The proposed training program is designed to facilitate the ability of Dr. Edward Sherwood to develop an independent and productive research career in the area of injury-induced immunosuppression. The training goals of the project are to: 1) provide didactic training in cellular and molecular immunology as well as the pathophysiology of trauma and burns; 2) develop the technical and scientific skills necessary to conduct high quality research and 3) generate data to test the proposed hypotheses and form the foundation for future competitive grant applications and publications. He will be mentored by Professors Daniel Traber and Frank Schmalstieg, experienced investigators in the field of burn injury who have an extensive record of training young investigators. The proposed research project is designed to characterize and treat burn-induced immunosuppression. Thermal injury results in the induction of type 2 T cells that secrete immunosuppressive cytokines. Evidence indicates that lack of IL- 12 secretion is largely responsible for the predominance of type 2 T cells in burned patients. IL-12 and IL-18 are cytokines that stimulate the production of immunopotentiating type 1 T cells. Evidence indicates that administration of IL-12 to thermally- injured mice will promote type 1 T cell predominance and enhance resistance to infection. Our preliminary studies show that glucan is a potent promoter of the production of IL-12 and the type 1 cytokine interferon gamma (IFNgamma). The proposed studies are based on the hypotheses that: 1. IL-12 and IL-18 secretion and function are impaired following thermal injury resulting in the predominance of type 2 T cells; 2. Administration of IL-12 and IL-18 to thermally injured mice will promote type l cytokine expression and enhance resistance to infection; 3. Administration of glucan to thermally injured mice will promote IL-12, IL-18 and IFNgamma production, increase type 1 T cell predominance and enhance resistance to infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08GM061243-01
Application #
6090937
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2000-05-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$117,180
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Tao, Weike; Deyo, Donald J; Traber, Daniel L et al. (2004) Hemodynamic and cardiac contractile function during sepsis caused by cecal ligation and puncture in mice. Shock 21:31-7
Sherwood, Edward R; Lin, Cheng Y; Tao, Weike et al. (2003) Beta 2 microglobulin knockout mice are resistant to lethal intraabdominal sepsis. Am J Respir Crit Care Med 167:1641-9
Toliver-Kinsky, Tracy E; Lin, Cheng Y; Herndon, David N et al. (2003) Stimulation of hematopoiesis by the Fms-like tyrosine kinase 3 ligand restores bacterial induction of Th1 cytokines in thermally injured mice. Infect Immun 71:3058-67
Toliver-Kinsky, Tracy E; Varma, Tushar K; Lin, Cheng Y et al. (2002) Interferon-gamma production is suppressed in thermally injured mice: decreased production of regulatory cytokines and corresponding receptors. Shock 18:322-30
Varma, Tushar K; Lin, Cheng Y; Toliver-Kinsky, Tracy E et al. (2002) Endotoxin-induced gamma interferon production: contributing cell types and key regulatory factors. Clin Diagn Lab Immunol 9:530-43
Sherwood, E R; Varma, T K; Fram, R Y et al. (2001) Glucan phosphate potentiates endotoxin-induced interferon-gamma expression in immunocompetent mice, but attenuates induction of endotoxin tolerance. Clin Sci (Lond) 101:541-50
Varma, T K; Toliver-Kinsky, T E; Lin, C Y et al. (2001) Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice. Infect Immun 69:5249-63