OX‐40 antibody enhances for autoantigen specific Vβ8.2⁺ T cells within the spinal cord of lewis rats with autoimmune encephalomyelitis

Abstract

The V beta 8.2 T cell receptor (TCR) component is the predominant V beta gene product associated with antigen specific CD4+ T cell response to the major encephalitogenic epitope of myelin basic protein (MBP) in Lewis rats. Lewis rats were actively immunized with MBP in complete Freund's adjuvant and the V beta 8.2 positive and negative cells were analyzed for IFN-gamma mRNA production and OX-40 cell surface expression during the onset of EAE. The V beta 8.2+ T cells isolated from the spinal cord produced the majority of mRNA for IFN-gamma and also showed a marked enhancement for OX-40 expression compared to V beta 8.2+ T cells isolated from the lymph nodes. Only a fraction of IL-2 receptor positive T cells examined ex vivo from the inflammatory compartments co-expressed the OX-40 antigen. These results suggested that OX-40 cell surface expression could be used to identify and isolate the most recently activated T cells ex vivo. OX-40+ T cells isolated from the spinal cord were highly enriched for the V beta 8.2 T cell receptor component compared to OX-40- or unsorted spinal cord lymphocytes. OX-40+ T cells isolated from the spinal cord had an enhanced response to MBP, whereas OX-40+ cells isolated from the lymph nodes responded to both MBP and purified protein derivative. These data suggest that activated T cells can be isolated and characterized with the OX-40 antibody which only respond to the antigens present at the local site. The data also imply that isolation of OX-40+ T cells will be useful in identifying V beta biases and autoantigen specific cells within inflamed tissues even when the antigen specificity is unknown.

The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo

“…Furthermore, signaling through the CD134-CD134L pathway has been shown to reverse peripheral tolerance (45). CD134 ϩ T cells have also been associated with various autoimmune diseases (30,(32)(33)(34), and targeting of the CD134-CD134L pathway is believed to hold therapeutic potential in the treatment of autoimmunity and possibly in enhancing vaccine efficacy (46).…”

“…In vitro and in vivo evidence has demonstrated that the CD134-CD134L interaction can provide a costimulatory signal to T cells, increasing T cell proliferation and cytokine production (25,26) as well as influencing B cell proliferation and Ig production (27,28). CD134 ϩ T cells have been implicated in various immune-mediated diseases, such as experimental autoimmune encephalomyelitis (29,30), rheumatoid arthritis (31,32), inflammatory skin disease (33), as well as graft-vs-host disease (34). In experimental autoimmune encephalomyelitis, administration of a neutralizing anti-CD134L mAb or OX40-Fc fusion protein ameliorates disease (35,36), while in animals lacking CD28 costimulation, CD134-CD134L blockade can completely abrogate disease (37).…”

Strong expression of CD134 (OX40), a member of the TNF receptor family, in a T helper 2-type cytokine environment

“…Lewis rats immunized with myelin basic protein and complete Freund's adjuvant, which develop the Th1-mediated autoimmune disease EAE, show an increase of CD134 ϩ cells in their lymph nodes. The majority of these cells express an autoreactive T cell receptor, but comprise only a very small part of the total lymphocyte population [40]. CD134 ϩ Th1-type cells were also shown to specifically invade the spinal cord in a passive form of EAE, induced by transfer of an encephalitogenic T cell line [19]; depletion of these cells prevented disease induction [16].…”

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

“…If as we predict, the OX-40R ϩ cells at the tumor site or draining lymph nodes are the tumor-specific T cells in vivo (27)(28)(29), then engagement of the OX-40R in vivo should lead to an enhanced antitumor-specific response. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would lead to an increase in tumor-free survival or a delay in tumor development.…”

“…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). Spinal cord T cells isolated from the CNS of rats with experimental autoimmune encephalomyelitis (EAE), sorted based on OX-40R expression, had their TCR CDR3 regions (Ag-binding region) sequenced.…”