Animal Models of Acute and Chronic Graft VersusHost Disease

unit 4.3

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 (parent ^ offspring, or P ^ F1), immaturity (adult ^ neonate), or radiation- or chemotherapy-induced immune deficiency (donor ^ irradiated host). 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 (see Commentary), both can be induced by the two main methods presented: transfer of allogenic donor lymphocytes and stem cells into irradiated hosts (see Basic Protocol 1) and transfer of parental strain lymphocytes and stem cells into unirradiated, immune-competent F1 strain hosts (see Basic Protocol 2). The key factors in determining outcome (i.e., induction of acute versus chronic GVHD) are the selection of donor and host strains and the T cell number and subsets injected (see Tables 4.3.1 and 4.3.2).

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. These include assessment of survival rates (see Support Protocol 1), weight loss (see Support Protocol 2), chimerism (see Support Protocol 3), donor-host cytotoxicity (see Support Protocol 4), and cytokine and proliferative responses to mito-genic or allogeneic stimuli (see Support Protocol 5). Histopathology (see Support Protocol 6) and assays of B cell immune function (see Support Protocol 7) can also be used to evaluate the pathogenesis of GVHD.

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