speed up the formation of new T- and B-cells of the immune system that are responsible in identifying and preventing such complications. Currently, certain proteins and cell-infusions are used in the clinic that can increase the absolute number of immune cells by inducing division of existing mature cells that already recognize certain pathogens. However, the generation of new immune cells that can identify unknown pathogens that the HSCT recipient would encounter is necessary to completely restore the immune system.
The immune itself system arises from blood stem cells, known as hematopoietic stem cells (HSCs). HSCs reside in 'niches,' which are sites within specific tissues in the body in which cells reside at steady-state. In humans, the HSC niche is contained in the bone marrow. Using signals presented in the bone marrow, the HSCs undergo cell differentiation and ultimately end up as T- or B-cells. This project seeks to replenish the T- and B-cells using a synthetic bone marrow that can capture transplanted HSCs after an HSCT and induce their differentiation into specific types of immune cells that prevent the common complications associated with HSCT. To reconstitute bone containing bone marrow in a mouse, a porous scaffold substrate and a specific bone-forming protein are sufficient to produce bone marrow in a pocket below the skin and mimic a healthy HSC niche environment. In this work alginate was used, a sugar-based polymer that can form a gel-like scaffold. The interweaving polymer chains created a large surface area to provide sufficient space for HSCs to engraft. By adding specific ‘address labels’ in the form of biological signals it was possible to specify the differentiation of these HSCs into immune T- and B-cells. The synthetic marrow was able to rapidly induce the development of new T- and B-cells after a HSCT in a mouse model that rapidly restored the immune cell counts. It was observed that the diversity of the T-cell receptor, which recognizes pathogens, was significantly higher both in terms of gene rearrangement and the number of cells with a particular configuration in treated animals. Ongoing work seeks to induce the development of regulatory T-cells that are known to play a role in alleviating GVHD. To prevent the relapse of leukemia, the project will also investigate the combination of the synthetic marrow with a clinical vaccination regimen to induce the formation of T- and B-cells against specific targets that are known to the associated with leukemia. More broadly, there are a number of natural and induced events that can permanently or transiently weaken the immune system such as aging, autoimmune and infectious diseases. The technology development in this project could offer an option to restore the immune defenses in patients with a compromised immune system and to prevent life-threatening conditions.
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