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    T. Pugatsch

    In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of... more
    In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg(-1)) or higher dose (10, 10 and 20 mg·kg(-1)). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.
    Eimeria maxima gametocytes contain two major antigens with molecular masses of 56 and 82 kilodaltons (kDa) which are recognized by convalescent sera from immune chickens. Preparations enriched in these two antigens were used to immunize... more
    Eimeria maxima gametocytes contain two major antigens with molecular masses of 56 and 82 kilodaltons (kDa) which are recognized by convalescent sera from immune chickens. Preparations enriched in these two antigens were used to immunize mice, and several monoclonal antibodies which specifically reacted with the 56-kDa antigen were produced. One of these monoclonal antibodies of the immunoglobulin M subclass, along with immune chicken sera raised against affinity-purified 56- and 82-kDa antigens, was used to passively immunize chicks. On the basis of the parameter of total oocyst output, it was found that these antibodies provided partial protection (40 to 50% inhibition) against E. maxima challenge infections.
    We have attempted to induce immune-mediated graft-vs.-tumor (GVT) effects against solid tumors, using a murine model of mammary adenocarcinoma derived from BALB/c(H-2d) mice. A cell line (4Tl) isolated from this tumor model was highly... more
    We have attempted to induce immune-mediated graft-vs.-tumor (GVT) effects against solid tumors, using a murine model of mammary adenocarcinoma derived from BALB/c(H-2d) mice. A cell line (4Tl) isolated from this tumor model was highly tumorigenic in syngeneic (BALB/c) or haplo-identical (BALB/c x C57B1/6)F1 mice (F1), was only partially tumorigenic in an H-2d congenic strain of mice (DBA/2) and was non-tumorigenic in a major histocompatible (MHC)-unrelated (H-2b) strain of mice (C57B1/6). 4Tl cells express class I MHC antigens and adhesion molecules but do not express MHC class II antigens or B7-1 co-stimulatory molecules. Female BALB/c (H-2d) or F1 (H-2d/b) mice were reconstituted with male bone marrow (BM) cells derived from minor histocompatible (MiHC)-mismatched DBA (H-2d) donors or with MHC-mismatched C57B1/6 (H-2b) BM cells, respectively, 24 hr following lethal total body irradiation. Recipient mice carrying MiHC- or MHC-mismatched donor cells were inoculated with 4Tl cells 2-3 months following BM reconstitution. Chimeras reconstituted with allogeneic donor cells that were MiHC- or MHC-incompatible with tumor cells were able to down-regulate the development of the primary tumor expressing host-ype MHC alloantigens. Tumor size in BM chimeras across MiHC or MHC antigens was significantly smaller than tumor size observed in normal BALB/c or F1 controls. The GVT effect might be of help in improving immunotherapy for solid tumors in humans.
    A 2.5-year-old girl with neurogenic Gaucher's disease was transplanted with donor bone marrow from her HLA-compatible 12-year-old brother whose marrow was harvested 30 min post-mortem, after he suffered a severe head and... more
    A 2.5-year-old girl with neurogenic Gaucher's disease was transplanted with donor bone marrow from her HLA-compatible 12-year-old brother whose marrow was harvested 30 min post-mortem, after he suffered a severe head and neck injury. The marrow was stored in liquid nitrogen for 30 days prior to infusion. The post-transplantation period was uneventful with good engraftment and no signs of graft-versus-host disease. Currently, 6 months post-allogeneic bone marrow transplantation (alloBMT), analysis of both bone marrow and blood samples by PCR documented only cells of donor origin. This case demonstrates the feasibility of cadaveric marrow as a source of donor cells. To our knowledge, this patient is the only survivor of alloBMT from a cadaveric donor.