Experimental Autoimmune Encephalomyelitis EAE

EAE is a primarily CD4+ T cell-mediated demyelinating disease of the CNS, and it is widely used as an animal model for human multiple sclerosis (MS). EAE can be induced in susceptible animal strains by immunization with various myelin proteins or immunodominant peptide epitopes derived from myelin basic protein (MBP), proteolipoprotein (PLP), or myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in complete Freund's adjuvant (CFA) together with pertussis toxin treatment (Gonatas etal., 1986; Wekerle, 1991). THl-type responses appear to be responsible for EAE pathogenesis, while TH2 responses seem to be protective (Adorini and Sinigaglia, 1997; Liblau et al., 1995). The adjuvant and pertussis might be necessary to skew the systemic cytokine profile to TH1 phenotype, affect the blood-brain barrier, and support prolonged inflammation.

The therapeutic role of agonistic anti-CD137 on autoimmune disease was first evaluated in EAE model. Sun etal. (2002b) reported that agonistic anti-CD137 mAb (2A, rat IgG2a) (Wilcox et al., 2002b) treatment inhibited the development of EAE in various murine models. To induce EAE by active immunization, female C57BL/6 mice were immunized subcutaneously with 100 ^g of MOG35-55 peptide (MEVGWYRSPFSRVVHLYRNGK) emulsified in an equal volume of CFA containing 1 mg/ml Mycobacterium tuberculosis H37 RA on days 0 and 7. When C57BL/6 mice were treated with a single dose of 150 ^g of agonistic anti-CD137 monoclonal antibody (2A) i.p. on the day of the first s.c. immunization with MOG35-55 peptide emulsified in CFA, the development of EAE including disease incidence and severity was dramatically reduced with ablated spinal cord lymphocytic infiltration when compared with control rat IgG treated mice. These data suggest that CD137 engagement during the priming stage of an immune response strongly prevent the development of EAE.

Further studies showed that, draining lymph node cells from anti-CD137-treated mice failed to respond to antigen stimulation ex vivo and were not able to transfer disease to RAG-1 deficient recipient mice as that from control mice. In addition, 2A treatment inhibited delayed-type hypersensitivity (DTH) responses to MOG peptide. However, 2A treatment was not able to suppress disease development in an adoptive transfer model of EAE, which was established by transferring activated MOG-specific T cells by i.v. injection into sublethally irradiated C57BL/6 mice. Activated MOG-specific T cells were obtained by coculture for 4 days of MOG35-55 peptide with DLN cells from C57BL/6 mice immunized with MOG35-55 peptide emulsified in CFA. These results suggest that CD137 engagement during the priming stage of an immune response strongly inhibits the function of Ag-specific autoreactive T cells and prevent EAE development, and CD137 signaling plays a role before the effector phase of EAE pathogenesis.

More impressively, agonistic anti-CD137 treatment showed therapeutic effect in a more clinically relevant EAE model. The relapsing-remitting clinical course is a characteristic feature of MS. Immunization of SJL mice with s.c. injection of PLP139-151 (HSLGKWLGHPDKF) peptide in CFA containing 500 ^g of M. tuberculosis H37 RA results in the development of chronic relapsing-remitting EAE. When agonistic anti-CD137 treatment initiated on the days of immunization, it significantly reduced the severity of disease developed compared with control mice. When treatment was started after disease onset, EAE relapse was inhibited. As mentioned before, CD137 signaling plays a negative role during priming before the effector phase of EAE pathogenesis, why such treatment could still be efficient in suppressing EAE relapse after the onset of disease. One possibility is due to the "epitope spreading" during the chronic relapse-remitting EAE development. Epitope spreading is coined to describe the phenomenon that disease is induced in response to one epitope, however, T cell responses diversify to other epitopes within the same protein or to other proteins, due to autoimmune-mediated tissue damage and subsequent endogenous self-priming (Tuohy et al., 1998). It has been shown that, epitopes spread in a predictable fashion in PLPi39-i5i-induced EAE model in SJL mice: from PLP 139-151 to PLP 178-191 and then to MBP 84-104 (Vanderlugt et al., 2000; Yu et al., 1996). This spread appears related to relapse, since the incidence of relapse is reduced upon induction of tolerance to PLP 178-191 (Vanderlugt et al., 2000). It is possible that administration of agonistic anti-CD137 at the onset of first relapse inhibited the priming of neo-autoreactive T cells due to epitope spread leading to reduced later phase relapse. These studies support the notion that agonistic anti-CD137 mAb treatment tolerize autoreactive T cells and inhibited Th1-mediated autoimmune disease EAE.

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