Prevention of murine graft-versus-host disease by inducing and eliminating ASGM1+ cells of donor origin.

Abstract

In this study anti-asialo GM1 antibodies (anti-ASGM1) were used to further characterize the effector cells responsible for graft-versus-host (GVH)-induced histopathological lesions: Two different types of ASGM1+ cells were identified: an endogenous ASGM1+ population and an induced ASGM1+ population. Both of the ASGM1+ cell populations exhibited natural killer (NK) cell activity, as assessed by their ability to lyse YAC tumor targets in vitro. Donor C57BL/6 (B6) mice were treated in vivo with anti-ASGM1 to eliminate endogenous ASGM1+ cells. ASGM1+ cells were induced in B6 donor mice by treating the animals with 15 x 10(6) B6 x AF1 (B6AF1) lymphoid cells for 44-48 hr. The induced ASGM1+ cells were eliminated by in vivo treatment with anti-ASGM1. GVH reactions were induced by injecting B6 lymphoid cells into B6AF1 mice. Prior to GVH induction the B6 donor cells were tested for NK cell activity against YAC tumor target cells in vitro and for T and B cell functions by mitogen responses in vitro. GVH reactions were determined by splenomegaly, suppression of the plaque-forming cell (PFC) response to sheep red blood cells (SRBC), suppression of the T and B cell mitogen responses, and the development of GVH-associated histopathological alterations in the thymus, liver, and pancreas. Donor lymphoid cells depleted of endogenous ASGM1+ cells were effective at inducing splenomegaly, severe suppression of immune functions, and histopathological lesions. Donor lymphoid cells depleted of both the endogenous and induced ASGM1+ cells displayed normal T cell mitogen responses and were capable of inducing splenomegaly and partial suppression of the PFC response to SRBC when injected into B6AF1 recipients, however, these lymphoid cells failed to induce both GVH-associated histopathological lesions and severe suppression of T and B cell mitogen responses. These results suggest that semiallogeneic stimulation induces an ASGM1+ population in the donor inoculum that displays NK cell-like function (YAC killing) and that plays a crucial role in inducing GVH-mediated histopathological lesions and severe immunosuppression of both T and B cell responses.