The OX-40 receptor provides a potent co-stimulatory signal capable of inducing encephalitogenicity in myelin-specific CD4+ T cells

Kaleeba, Johnan A.R.; Offner, H.; Vandenbark, Arthur A.; Lublinski, A.; Weinberg, Andrew D.

doi:10.1093/intimm/10.4.453

Cited by 62 publications

(30 citation statements)

References 40 publications

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“…It has been shown that the inflammation associated with superantigen stimulation and clinical signs of EAE involves the production of Th1 cytokines (49). We have shown that engaging the OX-40R on Th1 lines accentuates T cell proliferation by up-regulating transcription and translation of IL-2 (39). We have also shown that effector T cells appear to be more sensitive to OX-40R-specific costimulation than naive T cells (23).…”

Section: Discussionmentioning

confidence: 81%

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

Weinberg

Rivera

Prell

et al. 2000

The Journal of Immunology

354

290

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The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20–55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host’s tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.

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Section: Discussionmentioning

confidence: 81%

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

Weinberg

Rivera

Prell

et al. 2000

The Journal of Immunology

354

290

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“…CD134 and CD134L are members of the TNF and TNFR superfamilies, respectively, and have been recently recognized as efficient T cell costimulatory molecules (25,42,43). CD134 is expressed on activated T cells, primarily on CD4 ϩ cells, although CD8 ϩ T cell expression is also found but to a lesser degree (18,44).…”

Section: Discussionmentioning

confidence: 99%

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

Yuan

Salama

Dong

et al. 2003

The Journal of Immunology

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The CD134-CD134 ligand (CD134L) costimulatory pathway has been shown to be critical for both T and B cell activation; however, its role in regulating the alloimmune response remains unexplored. Furthermore, its interactions with other costimulatory pathways and immunosuppressive agents are unclear. We investigated the effect of CD134-CD134L pathway blockade on allograft rejection in fully MHC-mismatched rat cardiac and skin transplantation models. CD134L blockade alone did not prolong graft survival compared with that of untreated recipients, and in combination with donor-specific transfusion, cyclosporine, or rapamycin, was less effective than B7 blockade in prolonging allograft survival. However, in combination with B7 blockade, long-term allograft survival was achieved in all recipients (>200 days). Moreover, this was synergistic in reducing the frequency of IFN-γ-producing alloreactive lymphocytes and inhibiting the generation of activated/effector lymphocytes. Most impressively, this combination prevented rejection in a presensitized model using adoptive transfer of primed lymphocytes into athymic heart transplant recipients. In comparison to untreated recipients (mean survival time (MST): 5.3 ± 0.5 days), anti-CD134L mAb alone modestly prolonged allograft survival (MST: 14 ± 2.8 days) as did CTLA4Ig (MST: 21.5 ± 1.7 days), but all grafts were rejected within 24 days. Importantly, combined blockade further and significantly prolonged allograft survival (MST: 75.3 ± 12.7 days) and prevented the expansion and/or persistence of primed/effector alloreactive T cells. Our data suggest that CD134-CD134L is a critical pathway in alloimmune responses, especially recall/primed responses, and is synergistic with CD28-B7 in mediating T cell effector responses during allograft rejection. Understanding the mechanisms of collaboration between these different pathways is important for the development of novel strategies to promote long-term allograft survival.

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“…Analysis of CD4 + T-cell responses following in vivo OX40 engagement showed an increase in antigen-specific T-cell expansion, enhanced cytokine production and an increase in the generation and stability of a memory T cells (Evans et al, 2001;Huddleston et al, 2006;Kaleeba et al, 1998;Weinberg et al, 1998). In mouse tumor models, OX40 engagement, with an agonist antibody or soluble ligand in the absence of immunization, produced antitumor effects against breast and colon cancers, melanoma, sarcoma and glioma (Kjaergaard et al, 2001;Kjaergaard et al, 2000;Morris et al, 2001;Pan et al, 2002;Weinberg et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain

Morris

Peters

Montler

et al. 2007

Molecular Immunology

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OX40 (CD134) is a potent costimulatory molecule found on the surface of activated CD4 + and CD8 + T cells. Immunotherapy with OX40 agonists administered in vivo has demonstrated efficacy in several murine tumor models. A phase I clinical trial is currently underway in patients with advanced cancer using a mouse anti-CD134 monoclonal antibody. Therapy with this antibody will likely be limited to one cycle because patients develop neutralizing human anti-mouse antibody (HAMA). Therefore, we developed a humanized OX40 agonist that links the extracellular domain of human OX40L to the Fc domain of human IgG 1 via a trimerizing isoleucine zipper domain (ILZ). Physical characterization by velocity sedimentation revealed that this novel construct, hFcILZOX40L, was assembled into hexamers in which the Fc domains formed three disulfidebonded dimers and the ILZ-OX40L domains formed two trimers. Trimerization of the ILZ domain was necessary to achieve appropriate assembly. In vitro biologic activity of the hFcILZOX40L hexamer was equivalent to the activity of agonist antibodies in plate-bound assays and was superior when the agonists were tested as soluble agents. Our ultimate goal is to use this recombinant molecule in a future clinical trial and we feel that the OX40L hexamer will have equivalent or superior agonist activity in vivo when compared to an anti-OX40 antibody.

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The OX-40 receptor provides a potent co-stimulatory signal capable of inducing encephalitogenicity in myelin-specific CD4+ T cells

Cited by 62 publications

References 40 publications

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

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

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

Development and characterization of recombinant human Fc:OX40L fusion protein linked via a coiled-coil trimerization domain

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