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Blockade Of Two Independent Innate Immunity Pathways Synergistically Prevent Lethal Graft-Versus-Host Disease

Year: 2010

Type: article

Abstract: Graft-versus-host disease (GVHD) is a major complication following hematopoietic cell transplantation. Innate immunity plays a major role in the development of GVHD both by aiding allogeneic T cell responses and by damaging target organs directly. MyD88 is an adaptor protein for the majority of toll-like receptors. The complement system is a central component of the innate immune response. We studied the role of these two pathways in the development of GVHD using the C57BL/6 into BALB/c model. Lethally irradiated recipients of MyD88-/- T cells survived slightly longer than recipients of wild type cells (median survival time: 48 vs. 32 days, P<0.05). Similarly, treatment with an anti-C5 antibody (clone BB5.1, 1 mg/dose, i.p., three times a week for 4 weeks), that blocks all three pathways of complement activation and prevents cell lysis, also moderately prolonged the survival of the mice with GVHD compared with the isotype control group (median survival time: 43 vs. 32 days). Treatment of MyD88-/- T cell recipients with anti-C5 antibody protected 80% of the animals from lethal GVHD at 100 days post transplantation, while only 20% in the MyD88-/- T cell recipients treated with isotype antibody group and 30% in the wildtype T cell recipients treated with anti-C5 antibody group survived (Table, P<0.01, compared with other groups). All MyD88-/- T cell recipients treated with anti-C5 antibody developed GVHD. However, the disease was less severe in these animals than those in the recipients of a single pathway blockade as measured by body weight and other clinical signs of GVHD. The anti-C5 antibody did not seem to prevent GVHD through inhibiting T cell activation and expansion because it did not inhibit mixed lymphocyte reactions. Levels of multiple pro-inflammatory cytokines were lower in the MyD88-/- T cell recipients treated with anti-C5 antibody compared with those in the control groups. These data clearly demonstrate that, even though blockade of MyD88 or complement pathway alone may prevent GVHD, GVHD can be better controlled by blocking both MyD88 and complement pathways.Tabled 1Blockade of two independent innate immunity pathways synergistically prevent lethal graft-versus-host diseaseGroupsnSurvival at day +50Survival at day +100TCD BM alone10100%100%Wildtype + isotype1020%10%Wildtype + anti-C51040%30%MyD88-/- + isotype1050%20%MyD88-/- + anti-C51090%80%P<0.01, MyD88-/- + anti-C5 vs. other groups. A representative experiment of three is shown. Open table in a new tab P<0.01, MyD88-/- + anti-C5 vs. other groups. A representative experiment of three is shown.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.429