Fecal shedding of virulent revertant polioviruses was examined in isolates from infants previously immunized with > or = 1 dose of orally administered live attenuated polio vaccine (OPV) alone, enhanced-potency inactivated polio vaccine (EIPV) alone, or a combination of both. After administration of OPV alone, vaccine poliovirus serotypes were recovered in feces within 1 week and for as long as 31-60 days in 30%-80% of subjects after 1 or 2 doses and in 30%-50% after immunization with > or = 3 doses. No revertant poliovirus shedding was observed after OPV challenge in subjects immunized previously with > or = 3 doses of OPV. However, fecal shedding of revertant poliovirus after OPV challenge was observed in 50%-100% of subjects previously immunized with > or = 3 doses of the EIPV. These findings suggest that prior immunization with EIPV does not prevent fecal shedding of revertant polioviruses after subsequent reexposure to OPV.

Adoptive T-cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively transferred tumor-reactive T cells and bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) lead to the generation of potent intratumoral DCs within the CNS compartment. We evaluated HSPC differentiation during ACT in glioma-bearing hosts and HSPC proliferation and differentiation using a T-cell coculture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells and To demonstrate the impact of HSPC differentiation and function on antitumor efficacy, we performed survival experiments. Transfer of HSPCs with concomitant ACT led to the production of activated CD86CD11cMHCII cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid-derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T-cell-released IFNγ to differentiate into DCs, activate T cells, and reject intracranial tumors. Our data support the use of HSPCs as a novel cellular therapy. Although DC vaccines induce robust immune responses in the periphery, our data demonstrate that HSPC transfer uniquely generates intratumoral DCs that potentiate T-cell responses and promote glioma rejection .

Immune checkpoint blockade using anti-PD-1 monoclonal antibodies has shown considerable promise in the treatment of solid tumors, but brain tumors remain notoriously refractory to treatment. In CNS malignancies that are completely resistant to PD-1 blockade, we found that bone marrow-derived, lineage-negative hematopoietic stem and progenitor cells (HSCs) that express C–C chemokine receptor type 2 (CCR2+) reverses treatment resistance and sensitizes mice to curative immunotherapy. HSC transfer with PD-1 blockade increases T-cell frequency and activation within tumors in preclinical models of glioblastoma and medulloblastoma. CCR2+HSCs preferentially migrate to intracranial brain tumors and differentiate into antigen-presenting cells within the tumor microenvironment and cross-present tumor-derived antigens to CD8+ T cells. HSC transfer also rescues tumor resistance to adoptive cellular therapy in medulloblastoma and glioblastoma. Our studies demonstrate a novel role for CCR2+HSCs in overcoming brain tumor resistance to PD-1 checkpoint blockade and adoptive cellular therapy in multiple invasive brain tumor models.

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Groups of infants were immunized with one or two doses of orally inoculated live attenuated Sabin poliovirus vaccine (OPV group) or with one or two doses of enhanced-potency inactivated poliovirus vaccine (EIPV) administered parenterally followed by one or two doses of OPV (EIPV-OPV group). The fecal specimens from both groups were tested for poliovirus shedding 1-2 months after OPV. The virus isolates were examined for nucleic acid sequences in the 5' noncoding regions (bases 480, 481, and 472 for serotypes 1, 2, and 3, respectively) to determine whether the viruses shed represented nonattenuated revertants, attenuated parent vaccine strains (nonrevertants), or both. In the OPV group, 4 of the 6 virus isolates recovered 30-60 days after the first immunization dose and 1 of the 3 isolates obtained after the second dose were found to be nonrevertants (parent vaccine strain). In contrast, 11 of the 12 isolates in the EIPV-OPV group were of the nonvaccine revertant virus types. The frequency for reversion appeared to differ for different poliovirus serotypes. However, all revertant type 3 isolates were recovered from subjects previously immunized with EIPV.

BACKGROUND. In human lupus nephritis (LN), tubulointerstitial inflammation (TII) on biopsy predicts progression to endstage renal disease (ESRD). However, only about half of patients with moderate-to-severe TII develop ESRD. We hypothesized that this heterogeneity in outcome reflects different underlying inflammatory states. Therefore, we interrogated renal biopsies from LN longitudinal and cross-sectional cohorts.METHODS. Data were acquired using conventional and highly multiplexed confocal microscopy. To accurately segment cells across whole biopsies, and to understand their spatial relationships, we developed computational pipelines by training and implementing several deep-learning models and other computer vision techniques.RESULTS. High B cell densities were associated with protection from ESRD. In contrast, high densities of CD8 + , γδ, and other CD4 -CD8 -T cells were associated with both acute renal failure and progression to ESRD. B cells were often organized into large periglomerular neighborhoods with Tfh cells, while CD4 -T cells formed small neighborhoods in the tubulointerstitium, with frequency that predicted progression to ESRD.CONCLUSION. These data reveal that specific in situ inflammatory states are associated with refractory and progressive renal disease.

Extensive clonal T cell expansion is associated with response to immunotherapy.

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