Herpes simplex virus type 1 (HSV-1) and Candida albicans are severe pathogens in thermally injured patients (TI patients). We are attempting to regulate these infections in TI patients immunologically. A predominance of type 1 T cell responses (an essential host's defense against these infections) was not produced in patient PBL-SCID chimeras (SCID mice inoculated with peripheral blood lymphocytes from TI patients) that were manifested by burn-associated type 2 T cell responses. In previous studies, the infection-associated mortality of patient PBL-SCID chimeras was markedly reduced when they were treated with IL-12 (an inducer of type 1 T-cell responses) and sIL-4R (an inhibitor of type 2 T cell responses) in combination. However, differences in the effectiveness of the combination therapy could be related to the levels of type 1/type 2 T cell responses that affect the severity of infection with HSV-1 and C. albicans. Because a very large number of patient PBLs with high activity of type 2 T cell responses is required to explore these questions, experiments utilizing patient PBL-SCID chimeras are impractical. Therefore, in this proposal a novel model of healthy donor's PBL-SCID chimeras with experimentally enhanced type 2 T cell responses will be used. To accomplish immunological regulations of burn-associated HSV-1 and C. albicans infections, the following studies are proposed; (1) to determine a soluble initiation factor(s) (or initiation cells) for the subsequent development of burn-associated type 2 T cell responses; (2) to induce various levels of type 2 T cell responses in human SCID chimeras (type 2/human SCID chimeras); (3) to enhance optimal levels of type 1 T cell responses in type 2/human SCID chimeras; and (4) to regulate various levels of established infections with HSV-1 or C. albicans in type 2/human SCID chimeras by the combination of IL-12 +/- IL-18 and sIL-4R. Established infections with these pathogens in type 2/human chimeras would be expected to be immunologically controlled by the combination therapy. To understand if it is possible to regulate HSV-1 and C. albicans in TI patients, the information obtained by this proposal might be critical.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044218-04
Application #
6632164
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Rothermel, Annette L
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$298,000
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555