Screening the Mycobacterium tuberculosisMycobacterium tuberculosis H37Rv, the etiologic agent of tuberculosis, accounts for more human causalities than any other single infection (1). Pathogenesis of M. tuberculosis is not attributable to any single gene product. In other bacterial pathogens such as Bordetella pertussis and Bacillus anthrax, adenylyl cyclase, the enzyme responsible for the synthesis of adenosine 3Ј,5Ј-monophosphate (cAMP), plays a pivotal role in pathogenesis (2). The secreted form of adenylyl cyclase from B. pertussis (3) and B. anthrax (4) invades a variety of eukaryotic cells and is activated by the intracellular calmodulin of the host. This results in the unregulated conversion of ATP to a supraphysiological concentration of cAMP, which in turn has a profound effect on the metabolism and immune function of the host cell (5, 6). Thus, in infections caused by B. pertussis and B. anthrax, adenylyl cyclase plays a critical role in the onset of the disease. To examine whether adenylyl cyclase in M. tuberculosis has any role in infection, we report in this paper the cloning of cya gene from M. tuberculosis H37Rv, heterologous expression in Escherichia coli, and characterization of adenylyl cyclase (Mtb AC, 1
CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.
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