Animal Models of Acute and Chronic Graft‐Versus‐Host Disease

Abstract

Graft-versus-host disease (GVHD) represents a special situation in transplantation immunology in which immunocompetent donor cells are engrafted into recipients that are incapable of rejecting them due to tolerance, immaturity, or radiation- or chemotherapy-induced immune deficiency. Donor T cells encountering allogeneic stimulators become activated, secrete cytokines, proliferate, and differentiate into effectors; this in vivo immune response is known as the graft-versus-host reaction (GVHR). The systemic effects of this initial donor anti-host reaction comprise a multiorgan syndrome, graft-versus-host disease (GVHD). Murine GVHD experiments have been utilized to model the clinical disorders of acute and chronic GVHD (AGVHD and CGVHD) that occur after allogeneic bone marrow transplantation, and also to study T cell regulation, induction of tolerance, and autoimmune diseases. Presented in this unit are methods for generating and assessing both AGVHD and CGVHD in mice. While the two syndromes differ markedly in immunopathogenesis, both can be induced by the two main methods presented: transfer of allogenic donor lymphocytes and stem cells into irradiated hosts, and transfer of parental strain lymphocytes and stem cells into unirradiated, immune-competent F1 strain hosts. Several endpoints of AGVHD and CGVHD should be evaluated in experimental mice, with comparisons made to the syngeneic transplant control or the T cell-depleted allogeneic control. To this end, protocols are provided for the assessment of survival rates, weight loss, chimerism, donor-host cytotoxicity, and cytokine and proliferative responses to mitogenic or allogeneic stimuli. Histopathology and assays of B cell immune function are also described for evaluation of the pathogenesis of GVHD.