Depleting tumor-specific Tregs at a single site eradicates disseminated tumors
JOURNAL OF CLINICAL INVESTIGATION
2013; 123 (6): 2447-2463
Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool
2011; 14 (9): 1142-U263
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
View details for DOI 10.1172/JCI64859
View details for Web of Science ID 000320093100018
Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
2007; 10 (12): 1538-1543
In multiple sclerosis and the experimental autoimmune encephalitis (EAE) mouse model, two pools of morphologically indistinguishable phagocytic cells, microglia and inflammatory macrophages, accrue from proliferating resident precursors and recruitment of blood-borne progenitors, respectively. Whether these cell types are functionally equivalent is hotly debated, but is challenging to address experimentally. Using a combination of parabiosis and myeloablation to replace circulating progenitors without affecting CNS-resident microglia, we found a strong correlation between monocyte infiltration and progression to the paralytic stage of EAE. Inhibition of chemokine receptor-dependent recruitment of monocytes to the CNS blocked EAE progression, suggesting that these infiltrating cells are essential for pathogenesis. Finally, we found that, although microglia can enter the cell cycle and return to quiescence following remission, recruited monocytes vanish, and therefore do not ultimately contribute to the resident microglial pool. In conclusion, we identified two distinct subsets of myelomonocytic cells with distinct roles in neuroinflammation and disease progression.
View details for DOI 10.1038/nn.2887
View details for Web of Science ID 000294284900014
View details for PubMedID 21804537
Neural transplantation of human MSC and NT2 cells in the twitcher mouse model
2006; 8 (5): 445-458
Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
View details for DOI 10.1038/nn2014
View details for Web of Science ID 000251172900010
View details for PubMedID 18026097
Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis
2006; 53 (7): 744-753
Accumulating evidence has demonstrated that the NT2 embryonal carcinoma cell line and multipotential stem cells found in BM, mesenchymal stromal cells (MSC), have the ability to differentiate into a wide variety of cell types. This study was designed to explore the efficacy of these two human stem cell types as a graft source for the treatment of demyelinating disorders such as Krabbe's disease and multiple sclerosis (MS).We examined the engraftment and in vivo differentiation of adult MSC and NT2 cells after transplantation into two demyelinating environments, the neonatal and postnatal twitcher mouse brain.Both types of xenografts led to anatomical integration, without tumor formation, and remained viable in the normal and twitcher mouse brain, showing differentiation into neurons, astrocytes and oligodendrocytes.This study represents a platform for further stem cell transplantation studies in the twitcher model and potentially has important therapeutic implications.
View details for DOI 10.1080/14653240600879152
View details for Web of Science ID 000241401800003
View details for PubMedID 17050249
Amyotrophic lateral sclerosis (ALS) is associated with increased numbers of microglia within the central nervous system (CNS). However, it is unknown whether the microgliosis results from proliferation of CNS resident microglia, or recruitment of bone marrow (BM)-derived microglial precursors. Here we assess the distribution and number of BM-derived cells in spinal cord using transplantation of green fluorescent protein (GFP)-labeled BM cells into myelo-ablated mice over-expressing human mutant superoxide dismutase 1 (mSOD), a murine model of ALS. Transplantation of GFP+ BM did not affect the rate of disease progression in mSOD mice. Mean numbers of microglia and GFP+ cells in spinal cords of control mice were not significantly different from those in asymptomatic mSOD mice and showed no change with animal age. The number of GFP+ cells and microglia (F4/80+ and CD11b+ cells) within the spinal cord of mSOD mice increased compared to age-matched controls at a time when mSOD mice exhibited disease symptoms, continuing up to disease end-stage. Although we observed an increase in the number of GFP+ cells in spinal cords of mSOD mice with disease symptoms, mean numbers of GFP+ F4/80+ cells comprised less than 20% of all F4/80+ cells and did not increase with disease progression. Furthermore, the relative rates of proliferation in CD45+GFP- and CD45+GFP+ cells were comparable. Thus, we demonstrate that the microgliosis present in spinal cord tissue of mSOD mice is primarily due to an expansion of resident microglia and not to the recruitment of microglial precursors from the circulation.
View details for DOI 10.1002/glia.20331
View details for Web of Science ID 000237017200008
View details for PubMedID 16518833