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Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development.

The Msx1 homeobox gene is expressed at diverse sites of epithelial-mesenchymal interaction during vertebrate embryogenesis, and has been implicated in signalling processes between tissue layers. To determine the phenotypic consequences of its deficiency, we prepared mice lacking Msx1 function. All Msx1- homozygotes manifest a cleft secondary palate, a deficiency of alveolar mandible and maxilla and a failure of tooth development. These mice also exhibit abnormalities of the nasal, frontal and parietal bones, and of the malleus in the middle ear. Msx1 thus has a critical role in mediating epith

Целенаправленная деградация белка разрушает ненаркомные цели, чтобы обратить вспять иммунное уклонение и терапию устойчивости к раку.

Таргетированная деградация белков (ТД) использует эндогенные протеолитические системы — систему убиквина и протеасомы и лизосомальные пути — для селективного удаления белков, вызывающих болезни, которые не реагируют на традиционное ингибирование. В онкологической иммунотерапии ТД разрушает критические иммунодепрессивные узлы в экзоцитоплазматическом, мембранном и цитоплазматическом компартментах, перепрограммируя микросреду опухоли от иммунологически «холодной» к «горячей» состоянию. Эта статья рассматривает молекулярные принципы инженерии бифункциональных деградаторов и обобщает клинические д

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… Representative technologies in this field include LYTAC, Glycan-linked Targeting Chimera (GlueTAC), AbTAC, and Kinetokine Targeting Chimera (KineTAC) ( 12 ). … Among lysosome-trafficking chimeras, soluble LYTACs (sLYTACs) ( 18 ), transferrin receptor-targeting chimeras (TransTACs) ( 19 ), integrin-facilitated lysosomal degradation (IFLD) ( 20 ), folate receptor-targeting chimeras (FRTACs) ( 21 ), ASGPR-driven nano-LYTACs ( 22 ), dual-receptor LYTACs ( 23 ), …

Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice.

Variants of the Bach2 gene are linked to vitiligo, celiac disease, and type 1 diabetes, but the underlying immunological mechanisms are unknown. In this study, we demonstrate that Bach2 plays crucial roles in maintaining T cell quiescence and governing the differentiation, activation, and survival of Foxp3(+) regulatory T (Treg) cells. Bach2-deficient T cells display spontaneous activation and produce elevated levels of Th1/Th2-type cytokines. Without Bach2, Treg cells exhibit diminished Foxp3 expression, depleted numbers, hyperactivation, enhanced proliferation, and profound loss of competiti

Alveolar epithelial cells orchestrate DC function in murine viral pneumonia.

Influenza viruses (IVs) cause pneumonia in humans with progression to lung failure. Pulmonary DCs are key players in the antiviral immune response, which is crucial to restore alveolar barrier function. The mechanisms of expansion and activation of pulmonary DC populations in lung infection remain widely elusive. Using mouse BM chimeric and cell-specific depletion approaches, we demonstrated that alveolar epithelial cell (AEC) GM-CSF mediates recovery from IV-induced injury by affecting lung DC function. Epithelial GM-CSF induced the recruitment of CD11b+ and monocyte-derived DCs. GM-CSF was a

EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors.

Epstein-Barr virus (EBV) persistently infects more than 90% of the human population and is etiologically linked to several B cell malignancies, including Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and diffuse large B cell lymphoma (DLBCL). Despite its growth transforming properties, most immune-competent individuals control EBV infection throughout their lives. EBV encodes various oncogenes, and of the 6 latency-associated EBV-encoded nuclear antigens, only EBNA3B is completely dispensable for B cell transformation in vitro. Here, we report that infection with EBV lacking EBNA3B leads to ag

A clinically feasible approach to induce delayed tolerance in recipients of prior kidney or vascularized composite allotransplants.

BACKGROUND: Mixed chimerism induces donor-specific tolerance to kidney and vascularized composite allotransplants (VCA). However, simultaneous kidney or VCA and bone marrow transplantation (BMT) is problematic because of the combined risk and time required for conditioning. Here, we developed a delayed tolerance induction strategy with mixed chimerism through BMT in prior kidney or VCA recipients. METHODS: Wistar Furth rats that received kidney transplantation (KTx) or VCA from allogeneic August-Copenhagen Irish donors were maintained on immunosuppression (IS) for 8 weeks. These recipients we

Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice.

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-γ produced by CD8⁺ lymphocytes stimulated by persistent antigen exposure. In these models and patients with "primary" HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8⁺ T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and s

Quantitative analysis of chimerism after allogeneic stem cell transplantation by real-time polymerase chain reaction with single nucleotide polymorphisms, standard tandem repeats, and Y-chromosome-specific sequences.

We compared the results of chimerism analyses with real-time SNP-PCR to those obtained by the classical STR-PCR method in 135 hematopoietic stem cell transplantation recipients. Using 10 different SNP gene loci, the SNP-PCR method was able to discriminate patient from donor cells in 125 of 135 cases (93%), whereas the use of 11 different STR gene loci with the STR-PCR analysis using agarose or polyacrylamide gel resolution resulted in accurate donor-host discrimination in all patients. Of the 470 analyzed samples we found in 74% concordant results for both chimerism methods. In all 26% discord

Apoptotic donor leukocytes limit mixed-chimerism induced by CD40-CD154 blockade in allogeneic bone marrow transplantation.

"Mini" allogeneic bone marrow transplants using non-myeloablative conditioning have reduced early treatment-related mortalities, but graft-versus-host disease (GVHD) and graft rejection remain clinical problems. Our preliminary studies indicated that low-dose busulfan conditioning and costimulatory blockade using anti-CD154 monoclonal antibody (mAb) in combination with a pretransplantation "tolerating" dose of bone marrow (BM) cells were sufficient to establish stable mixed-chimerism without GVHD when transplanting moderate doses of T cell depleted (TCD)-BM from major histocompatibility comple

An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes.

Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This "transchromosomic" mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and man

Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism.

To investigate the function of the Grb10 adapter protein, we have generated mice in which the Grb10 gene was disrupted by a gene-trap insertion. Our experiments confirm that Grb10 is subject to genomic imprinting with the majority of Grb10 expression arising from the maternally inherited allele. Consistent with this, disruption of the maternal allele results in overgrowth of both the embryo and placenta such that mutant mice are at birth approximately 30% larger than normal. This observation establishes that Grb10 is a potent growth inhibitor. In humans, GRB10 is located at chromosome 7p11.2-p

Donor chimerism and stem cell function in a murine congenic transplantation model after low-dose radiation conditioning: effects of a retroviral-mediated gene transfer protocol and implications for gene therapy.

OBJECTIVE: We investigated low-dose radiation conditioning for the transplantation of retrovirus-transduced cells in a C57Bl6/J murine model. MATERIALS AND METHODS: The effect of low-dose radiation on stem cell function was investigated using a competitive repopulation assay. Stem cell function of marrow cells that underwent a retroviral-mediated gene transfer (RMGT) protocol was examined by this assay, and donor chimerism of these cells when transplanted into 160-cGy conditioned syngeneic hosts was compared to fresh marrow. RESULTS: Irradiation with 300 or 160 cGy substantially decreased st

Successful major surgical recovery of a patient following haploidentical stem cell transplantation for chronic myeloid leukemia in blast crisis and aspergillosis.

A 44-year-old woman who underwent haploidentical stem cell transplantation (haplo SCT) for chronic myeloid leukemia in blast crisis and aspergillosis was admitted to the emergency room 7 months later because of severe right upper quadrant abdominal pain, fever, leukocytosis and peritoneal signs. Computer tomography disclosed cholecystitis and gallbladder perforation. Within hours, she underwent urgent open laparatomy and cholecystectomy. The postoperative period was uneventful and she was discharged 10 days later without any complications. Currently, she is 2(1/2) years posttransplantation in

IL-7 enhances the responsiveness of human T cells that develop in the bone marrow of athymic mice.

The beige/nude/xid/human (bnx/hu) model of human hematopoiesis provides a unique opportunity to study extrathymic human T lymphocyte development in an in vivo system. Purified human hematopoietic stem cells develop into mature T lymphocytes and immature progenitors in the bone marrow of athymic bnx mice. The human T cells are all TCR alpha beta(+) and display a restricted TCRV beta repertoire. In the current studies, we examined the effects of systemic human IL-7 (huIL-7) administration on the phenotype and the activation status of the bnx/hu T cells. In the majority of the mice that did not h

Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families.

Mutations of the telomeric survival motor neuron gene (SMN1) are related to spinal muscular atrophy (SMA). However, no phenotype-genotype correlation has been observed since the SMN1 gene is lacking in the majority of patients affected with either the severe form (type I) or the milder forms (types II and III). Here, we analyze the SMN, NAIP and P44 genes in 132 Chinese SMA patients and their families. At least three types of normal allele, and four types of mutant allele were found in this study. The combination of one normal allele with one mutant allele resulted in carriers of different typ

Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy.

In murine models of allogeneic bone marrow transplantation (BMT), MHC-mismatched recipients given a delayed infusion of donor leukocytes (DLI) at 21 days posttransplant develop significant GVHD whereas MHC-matched recipients do not. The current study was initially designed to test the hypothesis that small numbers of T cells in the MHC-mismatched donor bone marrow (BM) graft exacerbated graft-vs-host disease (GVHD) when DLI was administered at 21 days after BMT. Ex vivo depletion of Thy1+ cells from the donor BM had no impact on the severity of GVHD after DLI. However, depletion of donor T cel

Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts.

We compared the kinetic recovery of lymphocytes and their subsets in two groups of patients submitted to allogeneic peripheral blood progenitor cell transplantation (allo-PBT): those receiving lymphocyte-depleted leukaphereses by positive selection of CD34+ cells (group 1, n = 18) and those receiving unmanipulated leukaphereses (group 2, n = 15). Patients were conditioned with cyclophosphamide (120 mg/kg) and fractioned total body irradiation (13 Gy, group 1; 12 Gy, group 2). The mean number (x 10(6)/kg) of CD34+ and CD3+ cells infused was 4.0 and 0.67, respectively, in group 1 patients, and 4

Haploidentical hematopoietic stem cell transplantation for adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

To assess the efficacy of haploidentical hematopoietic stem cell transplantation (HSCT) in adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), we retrospectively analyzed 30 cases that presented at our institution. At the time of HSCT, 20 patients (66.7%) had achieved a response after receiving HLH-94 or salvage therapies. All patients underwent myeloablative conditioning followed by peripheral blood HSCT from their related, haploidentical donors. Twenty-six patients (86.7%) achieved donor cell engraftment. Of these, 23 (88.5%) achieved complete chim

Gαq controls rheumatoid arthritis via regulation of Th17 differentiation.

Gαq, the α-subunit of Gq protein, is ubiquitously expressed in mammalian cells. It initially attracted attention for its physiological significance in cardiovascular system. In recent years, studies have also indicated the important roles of Gαq in regulating immunity, supplying us a new insight into the mechanism of immune regulation. T helper type 17 (Th17) cells are potent inducers of tissue inflammation. Many studies have shown that Th17 cells are major effector cells in the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions such as rheumatoid arthritis

Bmi1 is required for regeneration of the exocrine pancreas in mice.

BACKGROUND & AIMS: Bmi1 is a member of the Polycomb protein family and represses transcription by modifying chromatin organization at specific promoters. Bmi1 is implicated in the control of stem cell self-renewal and has been shown to regulate cell proliferation, tissue homeostasis, and differentiation. Bmi1 is present in a subpopulation of self-renewing pancreatic acinar cells and is expressed in response to pancreatic damage. We investigated the role of Bmi1 in regeneration of exocrine pancreas. METHODS: Acute pancreatitis was induced in Bmi1(-/-) mice with cerulein; pancreatic cell regene