Amelioration of Experimental Autoimmune Encephalomyelitis with Anti-OX40 Ligand Monoclonal Antibody: A Critical Role for OX40 Ligand in Migration, But Not Development, of Pathogenic T Cells

Abstract

OX40 (CD134) and its ligand (OX40L) have been implicated in T cell activation and migration. In this study, we examined the contribution of these molecules to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) by administering a neutralizing mAb against murine OX40L (RM134L) to proteolipid protein (139–151) peptide-induced EAE in SJL mice. Administration of RM134L effectively ameliorated the disease in both actively induced and adoptively transferred EAE models. Histological examination showed that the RM134L treatment greatly reduced mononuclear cell infiltration into the spinal cord. The RM134L treatment did not inhibit the development of pathogenic T cells, given that proliferative response and IFN-γ production by draining lymph node cells were not reduced or rather enhanced upon restimulation with proteolipid protein (139–151) in vitro, and these cells effectively transferred EAE to naive SJL mice. Flow cytometric analyses showed that the RM134L treatment inhibited the accumulation of OX40-expressing CD4+ T cells and the migration of adoptively transferred CD4+ T cells in the spinal cord. Immunohistochemical staining showed that OX40L was most prominently expressed on endothelial cells in the inflamed spinal cord. These results suggest that the OX40/OX40L interaction plays a critical role for the migration of pathogenic T cells into the CNS in the pathogenesis of EAE.

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

“…1). This interpretation is quite compatible with observations in the EAE system, where OX40L blockade prevented the local spread of inflammation, effective at an early stage of disease when activated T cells are moving into neural tissue (24). Alternatively (or in addition) it is conceivable that T cells, if overly activated at the early stages of the response, may "burn out" faster and thereby not be capable of participating in sustained lesions.…”

“…in two different contexts, including BDC2.5/B6 g7 mice which are inherently insensitive to genetic influences, as the disease develops despite C57BL/6 alleles that normally confer diabetes resistance. These results are reminiscent of the protection afforded by the OX40L KO mutation against EAE and CIA (10,21,23,24). However, several of our findings are somewhat at odds with previous notions of OX40 function.…”

“…Our finding of an enhancement of T cell activity in early disease stages contrasts with previous reports claiming that the abrogation of OX40 signaling in vivo in EAE models (by neutralizing mAbs, a chimeric OX40-Ig molecule, or OX40L KO) reduced the expansion of effector CD4 ϩ T cell populations and/or prevented their migration to the target tissue (10,21,24). Similarly, other work had shown an impact of OX40/OX40L on early T cell responses in vitro, promoting the expansion and survival of cells in the days just after activation, perhaps through induction of anti-apoptotic molecules (10, 12, 14, 16 -18).…”

“…In this evaluation, the OX40L deficiency had a strong influence, almost completely eliminating leukocytic infiltration of islets. Thus, OX40/OX40L costimulation seems to play an essential role in the pathogenesis of type 1 diabetes in the NOD mouse, as it does in murine models of other autoimmune diseases (10,21,23,24).…”

“…Blocking OX40-OX40L interaction suppressed autoimmune attack by CD4 ϩ T cells in several experimental systems. Treatment with anti-OX40L reduced inflammation in the joints of mice with collagen-induced arthritis (CIA), and OX40/OX40L blockade dampened clinical signs of experimental autoimmune encephalomyelitis (EAE) (10,21,23,24). The mechanism of such protection has not been fully clarified: in the CIA model, CD4 ϩ T cells seemed to have reduced differentiation to the Th1 phenotype and helper activity; in the EAE model, the priming and activation of pathogenic T cells or their migration to the spinal cord were found to be differently affected in the various studies.…”