A5026079585- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- CAR-T cell therapy research
- Acute Myeloid Leukemia Research
- Cancer Immunotherapy and Biomarkers
- Lymphoma Diagnosis and Treatment
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Cutaneous lymphoproliferative disorders research
- Diabetes and associated disorders
- Cancer Genomics and Diagnostics
- RNA Interference and Gene Delivery
- Hematopoietic Stem Cell Transplantation
- Erythrocyte Function and Pathophysiology
- Clinical Laboratory Practices and Quality Control
- Fungal Infections and Studies
- Histiocytic Disorders and Treatments
- Renal and related cancers
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- Protein Degradation and Inhibitors
- Chronic Kidney Disease and Diabetes
- Intracerebral and Subarachnoid Hemorrhage Research
- RNA modifications and cancer
Brigham and Women's Hospital
2014-2024
Harvard University
2014-2024
Boston VA Research Institute
2020
Washington University in St. Louis
2003-2007
Loss of membrane MHC class I protein expression in most tumor cells advanced melanomas predicts primary resistance to anti–CTLA-4, but not anti-PD1, treatment.
Inhibitory signals through the PD-1 pathway regulate T cell activation, tolerance, and exhaustion. Studies of function have focused primarily on effector cells. Far less is known about in regulatory (T reg) To study role reg cells, we generated mice that selectively lack PD-1–deficient cells exhibit an activated phenotype enhanced immunosuppressive function. The vivo significance potent suppressive capacity illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) protection...
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of cell responses. Germline Ctla4 deficiency lethal, making investigation the function CTLA-4 on mature cells challenging. To elucidate cells, we have conditionally ablated in adult mice. We show that, contrast to germline knockout mice, deletion during adulthood does not precipitate systemic autoimmunity, but surprisingly confers protection from experimental autoimmune encephalomyelitis (EAE) and lead increased...
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer chronic infections. In murine bone marrow transplant models, PD-L1 expression on host tissues reduces the incidence of graft-versus-host disease (GVHD). also expressed cells; however, it unclear whether this population influences function. Here, we examined effects modulation function in GVHD. patients severe GVHD, was increased donor cells....
Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of cells (pDC). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics primary and modeling disease-associated mutations, we link acquired alterations RNA splicing to abnormal pDC development inflammatory response through Toll-like receptors. Loss-of-function mutations ZRSR2, X chromosome gene encoding a factor, enriched...
Loss of the Y chromosome (LOY) is one most common somatic genomic alterations in hematopoietic cells men. However, due to high prevalence LOY as sole cytogenetic finding healthy older population, differentiating isolated associated with clonal hematologic processes from aging-associated mosaicism can be difficult absence definitive morphological features disease. In past, various investigators have proposed that a percentage metaphases more likely represent expansion myeloid...
Macrocytic anemia with abnormal erythropoiesis is a common feature of megaloblastic anemias, congenital dyserythropoietic and myelodysplastic syndromes. Here, we characterized family multiple female individuals who have macrocytic anemia. The proband was noted to dyserythropoiesis iron overload. After an extensive diagnostic evaluation that did not provide insight into the cause disease, whole-exome sequencing members revealed presence mutation in X chromosomal gene ALAS2, which encodes...
TP53 mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between categories, remain unknown. We analyzed four neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), therapy-related acute leukemia (tAML)), identified differences types, spectrum, hotspots categories comparison to solid tumors. Missense DNA-binding domain were most common across...
Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics HS fine-needle aspiration (FNA) criteria for its diagnosis have not been established.A case series in 8 FNA samples from 6 patients was reviewed along with histopathologic clinical data. Immunohistochemistry performed on cell blocks (3 cases), core biopsies (5 surgical specimens (4 cases). Targeted-exome next-generation sequencing (NGS) resection 4...
The contribution of the kidney-draining lymph node (KLN) to pathogenesis ischemia-reperfusion injury (IRI) kidney and its subsequent recovery has not been explored in depth. In addition, mechanism by which repetitive IRI contributes renal fibrosis remains poorly understood. Herein, we have found that is associated with expansion high endothelial venules (HEVs) activation fibroblastic reticular cells (FRCs) KLN, as demonstrated significant extracellular matrix. lymphotoxin α signaling pathway...
Abstract The peptide spanning residues 48–62 of hen egg white lysozyme presented by I-Ak molecules gives rise to two T cell populations, types A and B, that recognize distinct conformers the complex generated in late recycling endosomes. class II–like accessory molecule H2-DM functions as a conformational editor, eliminating type B conformer Here, we show conformation complex, its susceptibility editing H2-DM, are determined amino-terminal flanking residues. Elimination these abolished...
Abstract Notch receptors participate in a signaling pathway which ligand-induced proteolysis frees the intracellular domain (NICD), allowing it to translocate nucleus, form transcription complex, and induce target gene expression. Chronic lymphocytic leukemia/small lymphoma (CLL/SLL), splenic marginal zone B-cell (SMZL), distinct subsets of diffuse large (DLBCL) are strongly associated with mutations 3′ end NOTCH1 or NOTCH2 that disrupt proline, glutamic acid, serine, threonine (PEST) degron...
Abstract Objective TP53 mutations, including missense and inactivating (frameshift, splice site, nonsense) occur in approximately 10% of myeloid neoplasms confer adverse outcomes. Classification by World Health Organization International Consensus standards recognizes the importance early detection mutations. p53 immunohistochemistry (IHC) is a widely accessible method used to detect mutations; however, previous studies have demonstrated variable accuracy, especially for Recently, sequencing...
Abstract We quantitated the amounts of peptides from hen egg-white lysozyme presented by I-Ak molecules in APC lines. The large chemical gradient presentation four epitopes observed cell lines expressing HLA-DM or H-2DM (referred to this study as DM) was significantly diminished T2.Ak line lacking DM. Differences levels between wild-type and DM-deficient were for all epitopes, but differences most evident highest affinity epitope. As a result these quantitative display, T cells impaired...
Abstract Type B T cells recognize a peptide-MHC conformer generated in recycling endosomes and eliminated by H2-DM late endosomes; as result, they exogenous peptide, but fail to respond the identical epitope from native protein. To investigate behavior of these vivo, we mice transgenic for type TCR recognizing 48-62 hen egg white lysozyme (HEL) presented I-Ak. responded only peptide ex vivo immunization with either protein or presence Freund’s adjuvant LPS. Presentation was...