|
|
|
|
|
|
I am interested in the effects of protein malnutrition on development and function of the immune system. Our studies have shown that protein malnourished mice develop an immunodeficiency syndrome characterized by thymic atrophy which leads to depressed immune responsiveness. Development of this syndrome appears to be triggered by increased serum corticosterone, which is responsible for the thymic atrophy. In addition, these mice exhibit reduced growth hormone levels. As malnutrition continues, the number of T lymphocytes decreases in the spleen as well as in the thymus. This immunodeficiency syndrome is important because T cells play a pivotal role in generation and maintenance of the immune responses necessary for prevention of, and recovery from, infection and cancer. Current research in my laboratory is aimed at determining how this immunodeficiency syndrome develops and what effects it has on the function of the immune system in host defense and tumor rejection.
We see thymic atrophy in this system, but it is not as severe as would be predicted based on the corticosterone levels in these mice. We hypothesize that elevated corticosterone (and reduced growth hormone?) levels induce apoptosis of immature thymic T cells, but that this process is somehow down-regulated by the relative inability of these cells to generate certain proteins required for rapid apoptosis due to the protein malnutrition. Therefore, we are investigating apoptosis and its regulation to gain insight into mechanisms responsible for thymic atrophy in this system. We've been looking at various apoptosis regulatory factors including, Bcl-2, Bax, Bcl-x, hsp70, hsp90 and glucocorticosteroid receptor. More on these as we publish the results, eh?
Our protein malnourished mice exhibit decreased resistance to infection with bacteria such as Listeria monocytogenes and Salmonella enteritidis. We are focusing on replacing depleted T cells by adoptive transfer as well as demonstrating reduced T cell synthesis of interferon-gamma to determine factors underlying low levels of macrophage activation in these mice. We are looking forward to developing an intracellular flow cytometry assay for interferon-gamma, which will allow simultaneous detection of how much of this cytokine is being produced, and by which cells.
Paradoxically, our protein malnourished mice also exhibit enhanced resistance to L1210 leukemia cells. We are focusing on single amino acid deficiency as a mode of induction to allow us to determine the relative importance of increased corticosterone and decreased growth hormone levels in fostering L1210 cell resistance. We are investigating apoptosis induced by high corticosterone and low growth hormone levels as a possible mechanism of L1210 cell death underlying the tumor resistance seen in these mice.
