Prevention of the acute graft-versus-host disease (GVHD) in rats by the immunomodulating drug leflunomide

Abstract

The grafting of immunocompetent allogeneic cells into MHC-discordant, genetically nonresponsive F1 hybrids of inbred rat strains consistently leads to an acute, lethal graft-versus-host disease (GVHD). The novel immunomodulating drug leflunomide, which has been shown to be efficacious in animal models of autoimmunity and adverse transplantation reactions, was studied in a rat model of GVHD. It was found that this drug not only was a powerful agent to prevent this otherwise terminal disorder, but was also proficient when used as a therapy of an established GVHD. Since leflunomide has been shown to be efficacious and safe in patients with chronic rheumatoid arthritis, it would also be reasonable to investigate this drug in clinical trials for bone marrow transplantation and GVHD in human beings.

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

“…In a number of these models, engraftment, reconstitution, chimerism, cell trafficking, and tolerance toward donor cells has been studied (Clancy et al, 1983; Oaks and Cramer, 1985; Ohajekwe et al, 1995; Engh et al, 2001; Foster et al, 2001; Okayama et al, 2004; Itakura et al, 2007; Klimczak et al, 2007; Nestvold et al, 2008; Zhou et al, 2008; Zhu et al, 2011; Zinöcker et al, 2011a;Lin et al, 2012). Furthermore, rat models have been employed to test prevention or treatment of GvHD by therapeutic regimens involving immunomodulatory drugs (Tutschka et al, 1979; Vogelsang et al, 1986; Vogelsang et al, 1988; Mrowka et al, 1994; Ohajekwe et al, 1995; Pakkala et al, 2001; Okayama et al, 2006; Wolff et al, 2006; Jäger et al, 2007), infusion or induction of various suppressive cell types (Itakura et al, 2007; Aksu et al, 2008; Nestvold et al, 2008; Kitazawa et al, 2010; Zinöcker et al, 2011b; Kitazawa et al, 2012; Zinöcker et al, 2012), UV irradiation (Ohajekwe et al, 1995; Gowing et al, 1998), serum transfusion (Shimizu et al, 1997), surgical techniques (Kobayashi et al, 1998), and prolonged distribution of a chemical agent with subcutaneously implanted osmotic pumps (Fidler et al, 1993). …”

Effects of long‐term oral treatment with leflunomide on allergic sensitization, lymphocyte activation, and airway inflammation in a rat model of asthma

“…The isoxazole derivative leflunomide is a novel and effective immunomodulatory and anti‐inflammatory substance that holds promise as a therapeutic agent. It has been demonstrated to have prophylactic and therapeutic effects in the treatment of several animal models of autoimmune disease [ 5, 6] and graft rejection [ 7–9] as well as being safe and effective in clinical trials of human rheumatoid arthritis [ 10]. While its full spectrum of activity is unknown, leflunomide is known to inhibit the proliferation of T lymphocytes [ 11, 12].…”

The effects of leflunomide on CD4+CD25+Foxp3+ T regulatory cells in mice receiving allogeneic bone marrow transplantation

“…T cells was not enhanced after LEF treatment [47]. It was also reported that LEF was a powerful agent for preventing GVHD in rats [48]. The reasons for the different response of CD4 ?…”