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Chen X.,SAIC | Oppenheim J.J.,Center for Cancer Research
Current Directions in Autoimmunity | Year: 2010

TNF-α (TNF) is a pleiotropic cytokine which can have proinflammatory or immunosuppressive effects, depending on the context, duration of exposure and disease state. The basis for the opposing actions of TNF remains elusive. The growing appreciation of CD4+FoxP3+ regulatory T cells (Tregs), which comprise ∼10% of peripheral CD4 cells, as pivotal regulators of immune responses has provided a new framework to define the cellular and molecular basis underlying the contrasting action of TNF. TNF by itself can overcome the profound anergic state of T cell receptor-stimulated Tregs. Furthermore, in concert with IL-2, TNF selectively activates Tregs, resulting in proliferation, upregulation of FoxP3 expression and increases in their suppressive activity. Both human and mouse Tregs predominantly express TNFR2, making it possible for TNF to enhance Treg activity, which helps limit the collateral damage caused by excessive immune responses and eventually terminates immune response. TNFR2-expressing CD4+FoxP3+ Tregs comprise ∼40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered. © 2010 S. Karger AG.

Roschewski M.,U.S. National Institutes of Health | Wilson W.H.,Center for Cancer Research
Best Practice and Research: Clinical Haematology | Year: 2012

Epstein-Barr virus (EBV) is a ubiquitous γ-herpes virus that infects most people but results in life-threatening diseases in only a small subset. Persons who are unable to maintain the virus in its latent state can develop uncontrolled EBV-driven lymphoproliferative disorders and lymphomas. EBV-associated lymphomas are well characterized in patients with known defects in cellular immunity as occurs post-transplantation or HIV/AIDS but are increasingly recognized in patients without overt immunodeficiencies. Improved understanding of the biology of these lymphomas and the role EBV plays in lymphomagenesis offer the opportunity for improved therapies targeted at important signaling pathways and immunotherapy specific against EBV viral antigens. © 2012 Elsevier Ltd. All rights reserved.

Fojo A.T.,Center for Cancer Research | Parkinson D.R.,Nodality
Clinical Cancer Research | Year: 2010

We describe the development and approval of biologically targeted agents in the clinic through examples chosen from the experience with inhibitors of the epidermal growth factor (EGF) and VEGF pathways. Despite extensive biological rationale for the use of these classes of molecules, marginal clinical benefits have been observed in broad patient populations, and the agents have entered into general clinical practice.We discuss why this situation is unsatisfactory because marginal general benefit may often be at the expense of toxicity to nonbenefiting or even harmed patients. Finally, we point out that emerging technologies bring the promise of allowing the identification of patients who might potentially benefit from a therapy. However, development of this technology will not move forward without broader recognition of its need by the range of stakeholders, including patients, advocates, academic and private oncologists, drug sponsors, and those who develop drugs and diagnostic tests. ©2010 AACR.

Capala J.,Center for Cancer Research | Bouchelouche K.,Copenhagen University
Current Opinion in Oncology | Year: 2010

Purpose of review: HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate individual approaches to targeted therapy of HER2-positive breast cancers. Recent findings: Because of the heterogeneity of breast cancer and possible discordance in HER2 status between primary tumors and distant metastases, assessment of HER2 expression by noninvasive imaging may become an important complement to immunohistochemistry or fluorescence in-situ hybridization analyses of biopsied tissue. Monoclonal antibodies such as trastuzumab and pertuzumab, or small scaffold proteins such as affibody molecules are used as HER2-targeting agents. For imaging purposes, these agents are labeled with positron or gamma-emitting radionuclides, optical dyes, or paramagnetic contrast molecules for positron emission tomography single photon emission tomography optical, and magnetic resonance imaging, respectively. HER2-specific molecular probes, combined with modern imaging techniques to provide information on HER2 expression not only in primary tumors but also in distant metastases not amenable to biopsy, may reduce problems with false negative results and, thereby, influence patient management by selecting patients that would benefit from HER2-targeted therapies. Summary: The new 'image and treat' strategy, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, may potentially improve efficacy of cancer treatment while reducing side effects. © 2010 Wolters Kluwer Health | Lippincott Williams and Wilkins.

Cytokine receptors expressed by CD4+FoxP3+ regulatory T cells (Treg cells) not only serve as a phenotypic marker for the identification of this important population of immunosuppressive cells, they also promote the function of Treg cells. CD25, the α-chain of interleukin-2 receptor, is a prototype of such a receptor, which enables Treg cells to be activated by interleukin-2. We and others have found that tumour necrosis factor receptor type 2 (TNFR2) is another important cytokine receptor preferentially expressed by Treg cells with important phenotypic and functional roles. TNFR2 is preferentially expressed by highly functional human and mouse Treg cells, and mediates the activating effect of TNF on Treg cells. We review here the studies of the regulation of expression of TNFR2 on functional Treg cells as well as on CD4+FoxP3- effector T cells (Teff cells). We document the critical role of this receptor in the activation, proliferative expansion and survival of Treg cells. The contribution of TNFR2 expression on Treg and Teff cells to the beneficial and detrimental effects of anti-TNF treatment in autoimmune disorders will also be discussed. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

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