Research Interests

Nutrition and the Immune System

The immune system acts to protect the host from infectious agents that exist in the environment (bacteria, viruses, fungi, parasites) and from other noxious insults (cancer, trauma, surgery, burns).  The long term goal of our research is to prevent or control infection, disease and/or autoimmunity through the development of nutrition-based strategies which support growth and immune system development. To accomplish our goal we must first elucidate the cellular targets and molecular mechanisms affected by dietary restrictions.

Our research examines the effects of a dietary deficiency in a single branched-chain essential amino acid, leucine, on the development and function of the immune system in mice. Amino acids are the building blocks of proteins, which are essential components of the cells and tissues that comprise a properly functioning immune system. In our work we compare immune system development and function in mice fed diets that are: 1) nutritionally complete or 2) leucine-devoid (diet with comparable protein/calories but lacking leucine) or 3) nutritionally complete, but protein/calorie restricted. We compare the responses to altered diet exhibited by normal mice, by mice lacking a protein kinase (GCN2) that is believed to be important in controlling protein synthesis in situations of dietary stress, and by mice deficient in the branched-chain a-keto acid dehydrogenase complex (BCKDH) kinase, BDK.

The goal of our first project is to establish the benefit of essential amino acid (EAA) supplementation on immune development in growing mice. While inhibitory effects of protein/EAA deficiency on immune populations are documented, the effects of EAA undernutrition and subsequent restoration on the physiology and functions of the thymus and spleen are largely unknown.

We propose to determine the effect of dietary stress (leucine and/or restricted protein/calories) and dietary restoration on immune responses in Gcn2^+/+ and Gcn2^-/- mice.  Five to six week old mice will be immunized at different times during EAA deprivation/restoration. We will measure levels of immunoglobulins and cytokines produced, determine which cell types are expanded or fail to be restored and the stress response pathways that are activated.

The data from this project will further our understanding of how the immune system responds to periods of EAA undernutrition and restoration, allowing the development of nutritional strategies such as timely amino acid supplementation, to improve responses to pathogens or vaccine programs in populations at risk (i.e. underprivileged, binge dieters, elderly, those with eating disorders or gastric bypass patients).

Funding for this research was received from Ajinomoto Amino Acid Research Program

The focus of our second project is to determine the effects of dietary branched-chain amino acids (BCAA) on the growth, immune development and immune function of neonatal normal mice, mice deficient in the protein kinase GCN2 and mice deficient in the branched-chain a-keto acid dehydrogenase complex (BCKDH) kinase, BDK.

This project will determine whether feeding Gcn2^-/- or BDK^-/- mice diets supplemented with the BCAA leucine will improve growth and immune function in these fragile mice. Our hypothesis is that the signaling pathways directing growth and immune development of  Gcn2^-/- or BDK^-/- mice are more profoundly impacted by changes in neonatal diet than those in  Gcn2^+/+ or BDK^+/+ mice and that Gcn2^-/- or BDK^-/- mice may require increased dietary BCAA to survive and develop normally. Thus, Gcn2^-/- or BDK^-/- mice fed a leucine-supplemented diet from d13 will thrive, with improved early growth, physiological, neurological and immune cell development and immune function.

To test our hypothesis, we will use a model of neonatal feeding of defined liquid diets d13, supplemented with solid foods d22.  Mice will be raised either with their dams, be fed liquid and solid diets of conventional protein content, or diets high in the BCAA leucine. They will be evaluated for growth, development and immune development and function.

Currently, little is known about the impact of changes in BCAA availability on the ability of the immune system to function. The successful completion of this project will increase our understanding of the requirements of BCAA for growth and immunity, and begin to unravel the role protein kinases GCN2 and BDK may play in BCAA utilization by lymphocytes. These data will lay the groundwork for further investigations of BCAA nutrition and immunity.

Selected Publications

Reinert, R.B. L. M. Oberle, S.A. Wek, P. Bunpo, X.P. Wang, I. Mileva, L.O. Goodwin, C.J. Aldrich, D.L. Durden, M.A. McNurlan, R.C. Wek, and T.G. Anthony. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase. J. Biol. Chem., 281(41):3122-33, 2006.

Hermel, E., A. Hart, H. Acton, C. Kim, M.Wurth, S. Uddin, C. Smith, I. Gunduz, K.F. Lindahl, and C.J. Aldrich. Molecular and cellular analyses of the polymorphism of the MHC class IB molecule Qa1.  Immunogenetics, 56(9):639-649, 2004.

Davies, A.H., S. Ramirez, B. Liang, C.J. Aldrich, F. Lemonnier, H. Jiang, R. Cotter, and M. Soloski. A peptide from heat shock protein 60 is the dominant peptide bound to Qa-1 in the absence of the MHC class Ia leader sequence peptide Qdm. J. Immunol. 170: 5027-5033, 2003.

Chun, T., E. Hermel, H.R. Gaskins, and C.J. Aldrich. Sequence and CTL recognition of the MHC class Ib molecule Qa1 in nonobese diabetic (NOD) mice. Immunogenetics, 53: 506-510, 2001.

Bai, A., C.J. Aldrich, and J. Forman. Factors controlling the trafficking and processing of a leader derived peptide presented by Qa-1. J. Immunol., 165: 7025-7034, 2000

Hermel, E., A. Hart, R. Miller and C.J. Aldrich. CTL and sequence analyses of MHC class IB antigens Qa-1^c (H2-T23^r) and Qa-1^d, (H2-T23^f). Immunogenetics, 49: 712-717, 1999.

Chun, T., C.J. Aldrich, M.E. Baldeon, L.V. Kawczynski, M.J. Soloski, and H.R. Gaskins. Constitutive and regulated expression of the class IB molecule Qa-1 in pancreatic b cells. Immunology: 94: 64-71, 1998.

Hermel, E., E. Grigorenko, C.J. Aldrich. Increased class IB antigen display on TAP-2 mutant cells by a mitochondrial function inhibitor. Cellular Immunology: 179: 10-15, 1997.

Soloski, M.J., A. DeCloux, C.J. Aldrich, and J. Forman.  Structural and Functional Characteristics of the Class IB molecule, Qa-1.  Immunological Reviews: 147: 67-89, 1995.

C.J. Aldrich, A. DeCloux, A. S. Woods, R. J. Cotter, M. J. Soloski, and J. Forman.  Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a Class IB antigen. 1994. Cell: 79: 649-658, 1994.

This work is supported in part by grants from : IUSM Diabetes Research Training Center.

Saturday February 24, 2007 12:03 PM -0600