Another Step Towards Mass Manufacture of Immune Cells

One of the more important ways in which the immune system declines with age is that its composition shifts towards large duplicated collections of comparatively useless cells involved in coordination and memory of threats, and this is at the expense of a shrinking population of cells capable of destroying those threats. The supply of new immune cells is a slow trickle in adults; evolutionary pressures led to a system that starts up very rapidly in youth and generates large numbers of cells at that time. By adulthood the organ responsible for marshaling new T cells of the adaptive immune system, the thymus, has atrophied. The pressures put on the immune system to shift cells into roles other than attacking and destroying pathogens don't let up, however. The end result is an immune system become ever more poorly configured as a whole: too many librarians and bureaucrats, too few warriors. The body is always under attack from pathogens, but the immune system is also responsible for destroying errant cells, such as those become cancerous or senescent. That the immune system falls down on this front is just as bad as the frailty that stems from a growing inability to resist common infectious diseases.

None of this considers the age-related toll of cellular damage or other harms caused to the stem cell populations responsible for generating immune cells. That is also an issue. Putting that to one side for the moment, however, there are several ways in which the aging immune system could be reconfigured. All of them are within reach of modern biotechnology, and have been demonstrated in the laboratory to some extent: all are in that awkward period of being technically feasible but not yet earnestly in development as a therapy. Firstly, the supply of new immune cells cells could be increased by regenerating the thymus such that it behaves as though the patient is young once more. Secondly the population of useless immune cells could be cleared away by targeted cell destruction technologies, which will prompt the body to replace them with new cells capable of attacking pathogens. Lastly large numbers of immune cells could be generated from the patient's own stem cells and delivered via infusion on a regular basis; in theory far more cells than usually present in the body could be provided in this way, greatly increasing the capabilities of the immune system while they survive.

The open access research quoted below is an example of that third approach. It is worth noting that I have painted with very broad strokes in the description above. The immune system is a city of many different specialized classes of inhabitant, each performing just a few of a very wide range of jobs. It is a very complex and dynamic system of interactions and behaviors. So it is the case that benefits might be obtained just by focusing down on a few specific subtypes of immune cell when generating and delivering large numbers of them as a therapy. The full paper is available in PDF format only at this point, but worth a look.

Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells

Invariant natural killer T (iNKT) cells comprise a small population of αβ T lymphocytes. They bridge the innate and adaptive immune systems and mediate strong and rapid responses to many diseases, including cancer, infections, allergies, and autoimmunity. However, the study of iNKT cell biology and the therapeutic applications of these cells are greatly limited by their small numbers in vivo (∼0.01-1% in mouse and human blood).

Here, we report a new method to generate large numbers of iNKT cells in mice through T-cell receptor (TCR) gene engineering of hematopoietic stem cells (HSCs). We showed that iNKT TCR-engineered HSCs could generate a clonal population of iNKT cells. These HSC-engineered iNKT cells displayed the typical iNKT cell phenotype and functionality. They followed a two-stage developmental path, first in thymus and then in the periphery, resembling that of endogenous iNKT cells.

When tested in a mouse melanoma lung metastasis model, the HSC-engineered iNKT cells effectively protected mice from tumor metastasis. This method provides a powerful and high-throughput tool to investigate the in vivo development and functionality of clonal iNKT cells in mice. More importantly, this method takes advantage of the self-renewal and longevity of HSCs to generate a long-term supply of engineered iNKT cells, thus opening up a new avenue for iNKT cell-based immunotherapy.


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