We hypothesize that reduced B-cell production in the bone marrow (BM) results in the selective accumulation of long-lived, antigen experienced cell in the periphery. We believe that eventually these cells dominate the peripheral repertoire and the immune system is forced to rely upon them to mount a response to newly encountered pathogens, such as West Nile Virus, SARS, influenza, etc.  In order to address the cause of decreased B-cell production in the bone marrow, we have developed unique and innovative tools to approach our hypothesis. These include a transgenic system in mice that allows quantification of aging, as well as the generation of conditionally and reversibly transformed long-term repopulating hematopoietic stem cell (LT-HSC) lines from young and aged mice. These cell lines appear to retain the defects identified in their precursors, i.e. the aged HSC line is unable to reconstitute the B cell compartment.

· Is the defect in B lymphopoiesis in immunologically aged mice a cell intrinsic defect, and/or do microenvironmental changes play a role?

· Can we define the molecular basis for the functional differences between HSCs from young and aged mice using conditionally immortalized stem cell lines?

 

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