Aged individuals exhibit increased susceptibility to infection and respond poorly to vaccination. This is due to defects in the immune system that accumulate with age. One defect is the decline in lymphopoiesis with increased age, which results in fewer naive B cells and T cells available to respond to new infections. Aged humans, mice, and rabbits have decreased B lymphopoiesis. In rabbits the loss of B cell development occurs by 2 months of age, and correlates with increased adipose tissue in the bone marrow. Aged humans accumulate adipose tissue in the bone marrow, making rabbit a good in vivo model to study the changes that occur in the bone marrow with age. We also discovered that adipocyte-derived factors inhibit human, mouse, and rabbit B lymphopoiesis in vitro. Although the mechanism by which adipocyte-derived factors inhibit B lymphopoiesis is unknown, by using in vitro co-cultures to study the impact of adipocyte-derived soluble factors on B cell development, we have preliminary data suggesting that adipocyte-derived soluble factors promote the accumulation of CD11b+ Gr1+ suppressor cells, which then inhibit B cell development. These CD11b+ Gr1+ suppressor cells resemble myeloid-derived suppressor cells (MDSCs). Because there is little to no data supporting the idea that MDSCs affect B lineage cells, we will determine if suppressor cells generated by treatment with adipocyte-derived soluble factors are classical MDSCs that are known to suppress T cells. Further, we will determine the mechanism by which CD11b+ Gr1+ suppressor cells inhibit B cell development. We will also elucidate the mechanism by which these MDSC-like cells develop, and determine if depletion of MDSCs can restore B lymphopoiesis in the bone marrow of rabbits that no longer generate new B cells. These studies will provide valuable information on the impact of increased adipose tissue on hematopoiesis in aged individuals. Uncovering the mechanisms by which adipocytes lead to the decline of B cell development will lead to therapies aimed at restoring B lymphopoiesis in aged individuals.
Aged individuals have increased adipose tissue present in the bone marrow and exhibit a decline in B lymphopoiesis. We have shown that adipocyte-derived factors promote the accumulation of myeloid-derived suppressor cells (MDSCs) that have the potential to inhibit B lymphopoiesis in vitro. Our goal is to determine the mechanisms by which adipocyte-derived factors generate MDSCs and by which MDSCs suppress B cell development.
|Kennedy, Domenick E; Knight, Katherine L (2017) Inflammatory Changes in Bone Marrow Microenvironment Associated with Declining B Lymphopoiesis. J Immunol 198:3471-3479|
|Kennedy, Domenick E; Witte, Pamela L; Knight, Katherine L (2016) Bone marrow fat and the decline of B lymphopoiesis in rabbits. Dev Comp Immunol 58:30-9|
|Kennedy, Domenick E; Knight, Katherine L (2015) Inhibition of B Lymphopoiesis by Adipocytes and IL-1-Producing Myeloid-Derived Suppressor Cells. J Immunol 195:2666-74|