Research
Dendritic Cell Development and Function
Annette Schlueter, M.D., Ph.D.
Associate Professor
Assistant Medical Director, DeGowin Blood Center
Head of Transplant Services
1117 ML
319-356-0370
My laboratory is interested in the contribution of dendritic cells (DC) to disease. Specifically, we study the defects induced in DC by chronic ethanol (EtOH) exposure that contribute to increased incidence and severity of infectious disease, and the influence of aging on DC ability to induce more severe graft vs. host disease following allogeneic hematopoietic cell transplant (HCT).
It is clear that chronic alcohol abuse results in immunodeficiency, characterized by loss of some lymphocyte subsets and persistent alterations in the function of other subsets. Evidence from our mouse model of alcoholism indicates that chronic ethanol feeding results in decreased numbers of DC in spleen and epidermis. Studies in my laboratory indicate that these losses are partially due to defective DC migration in the presence of EtOH. EtOH-exposed DC are also unable to activate T cells appropriately, as a result of dysregulated costimulatory molecule expression and cytokine secretion. In addition, they increase the frequency of adaptive regulatory T cell formation. Preliminary evidence suggests that the mechanism for these changes may be EtOH induced increases in oxidative stress. We are investigating additional ways in which EtOH exposure in vivo may influence DC function, thereby increasing the susceptibility of alcoholics to infection. Additional studies are investigating the stability of these changes after EtOH cessation (modeling the recovered human alcoholic), and the effect of fetal and neonatal EtOH exposure on dendritic cell function (modeling human fetal alcohol exposure).
In separate studies, my laboratory is interested in understanding the role DC play in the increased susceptibility of advanced age allogeneic HCT patients to graft-versus host disease (GVHD). It is clear that recipient DC play a key role in the development of GVHD, but very little is known about the mechanism by which this occurs. We are studying the functional characteristics of DC from older and young HCT patients, as well as older and young mice in murine models of HCT, and have found that older DC subjected to HCT prepartory regimens are more likely to secrete immunostimulatory cytokines than young DC. Understanding functional changes in DC populations with age will allow us ultimately to design therapeutic interventions that may limit the toxicity of GVHD, and allow the life-saving therapy of HCT to be offered to more advanced age patients. Finally, we are investigating treatment of murine GVHD with cultured regulatory DC, to understand the mechanism by which this therapy prevents the disease and to determine if it is feasible to translate this therapy to humans.
Related bibliography:
- Ness KJ, Fan J, Wilke WW, Coleman RA, Cook RT, Schlueter AJ. Chronic ethanol consumption decreases murine Langerhans cell numbers and delays migration of Langerhans cells as well as dermal dendritic cells. Alcoholism: Clinical and Experimental Research, in press.
Goldman FD, Aubert G, Klingelhutz AJ, Hills M, Cooper SR, Hamilton WS, Schlueter AJ, Lambie K, Eaves CJ, Lansdorp PM. Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita. Blood, 2008 Feb 29.
Cook RT, Schlueter AJ, Coleman RA, Tygrett LT, Ballas ZK, Jerrells TR, Nashelsky MB, Ray NB, Haugen TH, Waldschmidt TJ. Thymocytes, pre-B cells and organ changes in a mouse model of chronic ethanol ingestion--absence of subset-specific glucocorticoid-induced immune cell loss. Alcoholism: Clinical and Experimental Research 31:1746-1758, 2007.
Schlueter AJ, Glasgow J. Phenotypic comparison of multiple monocyte-related populations in murine peripheral blood and bone marrow. Cytometry 69A:281-290, 2006.
Nagendra S, Schlueter AJ. Absence of crossreactivity between murine Ly-6C and Ly-6G. Cytometry Part A 58A:195-200, 2004.
Lee C-K, deMagalhaes-Silverman M., Hohl, RJ, Hayashi M, Buatti J, Wen B-C, Schlueter AJ, Strauss RG, and Gingrich RD. Donor lymphocyte infusions. Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft. Bone Marrow Transplant 31:121-128, 2003.
Lee C-K, de Magalhaes-Silverman, Hohl RJ, Hayashi M, Buatti J, Wen BC, Schlueter AJ, Strauss RG and Gingerich RD. Donor lymphocyte infusion. Prophylactic T cell infusion after T cell-depleted bone marrow transplantation in patients with refractory lymphoma. Bone Marrow Transplant 29:615-620, 2002.
Schlueter AJ, Bhatia SK, Li X, Tygrett LT, Yamashita Y, de Vries P, Waldschmidt TJ. Delineation among eight major hematopoietic subsets in murine bone marrow using a two-color flow cytometric technique. Cytometry 43:297-307, 2001.
|
