Previous work supported by this grant has identified a number of immunological abnormalities in patients following major burn or traumatic injury and in an animal burn model. These abnormalities include deficient T cell responses, especially deficiency in secretion of the major T cell growth factor interleukin-2 (IL-2) and increased secretion of proinflammatory cytokines by monocytes/macrophage and these observations have been confirmed at the molecular level. The applicant has observed increased IL-4 and IL-10 and decreased IFN^H production by cultured PBMC and murine splenocytes post- injury which have been associated with increased susceptibility to life-threatening infection. A hypothesis consistent with these recent observations from the P.I.'s laboratory and from other laboratories is that the immunologic dysfunction seen after serious injury is in part the result of a change in lymphocyte cytokine production from that typical of T helper 1 (Th1) cells to that typical of T helper 2 (Th2) cells and that reversal of this change will benefit the host. A secondary related hypothesis is that the shift to Th2 cytokine production results from: 1) apoptosis and/or unresponsiveness of pre-existing Th1 cells, 2) conversion of naive T cells to the phenotype by the continuing presence of IL-4 in the lymphoid microenvironment, 3) diminished production by monocytes/macrophages of the Th1 inducing cytokine, IL-12, and overproduction of mediators inhibitory of Th1 cells. These hypothesis will be tested by studying peripheral blood mononuclear cells from human burn and trauma patients and splenocytes and lymph node cells from a mouse model of burn injury with the following specific aims: (1) Determination of the time course of increased IL-4 and IL-10 production and mRNA expression and of decreased interferon (IFN-gamma) production and mRNA expression after injury and identification of the cell types involved; (2) Characterization of the Th population found after injury; (3) Determination of the mechanisms underlying the change in cytokine production after injury; (4) Reversal of altered cytokine production after injury.
| Hanschen, Marc; Tajima, Goro; O'Leary, Fionnuala et al. (2012) Phospho-flow cytometry based analysis of differences in T cell receptor signaling between regulatory T cells and CD4+ T cells. J Immunol Methods 376:1-12 |
| Stoecklein, Veit M; Osuka, Akinori; Lederer, James A (2012) Trauma equals danger--damage control by the immune system. J Leukoc Biol 92:539-51 |
| Osuka, Akinori; Hanschen, Marc; Stoecklein, Veit et al. (2012) A protective role for inflammasome activation following injury. Shock 37:47-55 |
| O'Leary, Fionnuala M; Tajima, Goro; Delisle, Adam J et al. (2011) Injury-induced GR-1+ macrophage expansion and activation occurs independently of CD4 T-cell influence. Shock 36:162-9 |
| Byrne, William L; Mills, Kingston H G; Lederer, James A et al. (2011) Targeting regulatory T cells in cancer. Cancer Res 71:6915-20 |
| MacConmara, Malcolm P; Tajima, Goro; O'Leary, Fionnuala et al. (2011) Regulatory T cells suppress antigen-driven CD4 T cell reactivity following injury. J Leukoc Biol 89:137-47 |
| Hanschen, Marc; Tajima, Goro; O'Leary, Fionnuala et al. (2011) Injury induces early activation of T-cell receptor signaling pathways in CD4+ regulatory T cells. Shock 35:252-7 |
| Fujimi, Satoshi; Lapchak, Peter H; Zang, Yan et al. (2009) Murine dendritic cell antigen-presenting cell function is not altered by burn injury. J Leukoc Biol 85:862-70 |
| Maung, Adrian A; Fujimi, Satoshi; MacConmara, Malcolm P et al. (2008) Injury enhances resistance to Escherichia coli infection by boosting innate immune system function. J Immunol 180:2450-8 |
| Purcell, Elizabeth M; Dolan, Sinead M; Kriynovich, Sara et al. (2006) Burn injury induces an early activation response by lymph node CD4+ T cells. Shock 25:135-40 |
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