Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.     

A new approach to prevent HIV transmission: Project Protect intervention for recently infected individuals

Past research suggests that as many as 50% of onward human immunodeficiency virus (HIV) transmissions occur during acute and recent HIV infection. It is clearly important to develop interventions which focus on this highly infectious stage of HIV infection to prevent further transmission in the risk networks of acutely and recently infected individuals. Project Protect tries to find recently and acutely infected individuals and prevents HIV transmission in their risk networks. Participants are recruited by community health outreach workers at community-based HIV testing sites and drug users' community venues, by coupon referrals and through referrals from AIDS clinics. When a network with acute/recent infection is identified, network members are interviewed about their risky behaviors, network information is collected, and blood is drawn for HIV testing. Participants are also educated and given prevention materials (condoms, syringes, educational materials); HIV-infected participants are referred to AIDS clinics and are assisted with access to care. Community alerts about elevated risk of HIV transmission are distributed within the risk networks of recently infected. Overall, 342 people were recruited to the project and screened for acute/recent HIV infection. Only six index cases of recent infection (2.3% of all people screened) were found through primary screening at voluntary counseling and testing (VCT) sites, but six cases of recent infection were found through contact tracing of these recently infected participants (7% of network members who came to the interview). Combining screening at VCT sites and contact tracing the number of recently infected people we located as compared to VCT screening alone. No adverse events were encountered. These first results provide evidence for the theory behind the intervention, i.e., in the risk networks of recently infected people there are other people with recent HIV infection and they can be successfully located without increasing stigma for project participants.