Reversing Myeloid Bias by Selective Destruction of Hematopoietic Cells

The hematopoietic cell populations of the bone marrow are responsible for producing red blood cells and immune cells. With advancing age, the production of immune cells shifts to bias myeloid cells of the innate immune system versus lymphocyte cells of the adaptive immune system. This is thought to be an important aspect of immune aging. Researchers here attempt to reverse this myeloid bias in immune cell production by selectively destroying some of the myeloid-focused hematopoietic cells, an interesting idea. The results are positive and intriguing.

During aging, the number of hematopoietic stem cells (HSCs) that make balanced proportions of lymphocytes and myeloid cells decline, while those that are myeloid-biased increase their numbers. This favors the production of myeloid cells. Early in human history, when people rarely left their birthplace and lived shorter lives, this gradual change probably had no consequences (it may even have been favorable) because people were likely to encounter all their surrounding pathogens by young adulthood and be protected by their memory lymphocytes. But now it’s distinctly disadvantageous.

The researchers wondered if they could tilt the balance back toward a younger immune system by depleting myeloid-leaning HSCs and allowing the more balanced HSCs to replace them. Their hunch was correct. Mice between 18 and 24 months old (doddering in the mouse world) that were treated with an antibody targeting the myeloid-leaning HSCs for destruction had more of the balanced HSCs – and more new, naïve B lymphocytes and naïve T lymphocytes – than their untreated peers even several weeks later.

“These new, naïve lymphocytes provide better immune coverage for novel infections like those humans increasingly encounter as our world becomes more global. Without this renewal, these new infectious agents would not be recognized by the existing pool of memory lymphocytes. Not only did we see a shift toward cells involved in adaptive immunity, but we also observed a dampening in the levels of inflammatory proteins in the treated animals. We were surprised that a single course of treatment had such a long-lasting effect. The difference between the treated and untreated animals remained dramatic even two months later.”

When the treated animals were vaccinated eight weeks later against a virus they hadn’t encountered before, their immune systems responded more vigorously than was the case for the untreated animals, and they were significantly better able to resist infection by that virus. Finally, the researchers showed that mouse and human myeloid-biased HSCs are similar enough that it may one day be possible to use a similar technique to revitalize aging human immune systems, perhaps making a person less vulnerable to novel infections and improving their response to vaccination.