Kinetics of cellular and cytokine responses in a chimeric mouse model for the study of staphylococcal enterotoxin B pathogenesis.
The mechanisms by which superantigens, such as staphylococcal enterotoxin B (SEB), contribute to microbial pathogenicity have been poorly defined. The study of such pathogenic processes has been hampered by the lack of an adequate animal model. We utilized a previously described murine chimeric model to determine the cytokines and cell populations that might be involved in SEB toxicity. In the absence of bone marrow transplantation (BMT), all total body irradiated (TBI) mice died, while all transplanted mice survived up to 6 months. Compared with non-TBI and non-BMT mice, chimeric mice had an increased percentage of CD11b (Mac-1)-positive splenocytes (17 vs. 59%, P < 0.05) and decreased CD45R-positive (B) cells (33 vs. 6%, P < 0.05) at 6 weeks after BMT. The relative numbers of splenocyte CD4 and CD8 cells were similar in chimeric and normal mice. Susceptibility of chimeric animals to 10 or 100 microg SEB was time-dependent: no mice challenged at 2 weeks post-BMT died, but 15% of mice challenged at 4 weeks and 50% of those challenged at 6-8 weeks died. Compared with TBI and non-BMT C3H/HeJ mice, SEB-challenged chimeric mice at 6-8 weeks had (1) increased splenocyte mRNA expression for: IFN-gamma (3.5 x optimally at 1 h), TNF-alpha (6.5 x at 2 h), IL-6 (4.8 x at 4 h), IL-1beta (8.4 x at 4 h), IL-2 (4.7 x at 4 h), and IL-10 (3 x at 16 h), and (2) increased and earlier peak serum levels of IFN-gamma, IL-6, IL-1beta and IL-2, but no increase in serum TNF-alpha or IL-4. These data support the hypothesis that the decreased percentage of B cells and increased macrophages in chimeric mice lead to enhanced T cell-macrophage interactions after SEB administration and a lethal burst of T cell and macrophage cytokine release. This model will provide insight into cell populations and mechanisms that mediate superantigen-induced toxicity.
Yuan
L
L
Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Lowell
G H
GH
Hoover
D L
DL
Colleton
C A
CA
Hammack
C A
CA
Young
L D
LD
Fischer
R
R
Patchen
M L
ML
Cross
A S
AS
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D005260:Female; D015870:Gene Expression; D007700:Kinetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity
D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D004768:Enterotoxins; D016177:Macrophage-1 Antigen; D018089:Superantigens; C031818:enterotoxin B, staphylococcal