Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.
Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA + PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA + PC. Furthermore, mice with an over-abundance of IgA + PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA + PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.
We studied the feasibility, efficacy, and mechanisms of dendritic cell (DC) immunotherapy against murine malignant glioma in the experimental GL261 intracranial (IC) tumor model. When administered prophylactically, mature DCs (DCm) ex vivo loaded with GL261 RNA (DCm-GL261-RNA) protected half of the vaccinated mice against IC glioma, whereas treatment with mock-loaded DCm or DCm loaded with irrelevant antigens did not result in tumor protection. In DCm-GL261-RNA-vaccinated mice, a tumor-specific cellular immune response was observed ex vivo in the spleen and tumordraining lymph node cells. Specificity was also shown in vivo on the level of tumor challenge. Depletion of CD8 DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental gliomaWim Maes, Georgina Galicia Rosas, Bert Verbinnen, Louis Boon, Steven De Vleeschouwer, Jan L. Ceuppens, and Stefaan W. Van Gool Clinical Immunology, Department of Experimental Medicine (W.M., G.G.R., B.V., S.D.V., J.L.C., S.W.V.G.), Experimental Neurosurgery and Neuroanatomy (S.D.V.), and Pediatric Hemato-Oncology, Department of Child and Woman (S.W.V.G.), Katholieke Universiteit Leuven, University Hospital Gasthuisberg, Leuven, Belgium; Bioceros BV, Utrecht, The Netherlands (L.B.) Received October 23, 2008; accepted December 24, 2008. Address correspondence to Stefaan W. Van Gool, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium (Stefaan .VanGool@uz.kuleuven.be).clearly demonstrate the effectiveness of DC vaccination for the induction of long-lasting immunological protection against IC glioma. They also show the beneficial effect of Treg depletion in this kind of glioma immunotherapy, even combined with DC vaccination. NeuroOncology 11, 529-542, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00292, March 31, 2009 DOI: 10.1215 DOI: 10. /15228517-2009 Keywords: anti-CD8, anti-CD25, DC immunotherapy, glioma, regulatory T-cells E scape from immunosurveillance is nowadays considered one of the hallmarks of malignant cell growth, and several mechanisms leading to immune suppression or immune escape have been described. 1 On the other hand, it is generally accepted that a patient's immune system can be instructed to recognize and attack several types of malignant lesions more efficiently.2,3 Hence, immunotherapy based on immunization with tumor antigen (Ag)-loaded dendritic cells (DCs) as professional Ag-presenting cells (APCs) represents a promising strategy in the multimodal treatment for different types of cancer, 4,5 including malignant glioma. [6][7][8][9][10][11][12][13][14][15] Immunotherapeutic approaches for malignant glioma are currently under investigation by our group [14][15][16] and others. 17,18 Results of in vitro experiments 19,20 and animal studies, 21 together with pilot data from clinical trials, [14][15][16] are very promising, although it is still too early to draw definitive conclusions. Orthotopic rodent glioma models are highly useful to address fundamental questions regarding the bala...
Blocking of costimulatory signals for T cell activation leads to tolerance in several transplantation models, but the underlying mechanisms are incompletely understood. We analyzed the involvement of regulatory T cells (Treg) and deletion of alloreactive cells in the induction and maintenance of tolerance after costimulation blockade in a mouse model of graft-vs-host reaction. Injection of splenocytes from the C57BL/6 parent strain into a sublethally irradiated F1 offspring (C57BL/6 × C3H) induced a GVHR characterized by severe pancytopenia. Treatment with anti-CD40L mAb and CTLA4-Ig every 3 days during 3 wk after splenocyte injection prevented disease development and induced a long-lasting state of stable mixed chimerism (>120 days). In parallel, host-specific tolerance was achieved as demonstrated by lack of host-directed alloreactivity of donor-type T cells in vitro and in vivo. Chimerism and tolerance were also obtained after CD25+ cell-depleted splenocyte transfer, showing that CD25+ natural Treg are not essential for tolerance induction. We further show that costimulation blockade results in enhanced Treg cell activity at early time points (days 6–30) after splenocyte transfer. This was demonstrated by the presence of a high percentage of Foxp3+ cells among donor CD4+ cells in the spleen of treated animals, and our finding that isolated donor-type T cells at an early time point (day 30) after splenocyte transfer displayed suppressive capacity in vitro. At later time points (>30 days after splenocyte transfer), clonal deletion of host-reactive T cells was found to be a major mechanism responsible for tolerance.
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