Variable effects of cyclophosphamide in rodent models of experimental allergic encephalomyelitis

Abstract

SummaryIn this study, we have evaluated the effects of cyclophosphamide on the development of experimental allergic encephalomyelitis (EAE) in four EAE rodent models: monophasic EAE in Lewis rats, protracted relapsing (PR)-EAE in DA rats, myelin oligodendrocyte protein (MOG)-induced EAE in C57Bl/6 mice and proteolipid protein (PLP)-induced EAE in Swiss/Jackson Laboratory (SJL) mice. Cyclophosphamide, administered either prophylactically or therapeutically, suppressed most strongly the clinical symptoms of PR-EAE in DA rats. Treated rats in this group also exhibited the lowest degree of inflammatory infiltration of the spinal cord, as well as the lowest levels of nuclear factor kappa B, interleukin-12 and interferon-gamma. Cyclophosphamide prophylactically, but not therapeutically, also delayed significantly the onset of EAE in Lewis rats. In contrast, regardless of the treatment regimen used, was unable to influence the clinical course of EAE in either MOG-induced EAE in C57Bl/6 mice or PLP-induced EAE in SJL mice. This heterogeneous pharmacological response to cyclophosphamide suggests that significant immunopathogenic differences exist among these EAE rodent models that must be considered when designing preclinical studies. In addition, the effectiveness of cyclophosphamide in dark Agouti (DA) rats with PR-EAE suggests that this may be a particularly useful model for studying novel therapeutic approaches for refractory and rapidly worsening multiple sclerosis in human patients.

Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

“…It was developed in 1971 by Teitelbaum and colleagues in the laboratory of M. Sela, who was conducting extensive studies (Ridge et al, 1985;Levine and Saltzman, 1986;Lublin et al, 1987;Tischner and Reichardt, 2007;Mangano et al, 2010;) Cyclophosphamide Yes Glucocorticoids…”

“…This has significant implications both for the presumed pathogenesis and for therapeutic opportunities. As regards the pathogenesis, such a restricted receptor use could imply an inciting or causative infectious agent such as a virus; it could also explain Tolerizing DNA vaccines (Waisman et al, 1996;Lobell et al, 1998;Selmaj et al, 2000) ( Bar-Or et al, 2007;Garren et al, 2008) Antibiotics with immunomodulatory and neuroprotective functions: minocycline (Brundula et al, 2002;Giuliani et al, 2005a,b) Zabad et al, 2007;Zhang et al, 2008) Immunosuppressants Azathioprine Cyclophosphamide Mitoxantrone (Blaszczyk et al, 1978) (Mangano et al, 2010) (Ridge et al, 1985;Lublin et al, 1987) Hauser Hafler et al, 1991;Noseworthy et al, 1993;van de Wyngaert et al, 2001;Hartung et al, 2002;Krapf et al, 2005;Massacesi et al, 2005;Smith et al, 2005;Casetta et al, 2007 Haematopoietic stem cell transplantation (Karussis et al, 1992;Karussis et al, 1993b;Burt et al, 1995;Burt et al, 1998;Karussis et al, 1999;van Bekkum, 2000;Cassiani-Ingoni et al, 2007) ( Muraro et al, 2003;Burt et al, 2009;Muraro and Uccelli, 2010;Pasquini et al, 2010) i.v. immunoglobulins (Achiron et al, 1994;Achiron et al, 2000;Ephrem et al, 2008) ( Achiron et al, 1998;Haas, 2000;Strasser-Fuchs et al, 2000;Katz et al, 2006) BJP CS Constantinescu et al…”

Improved clinical behavior of established relapsing-remitting experimental autoimmune encephalomyelitis following treatment with endogenous opioids: Implications for the treatment of multiple sclerosis

“…Animals were immunized with subcutaneous injections of 100 g of myelin proteolipid protein 139-151 (PLP 139-151 ) (Peptides International, Louisville, KY) following established protocols (Hammer et al, 2013;Jackson et al, 2009;Mangano et al, 2009). PLP 139-151 was prepared by dissolving 100 g in 0.15 ml sterile phosphate buffered saline (PBS) and emulsifying with 0.15 ml incomplete Freund's adjuvant (Sigma-Aldrich, St. Louis, MO) plus 250 g Mycobacterium tuberculosis (H37RA, Difco Laboratories, Detroit, MI).…”

Are current disease‐modifying therapeutics in multiple sclerosis justified on the basis of studies in experimental autoimmune encephalomyelitis?

“…Open‐label studies have given conflicting results but it has been suggested to be beneficial in non‐responders to first‐line therapies or those with particularly aggressive MS (Weiner and Cohen 2002). A recent study has tested its use in four different EAE rodent models (Mangano et al. 2009).…”