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Published ahead of print on March 5, 2003, doi:10.1164/rccm.200208-950OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 12, June 2003, 1641-1649

A more recent version of this article appeared on June 15, 2003
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Submitted on August 27, 2002
Accepted on March 3, 2003

{beta}2 Microglobulin Knockout Mice are Resistant to Lethal Intra-abdominal Sepsis

Edward R Sherwood1*, Cheng Y Lin1, Weike Tao1, Christopher A Hartmann1, Jay E Dujon1, Andrew J French1, and Tushar K Varma1

1 Anesthesiology, University of Texas Medical Branch, Shriners Hospital For Children-Galveston Burns Unit, Galveston, Texas, USA

* To whom correspondence should be addressed. E-mail: ersherwo{at}utmb.edu.

Beta 2 microglobulin knockout({beta}2M-/-) 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 following 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 to wild type mice, {beta}2M-/- mice treated with anti-asialoGM1 produced decreased amounts of pro-inflammatory 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 exhibited 40% longterm survival following CLP. Furthermore, treatment of wild type mice with antibodies to CD8 and asialoGM1 conferred significant survival benefit compared to control wild type mice. 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.
Key words: CD8+T lymphocytes Natural Killer Cells Septic Shock




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