Mechanisms of protective immunity to larvae of Brugia pahangi were studied in congenitally athymic nude C3H/HeN mice and their syngeneic heterozygous littermates. An average 11% if subcutaneous larval inocula was recovered from control nudes 28 days after inoculation. No worms were recovered from nude recipients of viable splenic Thy 1·2+ T lymphocytes from heterozygotes which had killed a priming does of B. pahangi larvae. Primed T lymphocytes, depleted of either Lyt 1·1+of Lyt 2·1+cells or incubated with anti-Thy 1.2 monoclonal antibody and complement, failed to protect nude mic against a larval challenge. Nor were primed B lymphocytes depleted by Thy 1·2+T cell contaminants protective. Treatment with cyclosporin A (CsA) did not increase the numbers of worms recovered from heterozygotes nor did CsA treatment of heterozygous cell donor abolish the ability of primed Thy 1·2+T lymphocytes to transfer protection to nude mice. IgG but not IgM antibody titres to B. pahangi antigens were depressed in all CsA-treated mice. CsA treatment of nude mice had no direct effect upon development of B. pahagi larvae. These results show that ptotective immunity to larvae of B. pahangi in mice depends upon small numbers of Thy 1·2+T cells which are CsA-resistant.

Cyclosporin A (CsA) is a widely investigated experimental anti-parasitic drug whose mode of action remains unresolved. The immunosuppressive action of CsA depends on the drug binding to the intracellular receptor cyclophilin (CyP). This study investigates whether complexing of CsA with parasite CyP is equally essential for its anthelmintic action. The correlation between initial cyclosporin-induced damage in vitro and drug binding to parasite CyP has been examined. CsA and the analogues B-5-49, CsH and CsA-acetate all induced similar damage to the tapeworm Hymenolepis microstoma in vitro in incubations between 2h and 4 days. The initial foci of drug damage were the parasite surface and mitochondria in the syncytium. In a competitive binding assay only B-5-49 displaced [H3]-CsA from either crude parasite cytosolic CyP or affinity-purified CyP while CsH and CsA-acetate had no effect. These data suggest strongly that cyclosporins act on the surfaces of helminth parasites but that drug action does not involve complex formation with CyP. An alternative drug-binding site must therefore be identified which may lead to the rational design of novel anthelmintic drugs.

We present the case of a 58-year-old diabetic renal transplant patient who developed a left jugular foramen syndrome, secondary to an ipsilateral staphylococcal malignant (necrotizing) otitis externa. This followed a protracted episode of uncomplicated otitis externa with no evidence of bone involvement on computed tomography (CT) scanning. Cyclosporin-induced hypertrichosis (excess hair growth) in his external auditory canal contributed greatly to the initial difficulty in managing his otitis externa. Following an initial successful treatment with prolonged intravenous antibiotics the patient relapsed with a secondary infection in the same anatomical site due to Candida parapsilosis. Despite further intensive treatment including antimicrobials, a subtotal petrosectomy and hyperbaric oxygen therapy he eventually succumbed to his disease.

The drug cyclosporin A (CsA) exerts its immunosuppressive action by binding to the cytosolic protein, cyclophilin (CyP) and, as a complex, binding to and inhibiting the calcium/calmodulin-dependent serine threonine phosphatase, calcineurin. It is unknown whether a similar mode of action occurs during the drug's antiparasite activity. Calmodulin-binding proteins from the helminth parasites Hymenolepis microstoma and H. diminuta were purified by affinity chromatography, yielding single polypeptide bands of 60000 Mr, according to SDS–PAGE. These proteins were tested for calcineurin activity by the dephosphorylation of the RII peptide (part of the catalytic subunit of cAMP-dependent protein kinase). Both proteins were calcium- and calmodulin-dependent and were inhibited by mammalian cyclophilin complexed with cyclosporin A (IC50 values of 0·75 μg CyP for H. microstoma and 0·90 μg CyP for H. diminuta). However, neither of the parasite calcineurins was inhibited by H. microstoma cyclophilin/CsA. These data suggest the anthelmintic mode of action of CsA in these helminth models does not involve the inhibition of a signal transduction pathway requiring interaction with calcineurin.