Selective depletion of myelin–reactive T cells with the anti–OX–40 antibody ameliorates autoimmune encephalomyelitis

Abstract

The OX-40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)-specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX-40 immunotoxin was used to target and eliminate MBP-specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX-40 immunotoxin bound exclusively to myelin-reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX-40 antigen was also found in peripheral blood of patients with acute graft-versus-host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX-40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen.

Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity

“…We have found that the OX-40R is only expressed on CD4 ϩ T cells isolated from the "inflammatory sites" in cancer and autoimmune disease and is turned over quite rapidly (within 24 -48 h) (26,29). However, it has been shown that both CD4 and CD8 T cells can express the OX-40R if stimulated in vitro with Con A or PHA (42).…”

“…Further support for this hypothesis was derived from experiments that depleted OX-40R ϩ T cells in animals with EAE. An anti-OX-40 immunotoxin was injected into animals with ongoing signs of EAE, and after treatment the disease did not progress and the autoantigen reactive cells were no longer present within the inflammatory site (26). We propose that the OX-40R ϩ T cells found within the inflammatory compartments in cancer (29) are the tumor-reactive T cells and if they can be specifically expanded it should lead to an increase in tumor-specific immunity.…”

“…ϩ T cells (25,26). Approximately 15-40% of the T cells that invade the inflammatory tissue during an acute episode of autoimmune encephalomyelitis (an animal model for multiple sclerosis) are OX-40R ϩ , whereas 100% of the invading T cells express the IL-2R (25,27).…”

Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery

“…Furthermore, this observation is also interesting in the context of the data on several immunological diseases, namely, multiple sclerosis, rheumatoid arthritis and GVHD, suggesting that OX40 is a reliable indicator of pathogenic T cells which have been recently antigen-activated; anti-OX40 immunotherapy may therefore be a promising approach in T cell-mediated diseases [27,29].…”

“…The expression of these costimulatory molecules is tightly regulated in healthy subjects, as shown by the minimal levels of expression in peripheral blood lymphocytes [27,28]. An over-expression of CD40L in lymphocytes from patients with systemic lupus erythematosus (SLE) was recently described [28], and evidence from experimental models of autoimmune diseases, allographic transplantation and graft versus host disease (GVHD) suggested that these molecules may represent important targets for therapeutic intervention [27][28][29][30][31]. Moreover, recent data indicate that CD40L is required for the development of retrovirus murine AIDS (MAIDS) and that the use of anti-CD40L MoAb inhibited the disease progression in this model of immunodeficiency [32].…”