Beta 2 microglobulin knockout mice are resistant to lethal intraabdominal sepsis.
beta 2 microglobulin knockout (beta2M-/-) mice lack CD8+ T and natural killer T cells. We hypothesized that beta 2M-/- mice are resistant to lethal intraabdominal sepsis. To test this hypothesis, mortality, cytokine production, and physiologic function were assessed in beta 2M-/- mice during sepsis caused by cecal ligation and puncture (CLP). beta 2M-/- mice survived significantly longer than wild-type mice after CLP but ultimately exhibited 100% mortality. Treatment of beta 2M-/- mice with anti-asialoGM1 to deplete natural killer cells conferred greater than 70% long-term survival. Compared with wild-type mice, beta 2M-/- mice treated with anti-asialoGM1 produced decreased amounts of proinflammatory cytokines and did not exhibit hypothermia or metabolic acidosis after CLP. Adoptive transfer of CD8+ T and natural killer cells into beta 2M-/- mice treated with anti-asialoGM1 re-established CLP-induced mortality. CD8 knockout mice treated with anti-asialoGM1, which are specifically deficient in CD8+ T and natural killer cells, exhibited 40% long-term survival after CLP. Furthermore, treatment of wild-type mice with antibodies to CD8 and asialoGM1 conferred a significant survival benefit compared with wild-type mice treated with nonspecific IgG. These findings demonstrate that beta 2M-/- mice treated with anti-asialoGM1 are resistant to CLP-induced mortality and that depletion of CD8+ T and natural killer cells largely accounts for the survival benefit observed in these mice.
Sherwood
Edward R
ER
Department of Anesthesiology, University of Texas Medical Branch, Shriners Hospital for Children, Galveston, TX 77555-0591, USA. ersherwo@utmb.edu
Lin
Cheng Y
CY
Tao
Weike
W
Hartmann
Christopher A
CA
Dujon
Jay E
JE
French
Andrew J
AJ
Varma
Tushar K
TK
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002432:Cecum / Q000293:injuries / Q000601:surgery; D004195:Disease Models, Animal; D005260:Female; D005677:G(M1) Ganglioside / Q000037:antagonists & inhibitors; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007249:Inflammation; D007694:Killer Cells, Natural / Q000276:immunology*; D008026:Ligation; D008231:Lymphopenia / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics / Q000276:immunology*; D010538:Peritonitis / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D018805:Sepsis / Q000209:etiology / Q000276:immunology* / Q000401:mortality; D016019:Survival Analysis; D001613:beta 2-Microglobulin / Q000235:genetics
D001613:beta 2-Microglobulin; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside