No abstract

The disease anthrax is caused by lethal factor, an enzyme component of the toxin produced by the spore-forming bacterium Bacillus anthracis. Here we describe substrate molecules for this factor that offer a means for high-throughput screening of potential inhibitors for use in anthrax treatment. Our assay should help to answer the urgent call for new and specific therapies to combat this pathogen after its recent emergence as a terrorist bioweapon.

Research efforts have shed light on the immunological obstacles to long-term survival of pig organs transplanted into primates and allowed the identification of targets for specific immune intervention. Accordingly, the development of genetically engineered animals has overcome the hyperacute rejection barrier, with acute humoral xenograft rejection (AHXR) currently remaining the most important immunological obstacle. At this stage, a better control of the elicited anti-pig humoral immune response and avoidance of coagulation disorders are the two primary research fronts being pursued in order to overcome AHXR. Nonetheless, it is encouraging that porcine xenografts can sustain the life of non-human primates for several months. Proactive research aimed at the development of a safer organ source is also underway. It is anticipated that ongoing research in several fields, including accommodation, tolerance, immune suppression and genetic engineering, will result in further improvements in non-human primate survival. However, until convincing efficacy data and a more favourable risk/benefit ratio can be established in relevant animal models, progression to the clinic should not be viewed as an option.

The aim of this study was to analyze the incidence of ureteral stenosis in a life-supporting human decay-accelerating factor (hDAF) transgenic pig-to-cynomolgus monkey kidney transplantation model and determine the role of possible immunological events in its pathogenesis. Thirty consecutive bi-nephrectomized cynomolgus monkeys received a kidney from hDAF transgenic pigs with or without a ureteral stent. Four monkeys were euthanized prematurely after transplantation. In the remaining 26 cases, the mean survival was 24 +/- 19 days. Except in one case, there was a close relationship between ureter and kidney in terms of type and severity of rejection. There were six ureteral stenoses; five were repaired by stent positioning and resurgery extended survival for an additional 16 +/- 10 days. The stenotic ureters showed diffuse acute humoral xenograft rejection (AHXR), while all cases with no or only focal signs of ureteral rejection never revealed ureteral obstruction. Use of a ureteral stent extends the survival of a xenografted primate, thereby helping to clarify the immunological events surrounding the onset of AHXR in kidneys in long-term xenograft recipients.

These studies suggest that CORM-3 has anti-inflammatory and immunomodulatory properties in primates that may result in clinical benefit to allo- and xenografted organs.