Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
29
1
2009
Immunotherapeutic Approaches for Glioma
1-42
10.1615/CritRevImmunol.v29.i1.10
Hideho
Okada
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Gary
Kohanbash
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Xinmei
Zhu
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Edward R.
Kastenhuber
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Aki
Hoji
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Ryo
Ueda
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
Mitsugu
Fujita
Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
The development of effective immunotherapy strategies for glioma requires adequate understanding of the unique immunological microenvironment in the central nervous system (CNS) and CNS tumors. Although the CNS is often considered to be an immunologically privileged site and poses unique challenges for the delivery of effector cells and molecules, recent advances in technology and discoveries in CNS immunology suggest novel mechanisms that may significantly improve the efficacy of immunotherapy against gliomas. In this review, we first summarize recent advances in the CNS and CNS tumor immunology. We address factors that may promote immune escape of gliomas. We also review advances in passive and active immunotherapy strategies for glioma, with an emphasis on lessons learned from recent early-phase clinical trials. We also discuss novel immunotherapy strategies that have been recently tested in non-CNS tumors and show great potential for application to gliomas. Finally, we discuss how each of these promising strategies can be combined to achieve clinical benefit for patients with gliomas.
Function of Neurotrophic Factors Beyond the Nervous System: Inflammation and Autoimmune Demyelination
43-68
10.1615/CritRevImmunol.v29.i1.20
Ralf
Linker
Department of Neurology, St. Josef Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany
Ralf
Gold
Department of Neurology, St. Josef Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany
Fred
Luhder
Institute for Multiple Sclerosis Research, University of Göttingen and Gemeinnützige Hertie-Stiftung, Waldweg 33, 37073 Göttingen, Germany
In the nervous system, neurotrophic factors play a role during development, especially for the differentiation of neuronal and glial cells. Moreover, they promote cell survival of neurons, axons, and oligodendrocytes, as well as their precursors, in vitro and in lesional paradigms. In recent years, several functions of neurotrophic factors outside the nervous system have been described, with a special focus on the immune system as well as on models of autoimmune demyelination, such as experimental autoimmune encephalomyelitis (EAE). In the family of neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were investigated. NGF may influence B-cell as well as T-cell function and particularly plays a role in macrophage migration into inflamed lesions. BDNF is produced by several immune-cell subtypes in vitro and also in multiple sclerosis (MS) plaques. This observation gave rise to the concept of neuroprotective autoimmunity, implying that immune-cell infiltration in the nervous system may not only be detrimental but may also play a beneficial role, for example, through the production of neurotrophic factors. In the family of neurotrophic cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) share some common protective roles in axons and oligodendrocytes. In EAE, endogenous CNTF targets myelin, oligodendroglial cells, and axons. In contrast, LIF exerts protective functions on oligodendrocytes in some models but is also able to interact with the immune response and may modulate T-cell, monocyte and neutrophil functions. In summary, neurotrophic factors have distinct roles in the immune system during autoimmunity and may modulate immune responses as well as the susceptibility of the target tissue.
Regulation of Dendritic- and T-Cell Fate by Injury-Associated Endogenous Signals
69-86
10.1615/CritRevImmunol.v29.i1.30
Angelo A.
Manfredi
Vita-Salute San Raffaele University & San Raffaele Scientific Institute, 20132 Milano, Italy
Annalisa
Capobianco
Vita-Salute San Raffaele University & San Raffaele Scientific Institute, 20132 Milano, Italy
Marco E.
Bianchi
Vita-Salute San Raffaele University & San Raffaele Scientific Institute, 20132 Milano, Italy
Patrizia
Rovere-Querini
Vita-Salute San Raffaele University & San Raffaele Scientific Institute, 20132 Milano, Italy
Two events characterize tissue injury and sterile inflammation: (1) generation/release of autoantigens, and (2) generation of homeostatic inflammatory signals. Homeostatic signals recruit leukocytes and promote cell migration and division to replace injured cells. Moreover, they activate antigen-presenting phagocytes, in particular, dendritic cells (DCs), in anticipation of microbial invasion. Activated DCs undergo a differentiation process, referred to as maturation, and migrate to secondary lymphoid organs. Maturing DCs upregulate the molecular machinery required for the priming of naive T cells, including T lymphocytes recognizing autoantigens, which represent a substantial fraction of the host T-cell repertoire. Recent data indicate that cues generated at sites of injury shape T-cell clonal expansion, regulating sensitivity to activation-dependent apoptosis and commitment towards a Th1, Th2, Th7, or regulatory T-cell fate. Endogenous signals of tissue injury, also called damage-associated molecular patterns (DAMPS) or alarmins, therefore provide a code for switching the outcome of the presentation of autoantigens towards results as diverse as T-cell-mcdiated protective immunity, tissue repair, persistent inflammation and autoimmunity, or tolerance.