TNF-α has long been regarded as a proimmune cytokine involved in antimicrobial type 1 immunity. However, the precise role of TNF-α in antimicrobial type 1 immunity remains poorly understood. We found that TNF-α-deficient (TNF -/-) mice quickly succumbed to respiratory failure following lung infection with replication-competent mycobacteria, because of apoptosis and necrosis of granuloma and lung structure. Tissue destruction was a result of an uncontrolled type 1 immune syndrome characterized by expansion of activated CD4 and CD8 T cells, increased frequency of antigen-specific T cells, and overproduction of IFN-γ and IL-12. Depletion of CD4 and CD8 T cells decreased IFN-γ levels, prevented granuloma and tissue necrosis, and prolonged the survival of TNF -/-hosts. Early reconstitution of TNF-α by gene transfer reduced the frequency of antigen-specific T cells and improved survival. TNF-α controlled type 1 immune activation at least in part by suppressing T cell proliferation, and this suppression involved both TNF receptor p55 and TNF receptor p75. Heightened type 1 immune activation also occurred in TNF -/-mice treated with dead mycobacteria, live replication-deficient mycobacteria, or mycobacterial cell wall components. Our study thus identifies TNF-α as a type 1 immunoregulatory cytokine whose primary role, different from those of other type 1 cytokines, is to keep an otherwise detrimental type 1 immune response in check.

Sepsis represents a growing concern in high-risk patients and there has been a lack of effective preventives and therapies. Bacterial/permeability increasing protein (BPI) is a human neutrophil granule-associated defense molecule specific for Gram-negative bacteria and their products. To develop a BPI-transgene-based prophylactic or therapeutic modality, we have developed a recombinant, replication-deficient adenoviral vector expressing full-length human BPI protein (Adh- BPI IntroductionSepsis is a heterogeneous condition with approximately 400 000 to 500 000 cases presented in the United States annually. 1,2 The mortality rate for all septic episodes is estimated between 30% to 50%, and approximately 70% of all septic episodes involve Gram-negative bacteria. 2,3 The Centers for Disease Control and Prevention has reported an increase in the incidence of sepsis over the last decade, which can be attributed to an increase in the number of patients at high risk for developing sepsis. 1 High-risk patients include those who are immunocompromised from HIV infection, undergoing cancer therapy, or on immunosuppressive drugs, and those undergoing invasive surgical procedures. These patients are at greater risk of exposure to bacteria, especially in the clinical setting. 4 The goal of sepsis management is to reduce or control the detrimental systemic inflammation responses to the infection using support therapies, while treatment therapies, such as antibiotics, attempt to eliminate the infection. 5 With the increase in incidence of both drug-resistant bacteria and immunocompromised septic patients, current aggressive therapies are ineffective or even detrimental, and new therapies must be developed to increase the survival of septic patients. 5-9 Moreover, it may be possible to prophylactically reduce the number of sepsis-induced mortalities by introducing a set of criteria to identify and treat high-risk individuals prior to surgery or cancer therapy.Various novel sepsis therapies currently under development or under evaluation in clinical trials include anticoagulant therapy, therapies directed at the neutralization of lipopolysaccharide (LPS), and cytokine therapies. Anticoagulant therapy aims to improve multiple organ failure by attenuating intravascular coagulation. 10 In this regard, the use of recombinant activated protein C has been shown to increase survival of patients. 10,11 However, activated protein C therapy addresses only one portion of the complex sepsis condition and does not address the important initial proinflammatory cytokine cascade elicited by LPS from Gram-negative bacteria. On the other hand, while therapies directed at the neutralization of proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF-␣), are promising in experimental models, they are largely ineffective in clinical trials. 12-17 The interleukin-10 (IL-10) cytokine therapy aiming to counter the expression and effect of TNF-␣ has also proved ineffective. 18 Such cytokine therapies are thus unlikely to be the best strategy. Seps...

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