Differential roles of IL-1 and TNF-α on graft-versus-host disease and graft versus leukemia

Abstract

We demonstrate an increase in graft-versus-host disease (GVHD) after experimental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy/TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) function was not altered. Histological analysis of the gastrointestinal tract demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, which permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LPS was increased in BMT recipients after Cy/TBI conditioning. Neutralization of IL-1 significantly reduced serum LPS levels and GVHD mortality, but it did not affect donor CTL activity. By contrast, neutralization of TNF-alpha did not prevent GVHD mortality but did impair CTL activity after BMT. When P815 leukemia cells were added to the bone marrow inoculum, allogeneic BMT recipients given the TNF-alpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leukemia (GVL) was due to effects on donor T cells, cohorts of animals were transplanted with T cells from either wild-type mice or p55 TNF-alpha receptor-deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells demonstrated a significant impairment in donor CTL activity after BMT and an increased rate of leukemic relapse compared with recipients of wild-type T cells. These data highlight the importance of conditioning in GVHD pathophysiology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not.

Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease

“…TNF-␣ is known to be an important mediator of tissue damage during GVHD. 16,17 TNF-␣ binds to two receptors, p55 and p75, both of which are expressed on all hematopoietic cells with the exception of erythroid and unstimulated T cells. TNF-␣ can induce cytotoxicity, which is predominantly linked to the p55 receptor.…”

“…[13][14][15] Furthermore, tumor necrosis factor (TNF)-␣, interferon (IFN)-␥ and IL-15 were reported to be involved in the development of GVHD. [15][16][17][18][19] In contrast, within the cytokine network, activation of these proinflammatory mediators is followed by increased production of endogenous inhibitory molecules, including antagonistic cytokines. 20 Among them, IL-10 has raised substantial interest: IL-10 is produced by both monocytes/macrophages and T cells belonging to the Th0, Th1 and Th2 subsets.…”

Alloreaction increases or restores CD40, CD54, and/or HLA molecule expression in acute myelogenous leukemia blasts, through secretion of inflammatory cytokines: dominant role for TNFβ, in concert with IFNγ

“…We then addressed whether the proinflammatory cytokines IL-1, TNFa, IFNg, IL-6 and IL-2 that have been described by others to participate into the GVHD-mediated host tissue damage, 8 were also present in major or minor histocompatibility mismatched MLR-Sn. Results shown in Table 3, indicated that high levels of IL-1, TNFa, IFNg and IL-6 were still present at day 5 of culture, when MLR-Sn were harvested.…”

“…Thus, the dissection of the patho-physiological mechanisms that are involved in GVHD demonstrates several sequential steps. [5][6][7][8][9] In the first phase, cytokines, such as TNFa, IL-1 and IL-6, are secreted during the conditioning regimen and contribute to activation of donor T cells. Subsequently, stimulation of donor T cells by host antigens in concert with the phase 1-secreted cytokines leads to production of cytokines, including, IL-2 and IFN-g, which amplify the allogeneic response and activate mononuclear phagocytes.…”

Differential effect of conditioning regimens on cytokine responses during allogeneic stem cell transplantation

“…Elevated serum levels of immunoregulating and inflammatory cytokines, such as tumour necrosis factor (TNF), interleukin (IL)-1b, IL-8 and interferon-g, have been observed before and during these complications. 6,7 In particular, TNF has been the focus of a number of studies and there are indications that high serum levels of TNF in the early phases of SCT are related to an increased risk of severe aGvHD. 8 Moreover, TNF antagonists, such as anti-TNF antibody, may partially prohibit the development of aGvHD.…”