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Biomedical subjects

Andrew D Weinberg

Publications and source records attributed to Andrew D Weinberg.

At least 19 recordsLinked to original sources
PubMed2007

Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination.

Dendritic-tumor heterokaryons generated by electrofusion are highly immunogenic. In animal studies, a single vaccination was therapeutic for tumors established in the lung, skin, and brain. However, effective therapy required a third signal which could be provided by exogenous IL-12 or the agonistic anti-OX-40R monoclonal antibody (mAb). In this study, we investigated the mechanism and mode of actions of these two seemingly distinct adjuvants. In immunotherapy of the MCA205 sarcoma, administration of the neutralizing anti-IL-12 mAb nearly completely blocked the adjuvant effect of IL-12, but had minimal inhibitory effects on anti-OX-40R mAb. By contrast, in vivo administration of the antagonistic anti-OX-40L mAb inhibited the adjuvant effects of both IL-12 and anti-OX-40R mAb. Thus, a common pathway of endogenous OX-40 interaction is critical for the development of a therapeutic immune response. Analysis of the third signal mechanism revealed that in the absence of an adjuvant, vaccination with fusion hybrids led to IL-10 production without eliciting IFN-gamma secreting cells. The addition of IL-12 to vaccination suppressed IL-10 production and initiated sensitization of specific IFN-gamma secreting cells, resulting in a type 1-like antitumor immunity. These findings underscore the significance of the third signal in the design of dendritic cell-based cancer vaccines.

Adjuvants, Immunologic↗
PubMed2007

Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses.

There is growing evidence that engagement of OX40 (CD134), a member of the TNF receptor superfamily, can directly stimulate antigen-specific CD8+ T cells. It has been shown that CD8+ T cells express OX40 following activation, but the response of antigen-specific CD8+ T cells to OX40 stimulation has not been fully characterized. We utilized an antigen-specific transgenic CD8+ T cell model (OT-I) to determine if OX40 engagement can boost the generation of antigen-specific CD8+ T cell memory. Our results demonstrate that enhanced OX40 costimulation, via an agonist anti-OX40 antibody, increases CD25 and phospho-Akt expression on the antigen-specific CD8+ T cells and significantly increases the generation of long-lived antigen-specific CD8+ memory T cells. The increased numbers of memory CD8+ T cells generated via anti-OX40 treatment still required the presence of CD4+ T cells for their long-term maintenance in vivo. In addition, anti-OX40 costimulation greatly enhanced antigen-specific CD8+ T cell recall responses. These data show that OX40 engagement in vivo increases the number of antigen-specific CD8+ memory T cells surviving after antigen challenge and has implications for the development of more potent vaccines against pathogens and cancer.

Adoptive Transfer↗
PubMed2006

Expression and function of the OX40/OX40L costimulatory pair during herpes stromal keratitis.

Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40(+) cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L(+) cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L(+) cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11c. Our findings demonstrate rapid infiltration of activated (OX40(+)) CD4(+) T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II(+) CD11c(+) DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.

Animals↗
PubMed2006

IL-18 bridges innate and adaptive immunity through IFN-gamma and the CD134 pathway.

IL-18 induces inflammation resulting in either enhanced protection from pathogens or exacerbation of autoimmunity, and T cells are profoundly activated during these responses. How IL-18 influences T cell activation is unknown, but this study in mice shows that IL-18 boosted Ag-specific T cell clonal expansion of effector T cells and induced a subpopulation of IFN-gamma superproducing T cells. Commitment to IFN-gamma production through IL-18 was independent of NK cells and IL-12 but dependent on host-derived IFN-gamma. To determine how expansion of these effectors occurred, IL-18 was shown to induce OX40L on dendritic cells, whereas peptide stimulation induced CD134 (OX40) on specific T cells. CD134 blockade inhibited T cell effector expansion thereby reducing the number of IFN-gamma superproducers by 12-fold. Thus, independent of IL-12, IL-18 impacts T cell immunity throughout lymphoid and nonlymphoid tissue by bridging the innate and adaptive arms of the immune system through IFN-gamma and the CD134 costimulatory pathway.

Adjuvants, Immunologic↗
PubMed2006

OX40 (CD134) engagement drives differentiation of CD4+ T cells to effector cells.

Naive, CD4+ T cells proliferate extensively but fail to differentiate when they are transferred into unirradiated recipients that express alloantigen or transgenic antigen on all MHC class II+ cells. Addition of an agonist antibody to OX40 (CD134), a costimulatory TNF receptor family member expressed on activated CD4+ T cells, enables the proliferating T cells to accumulate as differentiated effector cells and kill the host animals. The donor T cells from anti-OX40-treated animals express high levels of IL-2R alpha (CD25) and acquire the ability to secrete IFN-gamma when stimulated with IL-12 and IL-18. OX40 promotes differentiation by 48 h in T cell priming, before changes in Bcl-2 expression or cell recovery become apparent. We found that a Bcl-2 transgene or deficiency in Fas or TNFR1 failed to influence accumulation of differentiated donor cells, and found larger changes in expression of cytokine and cytokine receptor genes than in survival genes. Accumulation of differentiated CD4+ effector T cells is initiated directly through OX40, but some OX40-deficient donor cells can gain effector function as bystanders to OX40+/+ cells. Taken together, these data suggest that CD4+ T cell differentiation to effector function is an important effect of OX40 engagement under conditions of ubiquitous antigen presentation.

Animals↗
PubMed2006

Quality improvement case study: warfarin sodium interactions.

TOPIC: Dangerous Interactions Involving Antibiotic Use In Warfarin-Treated Nursing Facility Residents FACTS OF THE INCIDENT: All names, places and dates and some details have been changed to protect the confidentiality of this actual event.

Accidental Falls↗
PubMed2005

Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis.

CD4(+) T cells play a key role in granulomatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4(+) T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the presence of APCs, beryllium induced strong proliferation responses of BAL CD4(+) T cells, production of superoptimal concentrations of secreted proinflammatory cytokines, IFN-gamma, TNF-alpha,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4(+) T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4(+) T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4(+) T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease.

Antibodies, Monoclonal↗
PubMed2005

Modulation of TNF receptor family members to inhibit autoimmune disease.

Certain members of the TNF-receptor family have shown proinflammatory function during immune activation and can be directly involved with the pathogenic effects observed during an autoimmune episode. The TNF-R family members summarized in this review includes: TNF-RI + II, OX40, and 4-1BB and they are expressed on a variety of leukocytes within the body. Studies within the last decade suggest that all of these proteins or their natural ligands can be targeted with various agents designed to diminish clinical signs of disease in autoimmune models. The data from the preclinical models specifically involving TNF-blockade have led to the development of clinical trials for patients with multiple sclerosis and rheumatoid arthritis. This review will chronicle the preclinical development of agents designed to inhibit OX40 and 4-1BB functions in autoimmunity and discuss relevant preclinical and clinical data associated with TNF-blockade.

4-1BB Ligand↗
PubMed2004

Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR.

OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor family that is transiently expressed on T cells after T-cell receptor (TCR) ligation. Both naive and activated CD4(+)CD25+ regulatory T cells (T reg's) express OX40 but its functional role has not been determined. Since glucocorticoid-induced tumor necrosis factor receptor (GITR), a related TNF receptor family member, influences T reg function, we tested whether OX40 might have similar effect. Triggering either GITR or OX40 on T reg's using agonist antibodies inhibited their capacity to suppress and restored effector T-cell proliferation, interleukin-2 (IL-2) gene transcription and cytokine production. OX40 abrogation of T reg suppression was confirmed in vivo in a model of graft-versus-host disease (GVHD). In a fully allogeneic C57BL/6>BALB/c bone marrow transplantation, GVHD was lethal unless T reg's were cotransferred with the bone marrow and effector T cells. Strikingly, T reg suppression of GVHD was abrogated either by intraperitoneal injection of anti-OX40 or anti-GITR monoclonal antibodies (mAbs) immediately after transfer, or by in vitro pretreatment of T reg's with the same mAbs before transfer. Cumulatively, the results suggest that in addition to controlling memory T-cell numbers, OX40 directly controls T reg-mediated suppression.

Animals↗
PubMed2004

A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions.

To study mechanisms of peripheral self-tolerance, we injected small numbers of naive CD4(+) TCR-transgenic T cells into mice expressing the MHC/peptide ligand under the control of an MHC class II promoter. The donor T cells expand rapidly to very large numbers, acquire memory markers, and go out into tissues, but the animals remain healthy, and the accumulated T cells are profoundly anergic to restimulation with Ag in vitro. Provision of a costimulatory signal by coinjection of an agonist Ab to OX40 (CD134), a TNFR family member expressed on activated CD4 T cells, results in death of the mice within 12 days. TCR-transgenic T cells recovered at 5 days from anti-OX40-treated mice have a unique phenotype: they remain unresponsive to Ag in vitro, but they are larger, more granular, and strongly IL-2R positive. Some spontaneously secrete IFN-gamma directly ex vivo, and the majority make IFN-gamma in response to PMA and ionomycin. Although they are anergic by conventional tests requiring Ag recognition, they respond vigorously to cytokines, proliferating in response to IL-2, and secreting IFN-gamma when TCR signaling is bypassed with IL-12 and IL-18. We conclude that the costimulatory signal through OX40 allows otherwise harmless, proliferating, autoreactive T cells to acquire effector cell functions. The ability of these T cells to respond to cytokines by synthesizing additional inflammatory cytokines without a TCR signal may drive the fatal pathogenic process in vivo.

Animals↗
PubMed2004

The generation of T cell memory: a review describing the molecular and cellular events following OX40 (CD134) engagement.

OX40 (CD134), a membrane-bound member of the tumor necrosis factor-receptor superfamily, is expressed primarily on activated CD4(+) T cells. Following engagement on the cell surface, OX40 delivers a costimulatory signal that leads to potent, proinflammatory effects. Engagement of OX40 during antigen (Ag)-specific stimulation of T cells leads to increased production of memory T cells, increased migration of Ag-specific T cells, enhanced cytokine production by effector T cells, and the ability to break peripheral T cell tolerance in vivo. Therefore, OX40 engagement in vivo could have important ramifications for the enhancement of vaccine strategies and inhibition of unwanted inflammation. This review summarizes the molecular and cellular events that occur following OX40 engagement during Ag-specific T cell activation.

Animals↗
PubMed2004

CD25 expression distinguishes functionally distinct alloreactive CD4 CD134 (OX40) T-cell subsets in acute graft-versus-host disease.

CD134 (OX40) is expressed on activated CD4(+) donor T cells in allogeneic stem cell transplant recipients with acute graft-versus-host disease. The data presented here reveal that differential expression of CD25 by CD4(+) CD134(+) T cells allows separation of these activated cells into 2 phenotypically and functionally distinct alloreactive T-cell subsets. These subsets exhibit distinct tissue associations, with CD4(+) CD134(+) CD25(-) T cells preferentially found in lymphoid tissues and CD4(+) CD134(+) CD25(+) T cells located in lymphoid tissues and inflamed extralymphoid tissues. The CD25(-) T-cell subset exhibited potent proliferative responses to both concanavalin A and allogeneic host leukocytes. By contrast, the CD25(+) T-cell subset proliferated minimally in response to either treatment and inhibited alloantigen-induced proliferation of the CD25(-) subset. Proliferative unresponsiveness associated with the CD25(+) T-cell subset did not extend to cytokine secretion. When stimulated with alloantigen, both CD4(+) CD134(+) T-cell subsets responded by secreting interferon-gamma and interleukin (IL)-10, and neither T-cell subset produced detectable levels of IL-2 or IL-4. Three-day treatment of the CD25(+) T-cell subset with IL-2 restored the proliferative responsiveness of these cells to host alloantigens, suggesting that the proliferative unresponsiveness associated with this T-cell subset reflected a requirement for IL-2. The preferential tissue associations and distinct functional properties associated with these separable alloreactive CD4(+) CD134(+) T-cell subsets suggest that they participate differentially in clinical graft-versus-host disease.

Acute Disease↗
PubMed2004

4-1BB and OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus boost vaccine.

4-1BB (CD137) is a tumour necrosis factor receptor (TNFR) family member, expressed primarily on CD8 T cells after activation. Signalling through 4-1BB has been reported to enhance CD8 T-cell expansion and to protect activated CD8 T cells from death, resulting in an enlarged memory population. Although stimulating 4-1BB has been shown to significantly improve the immune response to weak immunogens such as tumours, little is known about its effect on the CD8 T-cell response to a powerful viral vector such as vaccinia. To test 4-1BB's ability to improve the murine CD8 T cell response to a DNA prime, poxvirus boost vaccine, similar to those used for human immunodeficiency virus and simian immunodeficiency virus vaccines, we administered 4-1BB agonist antibody at the time of the poxvirus boost. 4-1BB stimulation increased the number of functional memory CD8 T cells by two- to fourfold. However, we saw a similar enhancement at the peak of the response and in the memory phase, thus we found no evidence in the context of virus infection that 4-1BB stimulation could increase the percentage of CD8 T cells that survive the acute activation phase to become memory cells. OX40 (CD134) is an analogous TNFR family member expressed primarily on activated CD4 T cells. OX40 stimulation increased the number of antigen-specific CD4 T cells approximately threefold. Stimulating both 4-1BB and OX40 enhanced the CD8 T-cell response more than 4-1BB alone. Thus stimulating these receptors can improve the response to a powerful virus vector, and may be useful in vaccine development.

Animals↗
PubMed2003

OX40-mediated memory T cell generation is TNF receptor-associated factor 2 dependent.

Tumor necrosis factor receptor-associated factor 2 (TRAF2), an adapter protein that associates with the cytoplasmic tail of OX40, may play a critical role in OX40-mediated signal transduction. To investigate the in vivo role of TRAF2 in OX40-mediated generation of Ag-specific memory T cells, we bred OVA-specific TCR transgenic mice to TRAF2 dominant-negative (TRAF2 DN) mice. Following Ag stimulation and OX40 engagement of TRAF2 DN T cells in vivo, the number of long-lived OVA-specific T cells and effector T cell function was dramatically reduced when compared with wild-type T cells. We also demonstrate that CTLA-4 is down-regulated following OX40 engagement in vivo and the OX40-specific TRAF2 DN defect was partially overcome by CTLA-4 blockade in vivo. The data provide evidence that TRAF2 is linked to OX40-mediated memory T cell expansion and survival, and point to the down-regulation of CTLA-4 as a possible control element to enhance early T cell expansion through OX40 signaling.

Adoptive Transfer↗
PubMed2002

Survival in human colorectal cancer correlates with expression of the T-cell costimulatory molecule OX-40 (CD134).

BACKGROUND: The T-cell costimulatory molecule OX-40 (CD134) is expressed on activated CD4(+) ("helper") T cells. Such cells have been detected in human cancers, and engagement of OX-40 improves colon cancer immunity in an animal model. METHODS: Sections of primary colon cancers, normal margins, mesenteric lymph nodes, and metastases were stained for OX-40 by immunohistochemistry. Cancer registry data were reviewed. RESULTS: High levels of OX-40 positive tumor-infiltrating lymphocytes were found in 15 of 72 primary tumors. Thirty-one cases had prominent lymphocytic infiltrates expressing OX-40 at the invasive margin of the tumor. Overall, 50% of primary tumors showed high expression of OX-40. Nearly all mesenteric lymph nodes expressed OX-40, whether tumor was present or not. Normal margins of colon did not show high levels of OX-40. High OX-40 expression in the primary tumor correlated with better survival (mean survival high OX-40, 47 months, low OX-40, 35 months, P <0.05), although this correlation was not stage-independent. CONCLUSIONS: High levels of OX-40 positive lymphocytes are present in half of primary colon cancers, and this expression in primary tumors significantly correlates with better survival. This correlation with survival and our previous preclinical research suggest a basis for an OX-40 immunotherapy trial.

Adenocarcinoma↗
PubMed2002

OX40: targeted immunotherapy--implications for tempering autoimmunity and enhancing vaccines.

OX40 (CD134), a membrane-bound member of the tumor-necrosis-factor-receptor superfamily, is expressed primarily on activated CD4+ T cells. Recently, several groups have reduced clinical signs of autoimmunity in animal models by blocking the OX40-OX40-ligand interaction or depleting OX40+ T cells. By contrast, engagement of OX40 in the setting of active immunization has potent adjuvant properties, leading to enhanced cytokine production and increased numbers of antigen-specific memory T cells. These potent adjuvant effects lead to an enhancement of anti-tumor responses. OX40 has several unique features that make it a clinically relevant target. They include: (1) T cells isolated from a site of inflammation that express OX40 are T cells that have been stimulated recentlythrough the T-cell receptor in vivo; (2) OX40 is only expressed on T cells found at the site of inflammation, therefore, targeting this receptor does not interfere with the peripheral T-cell repertoire; and (3) the biological function of OX40 is limited primarily to effector CD4+ T cells, which are a major source of cytokines to induce and maintain ongoing immune responses.

Animals↗