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.
