Abstract

Graft versus-host disease (GVHD) is a major cause of morbidity and mortality after bone marrow transplantation (BMT). An allogeneic GVH reaction is a response of donor lymphoid cells to host minor or major histocompatibility antigens. Donor T cells can be activated through the innate and the adaptive immune mechanisms. Donor B cells produce antibodies directed to host cells. These mechanisms may activate complement pathways. Thus, complement may have a crucial role in inflammation during a GVH reaction, but direct evidence for this has not been shown. In this study, we investigated the possibility of complement inhibitor, anti-mouse C5 antibody (BB5.1), to ameliorate the symptoms of GVHD using an acute GVHD mouse model: C57BL/6 (H2b) →BALB/c (H2d). One million T cells were injected together with 1 x 107 T-cell-depleted bone marrow (TCD BM) cells via tail vein into lethally irradiated BALB/c (8.5 Gy) recipients. Anti-mouse C5 antibody or its isotype matched control was administered intraperitoneally at a dose of 1 mg/mouse, 3 doses/week, for 4 weeks. Recipients were weighed weekly, and their survival was monitored daily. Average body weight of C5 antibody treated mice was 15.8 g at day 84 (19.2 g at day 0, N=12), whereas average weight of control mice was 13.3 g (19.2 g at day 0, N=12) (P=0.05, Student’s t-test). Kaplan-Meier survival curves were also compared as shown in the Figure. Eight of 12 mice were alive at day 84 in the treated group, as compared to only 2 of 12 in the control group (P=0.03, Logrank test). A second experiment showed similar data. We, thus, observed the effect of anti-mouse C5 antibody to reduce the symptoms of GVHD using an acute GVHD mouse model. These results might open a new window for the prevention of acute GVHD. Further experiments are currently ongoing to clarify the exact mechanism between complement and GVHD.

Author notes

Disclosure:Employment: Russell Rother is an employee of Alexion Pharmaceuticals Inc. Ownership Interests: Russell Rother has equity ownership in the company. He has assigned to Alexion Pharmaceuticals his inventions made as an employee and has received no royalties from the company for these inventions.