Papers by Sarah Donatelli
Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunos... more Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural
killer (NK) cell function by yet-unknown mechanisms. Here we
show that TGF-β–treated human NK cells exhibit reduced tumor
cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of
activating killer Ig-like receptor 2DS4 and NKp44, despite intact
cytoplasmic stores of these receptors. Instead, TGF-β depleted
DNAX activating protein 12 kDa (DAP12), which is critical for surface
NK receptor stabilization and downstream signal transduction.
Mechanistic analysis revealed that TGF-β induced microRNA
(miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing
the DAP12 3′ untranslated region as well as in human NK cells
by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.
Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological fe... more Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33's immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif-bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.
Diabetes, 2011
OBJECTIVE-Immunotherapy using peptides from the b-cell antigen GAD65 can preserve glucose homeost... more OBJECTIVE-Immunotherapy using peptides from the b-cell antigen GAD65 can preserve glucose homeostasis in diabetesprone NOD mice; however, the precise mechanisms that arrest islet-reactive T cells remain unresolved. Our previous work revealed that a dominant GAD65 epitope contained two overlapping I-A g7 -restricted determinants, 524-538 and 530-543, with the former associated with amelioration of hyperglycemia. Here, we sought to discover whether p524-538-specific T cells could directly regulate islet-reactive T cells.
Clinical …, 2011
Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of... more Mitoxantrone is one of the few FDA-approved drugs available to treat rapidly progressing forms of multiple sclerosis; however, its utilization is compromised by a cardiotoxic potential and the risk of mitoxantrone-induced leukemia. BBR3378, a novel aza-anthrapyrazole, is structurally similar to mitoxantrone, but lacks the ring hydroxyls that may contribute to cardiotoxicity. Here, we investigated the therapeutic activity of BBR3378 in a C57BL/6 mouse model of multiple sclerosis. Mice given BBR3378, before or after the priming and expansion of MOG-specific responses, were protected from ascending paralysis. Strikingly, two doses of BBR3378 given a week after EAE induction were sufficient to provide significant protection from clinical symptoms and reduce MOG-specific proinflammatory T cell cytokine production, and serum IgG responses. Furthermore, while mitoxantrone is associated with persistent lymphopenia and cardiotoxicity, no such outcomes were detected in BBR3378-treated mice. Our findings show that BBR3378 can ameliorate encephalitogenic mechanisms in EAE and antagonize underlying autoimmune mechanisms.
The review of diabetic studies: …, 2009
Autoimmunity to islet cell antigens like glutamic acid decarboxylase 65kD (GAD65) is associated w... more Autoimmunity to islet cell antigens like glutamic acid decarboxylase 65kD (GAD65) is associated with the destruction of insulin-producing beta-cells and progression to type 1 diabetes (T1D) in NOD mice and humans. T cell responses to GAD65 are detectable in the spleen of prediabetic NOD mice and in the peripheral blood of humans prior to the onset of overt hyperglycemia. Previous findings from our lab revealed that GAD65(546-554)-specific cytotoxic T lymphocytes (CTL) are present in naïve NOD mice and are able to induce islet inflammation upon adoptive transfer into NOD.scid recipients. Additionally, we found that professional antigen-presenting cells (APC) generate the p546-554 epitope from a soluble GAD65 fragment, p530-554, and from GAD65 released by injured beta-cells in vivo. Here, we report that the GAD65 fragment p546-554 is a dominant CTL-inducing epitope which is naturally processed and presented by a GAD65-expressing beta-cell line. Further, co-culture of GAD65(546-554)-specific CTL with the beta-cells leads to a reduction in insulin production and the induction of perforin-mediated cell death. Collectively, these findings support a role for the cross-presentation of GAD65 antigen in the priming and enhancement of dominant GAD65-specific CTL responses, which can directly target beta-cells that display GAD65 epitopes.
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Papers by Sarah Donatelli
killer (NK) cell function by yet-unknown mechanisms. Here we
show that TGF-β–treated human NK cells exhibit reduced tumor
cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of
activating killer Ig-like receptor 2DS4 and NKp44, despite intact
cytoplasmic stores of these receptors. Instead, TGF-β depleted
DNAX activating protein 12 kDa (DAP12), which is critical for surface
NK receptor stabilization and downstream signal transduction.
Mechanistic analysis revealed that TGF-β induced microRNA
(miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing
the DAP12 3′ untranslated region as well as in human NK cells
by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.
killer (NK) cell function by yet-unknown mechanisms. Here we
show that TGF-β–treated human NK cells exhibit reduced tumor
cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of
activating killer Ig-like receptor 2DS4 and NKp44, despite intact
cytoplasmic stores of these receptors. Instead, TGF-β depleted
DNAX activating protein 12 kDa (DAP12), which is critical for surface
NK receptor stabilization and downstream signal transduction.
Mechanistic analysis revealed that TGF-β induced microRNA
(miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing
the DAP12 3′ untranslated region as well as in human NK cells
by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.