Migratory Activity and Functional Changes of Green Fluorescent Effector Cells before and during Experimental Autoimmune Encephalomyelitis

Flügel, Alexander; Berkowicz, Tomasz; Ritter, Thomas; Labeur, Marta; Jenne, Dieter E.; Li, Zhaoxia; Ellwart, Joachim W.; Willem, Michael; Lassmann, Hans; Wekerle, Hartmut

doi:10.1016/s1074-7613(01)00143-1

Cited by 406 publications

(372 citation statements)

References 47 publications

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“…The absence of priming functions by TIDC in brain gliomas strongly suggests that they are unable to reactivate glioma-infiltrating lymphocytes in situ, which could explain the reduction in T-cell numbers observed during the course of tumor development. Indeed, T-cell activation is critically important for the infiltration of T cells deep into the tumor tissue [40], and T cells which do not re-encounter their antigen disappear from the CNS, either via migration back to the periphery [41] or via apoptosis [42]. Interestingly, in glioblastoma patients, invading T cells have been reported to undergo apoptosis [43].…”

Section: Discussionmentioning

confidence: 99%

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

et al. 2009

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Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3 1 Treg and higher levels of TGF-b1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-b production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the antitumor immune response.Key words: DC . Immune privilege . Treg . Tumor immunity Supporting Information available online IntroductionMalignant gliomas, especially the most frequent and aggressive form known as glioblastoma multiforme, are among the most fatal types of tumors. The best standard of care for glioblastoma multiforme, consisting of surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months following diagnosis [1]. Gliomas have been shown to result in reduced peripheral T-cell responses [2], down-modulated function of circulating APC [3] and particularly to suppressed maturation of peripheral DC [4]. In addition, the localization of the glioma within the immune-privileged CNS, combined with the production of tumorderived immunosuppressive molecules including , , VEGF [9] and prostaglandins [10], is suggested to account for the absence of a successful anti-tumor immune Ã These authors contributed equally to this work. response. As a consequence, glioma patients fail to generate an effective immune response against the intracranially growing tumors. Although it occurs rarely, gliomas are able to metastasize to locations outside of the brain [11]. The low frequency of peripheral glioma metastases might be due to an efficient recognition of tumor cells outside of the CNS. Gliomas express tumor-associated antigens such as ER-2, gp100, and MAGE-1, which can be recognized by cytotoxic T lymphocyte clones [12]. Furthermore, T-cell clonal expansion has been detected in glioma patients [13] and vaccination of patients with autologous tumor lysate-pulsed DC or autologous tumor peptide-pulsed DC [14] can elicit tumor-specific T-cell responses and infiltration of cytotoxic and me...

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Section: Discussionmentioning

confidence: 99%

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

et al. 2009

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“…injection. 29 Mice were euthanized at 2 days post lesion (11 T PLP , 8 T OVA , and 10 naïve) and 7 days post lesion (7 T PLP , 8 T OVA , and 6 naïve). Unlesioned T OVA and T PLP mice (n ϭ 6 and 8, respectively) were euthanized at 11 days post transfer, when T PLP mice demonstrated symptoms of EAE grade 0 to 2.…”

Section: Pp Transectionmentioning

confidence: 99%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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“…7 Here, it is clear that autoreactive T cells provide the organ-specificity of disease. 8 They initiate a dynamic cascade of proinflammatory and regulatory events that ultimately produce a myelinotoxic microenvironment with eventual axonal destruction 1,2,9-16 ( Figure 1). Despite some limited success, disease is poorly managed and there is a real need for effective treatment.…”

Section: The Disease Processes In Cns Autoimmunitymentioning

confidence: 99%

“…69,70 As an alternative approach to achieving local CNS delivery, the migratory potential of primed T lymphocytes has been harnessed and thus allows for systemic delivery. 8 The majority of T cells within inflammatory lesions are probably not CNSspecific but are secondarily recruited to the inflammatory site because of their adhesion molecule and chemokine receptor phenotype. 10 These cells will be targeted to lesional areas and will be activated/maintained locally if they have specificity for myelin or other CNS antigens (Figure 1).…”

Section: Systemic Immunogene Therapy In Cns Autoimmunitymentioning

confidence: 99%

“…[55][56][57][58][59][60][61] These can even be tracked using coexpression of a marker protein and can be shown to enter lymphoid tissues as well as the CNS. 8,82 Through the local production of antagonizing molecules in situ they can then inhibit neighbouring pathogenic cells via a bystander effect through release of immunosuppressive and neuroprotective growth factors (Table 1) [55][56][57][58][59][60][61] Early studies used T-cell hybridomas as cell vectors and showed disease ameliorating potential, but these Gene therapy in demyelinating disease of CNS D Baker and DJR Hankey cells eventually killed the recipient because of unrestricted hybridoma (tumour) growth. 56,59,60 However, this has been reproduced with ex vivo cloned T cells.…”

Section: Systemic Immunogene Therapy In Cns Autoimmunitymentioning

confidence: 99%

See 1 more Smart Citation

Gene therapy in autoimmune, demyelinating disease of the central nervous system

Baker

Hankey

2003

Gene Ther

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Migratory Activity and Functional Changes of Green Fluorescent Effector Cells before and during Experimental Autoimmune Encephalomyelitis

Cited by 406 publications

References 47 publications

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Gene therapy in autoimmune, demyelinating disease of the central nervous system

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Migratory Activity and Functional Changes of Green Fluorescent Effector Cells before and during Experimental Autoimmune Encephalomyelitis

Cited by 406 publications

References 47 publications

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Gene therapy in autoimmune, demyelinating disease of the central nervous system

Contact Info

Product

Resources

About

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg