Injury induces deficient interleukin-12 production, but interleukin-12 therapy after injury restores resistance to infection

Autor: Mary L. Rodrick, Ann Lyons, Andreas Goebel, Inna Saporoschetz, James A. Lederer, John A. Mannick, Christopher C. Soberg, Eamon G. Kavanagh
Rok vydání: 2000
Předmět:
Zdroj: Annals of surgery. 231(2)
ISSN: 0003-4932
Popis: Serious injury induces diminished resistance to infection, and sepsis is a leading cause of death in injured patients who survive initial resuscitation. Attempting to explain this phenomenon, numerous investigators over the past two decades have documented an association between major traumatic or thermal injury and perturbations of both the innate and adaptive immune systems. 1 The cell type responsible for initiating most adaptive immune responses is the T lymphocyte, and observations from several laboratories, including our own, have demonstrated that injury induces alterations in T-cell function. 2–6 More recently, we and others have presented evidence that in patients and in animal models, serious injury is followed by loss of function of the T helper 1 (Th1) lymphocyte subset with preservation of T helper 2 (Th2) function, as indicated by cytokine production studied in vitro. 4–10 These in vitro observations have been complemented by the in vivo demonstration that major injury is associated with loss of production of antibody isotypes induced by Th1 cells with preservation of isotypes induced by Th2 cells. 11 Because Th1 cells are principal regulators of cell-mediated immune responses and of the production of complement fixing antibodies, 12 depressed function of this lymphocyte subset might be expected to be detrimental to the ability to resist infection. Indeed, in animal models of injury, therapeutic regimens designed to increase Th1 function have been associated with improved survival after a septic challenge. 13–15 Naive T cells can be induced to express the Th1 phenotype by exposure to the cytokine interleukin-12 (IL-12), whereas exposure to IL-4 induces the Th2 phenotype. 12 Major injury has been shown to result in increased IL-4 production in both humans and experimental animals, 4,5,7–9 and we have previously reported diminished IL-12 production by monocyte/macrophages in a murine burn model by day 10 after injury. 7 However, little is known about the effects of injury on IL-12 production in humans. With the recent availability of a reliable immunoassay for IL-12, we undertook an investigation of IL-12 production by circulating monocytes/macrophages at multiple time points after injury in a series of patients with major trauma or burns. We also were interested to see how the production of IL-12 was correlated with the production of the antiinflammatory Th2 type cytokine, IL-10. We had previously shown in a mouse model of burn injury that IL-12 therapy given for several days early after injury would increase survival after a septic challenge, cecal ligation and puncture (CLP). 13 Such treatment was associated with increased production of the proinflammatory cytokine interferon-gamma (IFNγ) and diminished production of IL-4. In the present studies, we wished to determine whether IL-12, given on alternate days in low doses, which corresponded to IL-12 regimens known to be minimally toxic in human clinical trials, would have a similarly beneficial effect on resistance to infection in the mouse burn model. Moreover, we wished to assess the safety and efficacy of low-dose IL-12 treatment carried out beyond the time of septic challenge. We were further interested in learning what effect such a treatment regimen would have on the production of the proinflammatory cytokines IFNγ and tumor necrosis factor-alpha (TNFα) and on the production of the antiinflammatory cytokine IL-10. Inhibition of the latter cytokine with a specific monoclonal antibody had been reported to be detrimental to survival in a similar animal model of sepsis. 16
Databáze: OpenAIRE
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