309: Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation

Abstract

Leukocyte function associated antigen-1 (LFA-1) regulates T cell adhesion and activation. LFA-1 is constitutively expressed on cell surface in an inactive state. The control of LFA-1 activation is critical in inflammatory and immune responses. We demonstrated previously that the I-domain, the ligand binding site of LFA-1, changes from the low-affinity state to high-affinity state upon activation. Therapeutic antagonist, such as lovastatin, stabilizes the I-domain in the low-affinity state and inhibits the LFA-1 activation. Here, we report that lovastatin can block mouse T cell adhesion and proliferation in vitro. First, we demonstrated that lovastatin treatment reduced the mortality and morbidity in the mouse GVHD model. Lovastatin treatment significantly decreased GVHD mortality with 80% mice survived over 28 days, whereas more than 70% of the control mice died within the first 10 days, and the p values was 0.045. There were significantly reduced tissue damages in the skin, intestine and liver of lovastatin-treated mice. Second, we found lovastatin treatment reduced donor T cell homing to lymph nodes. There was a 65% reduction of CD4+ T cells homing to lymph nodes in lovastatin treatment group compared to control. The reduction of CD8+ T cells was greater with about 76% less cells homing to lymph nodes in the lovastatin treatment group. Third, we found lovastatin treatment reduced donor-derived T cell proliferation in vivo. There were 37% CD4+ and 31% CD8+ T cells remained undivided in the lymph nodes of the control mice at day 4 post-transplant. The lovastatin-treated mice had reduced proliferation kinetics of both CD4+ and CD8+ T cells with about 55% and 42% remained undivided. In the control lymph nodes, there were 42% CD4+ and 59% CD8+ T cells proliferated beyond 5th and 6th cell-divisions respectively, whereas the lovastatin treatment reduced the number to 31% and 48% respectively. In summary, we demonstrated here that lovastatin prevents both homing and proliferating of donor-derived T cells in the secondary lymphoid organs, which are crucial sites for alloreactive expansion. While most of the control mice died of acute GVHD within the first week of post-transplant when alloreactive T cells infiltrated the targeted organs, lovastatin treatment prevented the activation and expansion of donor-derived T cells, and thus reduced the GVHD mortality and morbidity. Our study provides rationale for a potential novel treatment for GVHD.